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## **Meet the editor**

Dr. Varaprasad Bobbarala received his M.Sc. and Ph.D. from Andhra University in 2001 and 2008, respectively. He specialized in Biochemistry, Medicinal Chemistry and Microbiology. He has published over 85 original research articles, reviews and book chapters and edited three books. He is currently the Editor in Chief of the *International Journal of Bioassays* (ISSN: 2278-778X), Associate

Editor and member of several editorial boards as well as reviewer of dozens of high-impact international periodicals. Dr. Varaprasad previously served as the Chief Scientist of Research and Development (R&D) at Krisani Innovations Pvt. Ltd., before his current role as the Chief Scientist and Technical Director of Research and Development of Adhya Biosciences Pvt. Ltd., India. He is actively engaged in scientific research in the areas of antimicrobial resistance, isolation of bioactive metabolites and bio-efficacy studies.

## Contents

**Preface XI**

## **Section 3 The Alternatives 121**

## Preface

**Section 3 The Alternatives 121**

**VI** Contents

Bobbarala

Chapter 6 **Natural Products as Antibacterial Agents — Antibacterial**

Chapter 7 **Phytopharmaceutical Studies of Selected Medicinal Plants**

**from Thymus vulgaris L., Lamiaceae 123**

**Potential and Safety of Post-distillation and Waste Material**

Neda Gavarić, Jasna Kovač, Nadine Kretschmer, Nebojša Kladar, Sonja Smole Možina, Franz Bucar, Rudolf Bauer and Biljana Božin

**Subjected to Abiotic Elicitation (Stress) in Industrial Area 153**

Sr. Prema Kumari Jonnada, Louis Jesudas and Varaprasad

Antibacterial resistance is spreading globally where bacteria are less- or non-responsive with current antibacterial therapies to prevent bacterial infection, resulting in death and dis‐ ability of individuals. Infections caused by resistant bacteria often fail to respond to the present-day treatment, resulting in prolonged illness, higher health-care expenditures and a greater risk of death.

According to WHO's 2014 report on global surveillance of antimicrobial resistance, antibiot‐ ic resistance is no longer a prediction for the future; it is happening right now, across the world, and is putting at risk the ability to treat common infections in the community and hospitals. Without urging, coordinated action, the world is heading towards a post-antibiot‐ ic era, in which common infections and minor injuries, which have been treatable for deca‐ des, can once again kill.

In this concern, the present book mainly focuses on the new approaches to better under‐ stand antibacterial mechanisms and their mode of action and on searching for environmen‐ tal alternatives for controlling bacterial pathogens.

> **Dr. Varaprasad Bobbarala** Chief Scientist Krisani Innovations Pvt. Ltd., Hyderabad, Andhrapradesh, India

**Section 1**

## **The Concepts**

## **Antibacterial Drugs — From Basic Concepts to Complex Therapeutic Mechanisms of Polymer Systems**

Andreea Irina Barzic and Silvia Ioan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60755

## **Abstract**

Infections caused by diverse bacteria represent a major problem that threats the health of humans. This stimulates the scientists to find new solutions for treating these diseases by clarifying the interactions of antibacterial compounds with the biological medium. In this context, the chapter presents some basic concepts regarding the antibacterial drugs. The synthesis routes of novel compounds and specific design techniques with polymer materials are described in correlation with the *in vitro* and *in vivo* activity of antibacterial substances. Essential data about the mechanism of action, selected *in vivo* efficacy and mechanisms of resistance to the most used antibacterial drugs are reviewed.

**Keywords:** Antibacterial, drugs, classification, synthesis, polymers

## **1. Introduction**

In the past decades, many research findings were directed towards biomedical sciences in an attempt to give a solution to the present health issues caused by microorganism infections. Infectious diseases represent a considerable factor of human morbidity and mortality for most of human existence. The introduction of antimicrobial materials into general clinical use is one of the most successful approaches in chemotherapy, considera‐ bly contributing to the control of infections [1]. The existing antimicrobials in the clinical investigations have provided an array of choices when treating many types of infectious diseases. However, treatment options for patients are limited because the bacterial resistance

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

evolved more rapidly than the antibacterial drug development. Clinical results are reporting increasing rates of *in vitro* resistance among previously susceptible organisms and the occurrence of intrinsically resistant microorganisms as pathogens in immunocompro‐ mised hosts [2, 3]. To reduce the development and spread of antimicrobial resistance, the preservation of current antimicrobials through their appropriate use becomes mandatory. This motivates scientists to focus on discovery and production of new chemical substan‐ ces that destroy pathogenic microorganisms with minimal damage to host tissues [4]. Thus, the design of novel classes of antibacterial drugs is redirected on synthesis of compounds with a completely novel mechanism of action [5].

For a deeper understanding of the interactions occurring between the antibacterial drugs and the human beings, in this chapter the basic concepts regarding these bioagents, like definition and classification, are presented. The latter involves the presentation of the main principles, which were taken into consideration to define the effectiveness of an antibiotic. The classical and modern synthesis routes of the main antibacterial drugs are further discussed regarding the main categories of antimicrobial agents. The implications of the preparation methods in designing new therapeutic systems based on polymer materials are analyzed in accordance with the advantages and disadvantages of such delivery devices. A short review on the *in vitro* and *in vivo* activities of antibacterial substances is performed by highlighting the beneficial treatments, and also the secondary effects caused by some delivery systems. Essential data about the mechanism of action, selected *in vivo* efficacy and mechanisms of resistance to the most used antibacterial drugs is presented.

## **2. Definition and classification of antimicrobial drugs**

An antibacterial drug represents a chemical substance derived from a biological source or produced by chemical synthesis that is able to destroy or to inhibit the development/growth of bacteria.

Antibacterial drugs are commonly classified by considering the following criteria:

decrease toxicity and increase effectiveness of the first category. Synthetic drugs have an advantage that the bacteria are not exposed to the compounds until they are released. They are prepared to exhibit greater effectiveness and less toxicity. There is an inverse relationship between toxicity and effectiveness starting from natural to synthetic antibiotics (Figure 1);

**Figure 1.** Toxicity *versus* effectiveness for antimicrobial drugs derived from different sources

	- **◦** bacteriostatic

evolved more rapidly than the antibacterial drug development. Clinical results are reporting increasing rates of *in vitro* resistance among previously susceptible organisms and the occurrence of intrinsically resistant microorganisms as pathogens in immunocompro‐ mised hosts [2, 3]. To reduce the development and spread of antimicrobial resistance, the preservation of current antimicrobials through their appropriate use becomes mandatory. This motivates scientists to focus on discovery and production of new chemical substan‐ ces that destroy pathogenic microorganisms with minimal damage to host tissues [4]. Thus, the design of novel classes of antibacterial drugs is redirected on synthesis of compounds

For a deeper understanding of the interactions occurring between the antibacterial drugs and the human beings, in this chapter the basic concepts regarding these bioagents, like definition and classification, are presented. The latter involves the presentation of the main principles, which were taken into consideration to define the effectiveness of an antibiotic. The classical and modern synthesis routes of the main antibacterial drugs are further discussed regarding the main categories of antimicrobial agents. The implications of the preparation methods in designing new therapeutic systems based on polymer materials are analyzed in accordance with the advantages and disadvantages of such delivery devices. A short review on the *in vitro* and *in vivo* activities of antibacterial substances is performed by highlighting the beneficial treatments, and also the secondary effects caused by some delivery systems. Essential data about the mechanism of action, selected *in vivo* efficacy and mechanisms of resistance to the

An antibacterial drug represents a chemical substance derived from a biological source or produced by chemical synthesis that is able to destroy or to inhibit the development/growth

**• Targeted pathogens:** This category involves antibacterial, antiviral, and antifungal drugs. This grouping may be further subdivided because antibacterial drugs also include urinary antiseptics and anti-mycobacterial drugs. Antimicrobial drugs, especially antibacterial drugs, are strictly classified into chemotherapeutic agents (synthetic chemicals), and antibiotics, produced from living organisms, usually fungi. However, 'antibiotic' is often

**• Source**: Natural (mainly fungal sources), semi-synthetic (chemically-altered natural compound), and synthetic (chemically designed in the lab). The "natural" antibiotics arise from fungal sources. Organisms become resistant faster to the natural antimicrobials because they have been pre-exposed to these compounds in nature. Natural antibiotics are often more toxic than synthetic ones. Semi-synthetic drugs appeared as alternative to

Antibacterial drugs are commonly classified by considering the following criteria:

with a completely novel mechanism of action [5].

4 Concepts, Compounds and the Alternatives of Antibacterials

most used antibacterial drugs is presented.

used loosely to mean all antibacterial drugs;

of bacteria.

**2. Definition and classification of antimicrobial drugs**

**• Chemical structure**: Examples are penicillins and cephalosporins;

	- **◦** drugs that inhibit bacterial wall synthesis or activate enzymes that destroy the cell wall
	- **◦** drugs that enhance cell membrane permeability (causing leakage of intracellular mate‐ rial)
	- **◦** drugs that determine lethal inhibition of bacterial protein synthesis
	- **◦** drugs that generate nonlethal inhibition of protein synthesis
	- **◦** drugs that inhibit bacterial synthesis of nucleic acids
	- **◦** antimetabolites (disruption of specific biochemical reactions---decrease in the synthesis of essential cell constituents)
	- **◦** inhibitors of viral enzymes

For a better understanding of the different types of antimicrobial drugs, Figure 2 displays the main classes of these substances and their applications.

**Figure 2.** Classification of antimicrobial drugs and their applications

Antibiotics act by inhibiting the basic life-sustaining processes in the microorganism. In order to minimize toxicity, the targets of antibiotics must be selective. However, all antibiotics are toxic to some degree. Selective toxicity should be focused on harming the bacteria, not the host. Selection of the appropriate antibiotic depends on the following parameters:

Evaluation of susceptibility focuses mainly on the interaction of antimicrobial agents, the organisms, and their resistance mechanisms. The resistance to antimicrobial drugs is based on several mechanisms, including the following:

**◦** the broad-spectrum drug affects a wide range of disease-causing bacteria, including both

**◦** the narrow-spectrum antibacterial drug, which acts against specific families of bacteria.

For a better understanding of the different types of antimicrobial drugs, Figure 2 displays the

Antibiotics act by inhibiting the basic life-sustaining processes in the microorganism. In order to minimize toxicity, the targets of antibiotics must be selective. However, all antibiotics are toxic to some degree. Selective toxicity should be focused on harming the bacteria, not the host.

**•** Pharmacological properties of the antibiotic toxicity, binding, distribution, absorption

Selection of the appropriate antibiotic depends on the following parameters:

For example, ampicillin is a widely used broad-spectrum antibiotic.

Gram-positive and Gram-negative bacteria

6 Concepts, Compounds and the Alternatives of Antibacterials

main classes of these substances and their applications.

**Figure 2.** Classification of antimicrobial drugs and their applications

**•** Knowledge of organism's natural resistance

achievable levels in blood, urine

**•** Patient's immune status

**•** Previous experience with same species

**•** Nature of patients underlying pathology

Susceptibility tests are essentially artificial measurements that include *in vitro* response, approximate range of effective inhibitory action and reflect possible error equivalent to one tube dilution. The only true measure of bacterial response to an antibiotic drug is the clinical response of the patient (outcome or *in vivo* response).

The bacteria are innately resistant to some antibiotics since they lack a target site or are impermeable to the antibiotic. Resistance spreads between bacteria in three physical ways: conjugation (by direct contact), transduction (by phages), and transformation (uptake of free DNA). The resistance is acquired by spontaneous mutation and conjugation. This could be the results of two aspects as follows:

Delaying the emergence of resistance can be achieved by taking into account the following solutions:

It is very important that patients should be instructed to strictly follow their prescription particularly during the entire curing treatment period even though symptoms may subside before the full course has been completed. Otherwise, it is possible that interruption of the medication could lead to fail of the treatment and other drugs should be included in the cure. However, there are some disadvantages of antibiotic combinations as follows:

On the other hand, without doctor's advice, the patient might misuse the antibiotics leading to some issues like:

Generally, the prophylactic use of antimicrobial drugs can be divided in three categories: (1) surgery (cardiac, orthopedic, gastrointestinal tract surgery), (2) bacterial endocarditis, and (3) neutropenia. Antimicrobial drugs are also indicated in the treatment of other infections such as young women with recurrent urinary tract infection, prophylaxis against type A influenza with amantadine, lifelong prophylaxis of individuals who have had severe rheumatic carditis. The features of an ideal antibacterial drug are as follows:

## **3. Synthesis routes of antimicrobial drugs**

The mechanism of action of natural antibacterial agents inspired scientists to prepare more complex structures with improved properties for the cases where the natural products fail due to the resistance occurrence. In this context, the chemical synthesis of new drugs is in contin‐ uous evolution. The development of partially or fully synthetic routes to antibacterial com‐ pounds is a strategy whose constraints (molecular size and complexity, scalability) must be re-assessed in light of advances in modern chemical synthesis, both strategic and methodo‐ logical.

Natural products have been a rich source of antibacterial drugs since their discovery, but investments in this domain have been diminished over the past two decades. The main source of natural antibacterial agents is represented by plants, which are able to synthesize aromatic substances, like phenols or their oxygen-substituted derivatives [6]. Most of these substances are secondary metabolites that serve as plant defense mechanisms against predation by microorganisms, insects, and herbivores. Major classes of antimicrobial compounds obtained from plants are the following:

On the other hand, without doctor's advice, the patient might misuse the antibiotics leading

Generally, the prophylactic use of antimicrobial drugs can be divided in three categories: (1) surgery (cardiac, orthopedic, gastrointestinal tract surgery), (2) bacterial endocarditis, and (3) neutropenia. Antimicrobial drugs are also indicated in the treatment of other infections such as young women with recurrent urinary tract infection, prophylaxis against type A influenza with amantadine, lifelong prophylaxis of individuals who have had severe rheumatic carditis.

The mechanism of action of natural antibacterial agents inspired scientists to prepare more complex structures with improved properties for the cases where the natural products fail due to the resistance occurrence. In this context, the chemical synthesis of new drugs is in contin‐ uous evolution. The development of partially or fully synthetic routes to antibacterial com‐ pounds is a strategy whose constraints (molecular size and complexity, scalability) must be re-assessed in light of advances in modern chemical synthesis, both strategic and methodo‐

Natural products have been a rich source of antibacterial drugs since their discovery, but investments in this domain have been diminished over the past two decades. The main source of natural antibacterial agents is represented by plants, which are able to synthesize aromatic substances, like phenols or their oxygen-substituted derivatives [6]. Most of these substances

**•** attempted treatment of untreatable infection (viral infections);

**•** treatment in absence of adequate bacteriologic information

The features of an ideal antibacterial drug are as follows:

**•** High therapeutic index---ratio of toxic level to therapeutic level

**•** Narrow spectrum---does not kill normal flora

**•** Few adverse reactions---toxicity, allergy

**•** Various routes of administration

**•** Emergence of resistance is slow

**•** Good distribution to site of infection

**3. Synthesis routes of antimicrobial drugs**

**•** Good absorption

logical.

to some issues like:

**•** improper dosage;

**•** omission of surgical drainage.

8 Concepts, Compounds and the Alternatives of Antibacterials

**•** Selective target---target unique **•** Bactericidal---kills the bacteria

*Catechol* is produced industrially by the hydroxylation of phenol using hydrogen peroxide [7]:

$$\text{C}\_6\text{H}\_5\text{OH} + \text{H}\_2\text{O}\_2 \rightarrow \text{C}\_6\text{H}\_4\text{(OH)}\_2 + \text{H}\_2\text{O}$$

This natural antibacterial agent can also be obtained by hydrolysis of 2-substituted phenols, especially 2-chlorophenol, with hot aqueous solutions containing alkali metal hydroxides. Its methyl ether derivative converts to catechol via hydrolysis of the CH3-O bond as promoted by hydriodic acid.

*Terpenoids* are prepared by two metabolic pathways:

**a.** Mevalonic acid pathway

Many organisms manufacture terpenoids through the HMG-CoA reductase pathway, the pathway that also produces cholesterol. The reactions take place in the cytosol.

**b.** Non-mevalonate pathway

The 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway (MEP/ DOXP pathway), also known as mevalonic acid-independent pathway, occurs in the plastids of plants and apicomplexan protozoa, as well as in many bacteria. Pyruvate and glyceralde‐ hyde 3-phosphate are converted by DOXP synthase to 1-deoxy-D-xylulose 5-phosphate, and by DOXP reductase, (IspC) to 2-C-methyl-D-erythritol 4-phosphate (MEP). The subsequent three-reaction steps catalyzed by 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (YgbP, IspD), 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (YchB, IspE), and 2-Cmethyl-D-erythritol 2,4-cyclodiphosphate synthase (YgbB, IspF) favor the formation of 2-Cmethyl-D-erythritol 2,4-cyclopyrophosphate (MEcPP). Finally, MEcPP is converted to (E)-4 hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) by HMB-PP synthase (GcpE, IspG), and HMB-PP is converted to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophos‐ phate (DMAPP) by HMB-PP reductase (LytB, IspH). IPP and DMAPP are the end-products in either pathway, and are the precursors of isoprene, monoterpenoids (10-carbon), diterpenoids (20-carbon), carotenoids (40-carbon), chlorophylls, and plastoquinone-9 (45-carbon). Synthesis of all higher terpenoids proceeds via formation of geranyl pyrophosphate, farnesyl pyrophos‐ phate, and geranylgeranyl pyrophosphate.

*Lectins* with certain carbohydrate specificity have been purified from various plant tissues and other organisms. On the other hand, these substances can be obtained by recombinant techniques. A sizeable quantity of a lectin (~10g) can result by large-scale fermentation. This procedure is carried out in defined pH value, temperature, optical density at the time of induction, inducer concentration, and time of expression. The most commonly used inducer is isopropyl β-d-thiogalactoside. Subsequently, the cells are harvested by centrifugation. Lectins are released from the cells by resuspension in lysis buffer followed by sonication. Further chromatographic steps are needed for purification of lectins [8]. Isolation of lectins can be accomplished by a combination of several purification techniques. Acids [9], organic solvent, [10] or salt can be used to precipitate lectins. The chromatographic methods, such as affinity chromatography, ionic exchange chromatography, hydrophobic interaction chroma‐ tography, and gel filtration are employed. An increase in the number of purification steps usually results in a lesser amount of recovery.

The need for new antibacterial agents remains high, considering the increasing rates of resistance of the drugs available on the market. The results of many of the current therapies with natural products begin to fade, even for common infections.

Semisynthetic antibacterial agents appeared as a result of the researchers efforts to modify the antibacterial substances produced in nature. Thus, semisynthesis came to the forefront of antibacterial discoveries following innovative chemical alterations naturally occurring in some compounds. In the following paragraph, the main chemical insights that helped overcome the numerous limitations of cephalosporin, tetracycline, and macrolide antibacterial drugs, are discussed.

*Semisynthesis of β-lactams*. It was discovered that cultures of the mold *Cephalosporium acremo‐ nium* contained one or more substances that were antagonistic to bacteria. After purification of cephalosporin C from the *Cephalosporium* culture, the 7-aminocephalosporanic acid (7-ACA) is obtained by hydrolysis of cephalosporin C under acidic conditions.

**Sheme 1.** Hydrolysis of cephalosporin C under acidic conditions

The parenteral cephalosporins (cephalothin) present potent activity against Gram-positive organisms but only moderate activity against Gram-negative bacteria. Improved pharmaco‐ logical properties, as well as lower susceptibility to resistance mechanisms, are achieved by introducing innovative side chains at just two modifiable sites of 7-ACA---the amine function C7 and C3'.

*Semisynthesis of tetracyclines*. The development of semisynthetic tetracyclines has been marked by a series of specific, impactful discoveries. The C6-hydroxy group of the natural products oxytetracycline, tetracycline, and 6-demethyltetracycline could be removed reductively. Minocycline was obtained from 6-deoxy-6-demethyltetracycline (sancycline) by an electro‐ philic aromatic substitution reaction at C7, and it presented a broader spectrum of activity than prior tetracyclines.

**Sheme 2.** Preparation steps of minocycline

of all higher terpenoids proceeds via formation of geranyl pyrophosphate, farnesyl pyrophos‐

*Lectins* with certain carbohydrate specificity have been purified from various plant tissues and other organisms. On the other hand, these substances can be obtained by recombinant techniques. A sizeable quantity of a lectin (~10g) can result by large-scale fermentation. This procedure is carried out in defined pH value, temperature, optical density at the time of induction, inducer concentration, and time of expression. The most commonly used inducer is isopropyl β-d-thiogalactoside. Subsequently, the cells are harvested by centrifugation. Lectins are released from the cells by resuspension in lysis buffer followed by sonication. Further chromatographic steps are needed for purification of lectins [8]. Isolation of lectins can be accomplished by a combination of several purification techniques. Acids [9], organic solvent, [10] or salt can be used to precipitate lectins. The chromatographic methods, such as affinity chromatography, ionic exchange chromatography, hydrophobic interaction chroma‐ tography, and gel filtration are employed. An increase in the number of purification steps

The need for new antibacterial agents remains high, considering the increasing rates of resistance of the drugs available on the market. The results of many of the current therapies

Semisynthetic antibacterial agents appeared as a result of the researchers efforts to modify the antibacterial substances produced in nature. Thus, semisynthesis came to the forefront of antibacterial discoveries following innovative chemical alterations naturally occurring in some compounds. In the following paragraph, the main chemical insights that helped overcome the numerous limitations of cephalosporin, tetracycline, and macrolide antibacterial drugs, are

*Semisynthesis of β-lactams*. It was discovered that cultures of the mold *Cephalosporium acremo‐ nium* contained one or more substances that were antagonistic to bacteria. After purification of cephalosporin C from the *Cephalosporium* culture, the 7-aminocephalosporanic acid (7-ACA)

The parenteral cephalosporins (cephalothin) present potent activity against Gram-positive organisms but only moderate activity against Gram-negative bacteria. Improved pharmaco‐ logical properties, as well as lower susceptibility to resistance mechanisms, are achieved by introducing innovative side chains at just two modifiable sites of 7-ACA---the amine function

phate, and geranylgeranyl pyrophosphate.

10 Concepts, Compounds and the Alternatives of Antibacterials

usually results in a lesser amount of recovery.

discussed.

C7 and C3'.

with natural products begin to fade, even for common infections.

is obtained by hydrolysis of cephalosporin C under acidic conditions.

**Sheme 1.** Hydrolysis of cephalosporin C under acidic conditions

*Semisynthesis of macrolides*. Erythromycin, the first macrolide antibiotic (isolated the natural product from the culture broth of the soil-dwelling fungus *Saccharopolyspora erythrea*), is effective against a variety of Gram-positive bacterial infections. However, it possesses poor oral bioavailability and short *in vivo* half-life, and is unstable under acidic conditions, leading to side effects, such as stomach pain. When it is placed in acidic conditions erythromycin decomposes by intramolecular cyclization reactions beginning with addition of the C6 hydroxy group to the C9 ketone, forming anhydrohemiketal and spiroketal derivatives. One solution is to develop a 6-step sequence from erythromycin resulting in selective capping of the C6 hydroxy substituent with a methyl group, affording the antibacterial clarithromycin.

**Sheme 3.** Preparation stages of clarithromycin

Another innovative semisynthetic solution concerning the chemical instability of erythromy‐ cin is focused on removal of the C9 ketone from the erythromycin by a sequence comprising oxime formation, Beckmann rearrangement (ring expansion), and then hydrogenolysis of the iminoether intermediate.

Fully synthetic antibacterial drugs are an alternative solution to the other presented categories. These approaches have also led to important new classes of antibacterial agents and large numbers of approved drugs. The most appreciated examples of synthetic substances used in therapeutics are the chloramphenicol, metronidazole, fosfomycin, quinolones, carbapenems, and oxazolidinones.

*Chloramphenicol* is a natural compound that is more economical to produce on industrial scale by chemical synthesis rather than fermentation. The substitution of nitro group in chloram‐ phenicol with methanesulfonyl group leads to an increased potency and avoids the fatal aplastic anemia.

**Sheme 4.** Synthesis reactions leading to chloramphenicol

*Nitroimidazoles* (5-nitroimidazole, metronidazole) represent effective drugs for the treatment of trichomoniasis and infections produced by a variety of anaerobic bacteria (including *C. difficile*). 2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3) (http:// en.wikipedia.org/wiki/Metronidazole):

**Sheme 5.** Preparation steps of metronidazole

*Fosfomycin* is a polar and small molecule presenting bactericidal activity against both Grampositive and Gram-negative bacteria due to disruption of cell-wall biosynthesis. This drug prescribed for urinary tract infections is conveniently administered as a single-dose treatment [11]. Fosfomycin was obtained as a secondary metabolite in a glucose-asparagine medium containing citrate for growth and L-methionine combined with L-glutamate for stimulating the production of this compound [12]. More recently, asymmetric synthetic strategy for the synthesis of (-)-fosfomycin was performed using a biocatalytic reduction as the key step [13].

**Sheme 6.** Synthesis strategy to obtain fosfomycin

therapeutics are the chloramphenicol, metronidazole, fosfomycin, quinolones, carbapenems,

*Chloramphenicol* is a natural compound that is more economical to produce on industrial scale by chemical synthesis rather than fermentation. The substitution of nitro group in chloram‐ phenicol with methanesulfonyl group leads to an increased potency and avoids the fatal

*Nitroimidazoles* (5-nitroimidazole, metronidazole) represent effective drugs for the treatment of trichomoniasis and infections produced by a variety of anaerobic bacteria (including *C. difficile*). 2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesis, or from ethylenediamine and acetic acid, followed by treatment with lime, then Raney nickel. 2-Methylimidazole is nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated with ethylene oxide or 2-chloroethanol to give metronidazole (3) (http://

and oxazolidinones.

12 Concepts, Compounds and the Alternatives of Antibacterials

aplastic anemia.

**Sheme 4.** Synthesis reactions leading to chloramphenicol

en.wikipedia.org/wiki/Metronidazole):

**Sheme 5.** Preparation steps of metronidazole

*Quinolones* are more difficult to synthesize in the laboratory than sulfanilamides, but they are obtained by shorter synthetic routes. Norfloxacin is prepared by incorporation of both a fluorine atom at C6 and a piperazine substituent at C7 [8]. The resulted drug presents greatly improved Gram-negative activity and medium activity against Gram-positive bacteria. If the N1 ethyl group of norfloxacin is changed with a cyclopropyl substituent, one obtains cipro‐ floxacin, which can be used for treatment of respiratory tract, skin, and joint infections, including infections caused by *Pseudomonas aeruginosa*.

*Carbapenems* arise from the development of fully synthetic β-lactams, leading to a dramatic leap forward in the complexity of antibacterial molecules produced on an industrial scale using fully synthetic approaches. Thienamycin was the first natural "carbapenem" antimicrobial drug. It exhibits exceptional activity against both Gram-positive and Gram-negative organ‐ isms, including strains of *Pseudomonas aeruginosa* and organisms with acquired β-lactamase resistance mechanisms. In order to solve the chemical instability problems, it was tried to defer the introduction of the C2-cysteamine side-chain until late in the preparation procedure, enabling a series of analogs with structural variations in the thiol side-chain to be obtained. In the key step of the preparation, the bicyclic carbapenem core is generated in quantitative yield by rhodium-catalyzed cyclization of a diazo-keto ester. This impressive approach led to the discovery of imipenem and other derivatives (obtained by introduction of a C1-β-methyl substituent into the carbapenem core) [14].

*Oxazolidinones* are active against streptococci and staphylococci. In this class of antibacterial agents, linezolid is the first synthetic compound that helped in curing infections caused by Gram-positive bacteria, like MRSA and vancomycin-resistant enterococci. It is not developed by building upon a naturally occurring skeleton. Several approaches for the synthesis of linezolid have been reported in the chemistry literature [15], but the original preparation procedure developed by Upjohn [15] is lengthy, demands the use of expensive chemicals (palladium on carbon and the highly sensitive reagents methanesulfonyl chloride and nbutyllithium), and needs low-temperature conditions. Later syntheses have included an "atom-economical" method starting from D-mannitol [16] and a route starting from (S) glyceraldehyde acetonide (prepared from vitamin C) [15]. It was also reported the develop‐ ment of the "second-generation" of linezolid: a convergent, green synthesis starting from (S) epichlorohydrin, with higher yield and a 56% reduction in total waste [8]. However, long-term use can determine serious adverse effects including bone marrow suppression. Further development of oxazolidinones is based on the x-ray crystal structure of linezolid bound to its target, the large subunit of the bacterial ribosome [17].

A schematic representation of the main synthesis routes of the antibacterial agents is displayed in Figure 3.

**Figure 3.** The schematic representation of the main synthesis routes of the antibacterial agents

## **4. Design of therapeutic systems based on polymers**

The design of therapeutic polymer systems with antibacterial action is very complex and it involves special polymerization reactions or chemical functionalization for binding the drugs. Literature reports [18, 19] highlight the influence of some parameters, such as molecular weight, type and degree of alkylation, and distribution of charge on the bactericidal action of antimicrobial polymers. Considering the working principles of antimicrobial macromolecular systems, the design procedures can be divided in three categories (Figure 4), as follows:

**•** Polymer biocides

"atom-economical" method starting from D-mannitol [16] and a route starting from (S) glyceraldehyde acetonide (prepared from vitamin C) [15]. It was also reported the develop‐ ment of the "second-generation" of linezolid: a convergent, green synthesis starting from (S) epichlorohydrin, with higher yield and a 56% reduction in total waste [8]. However, long-term use can determine serious adverse effects including bone marrow suppression. Further development of oxazolidinones is based on the x-ray crystal structure of linezolid bound to its

A schematic representation of the main synthesis routes of the antibacterial agents is displayed

**Figure 3.** The schematic representation of the main synthesis routes of the antibacterial agents

The design of therapeutic polymer systems with antibacterial action is very complex and it involves special polymerization reactions or chemical functionalization for binding the drugs. Literature reports [18, 19] highlight the influence of some parameters, such as molecular

**4. Design of therapeutic systems based on polymers**

target, the large subunit of the bacterial ribosome [17].

14 Concepts, Compounds and the Alternatives of Antibacterials

in Figure 3.

**Figure 4.** Schematic representation of the design possibilities of antibacterial polymers based on the working principles of macromolecular systems

*Polymeric biocides* are macromolecules constituted of bioactive repeating units, namely polymers, represent multiple interconnected biocides, which act similarly to the monomers. They can be designed by synthetic routes that yield macromolecules with antimicrobial activity. Their function is not always understood. For instance, polymers and copolymers prepared from 2-methacryloxytroponones are able to kill bacteria. The design of this category of antimicrobial polymers is based on the concept that biocidal groups attached to a polymer act in the same way as analogous low molecular weight compounds, demonstrating that the repeating unit is a biocide. Taking into account the sterical hindrance exerted by the macro‐ molecular backbone, polymeric biocides are expected to be less active than the respective low molecular weight compounds. Literature [20] shows possibility to polymerize antibiotics maintaining their activity at the polymer backbone, e.g., by copolymerization of methacrylatemodified norfloxacin and PEG-methacrylates. Also, polymers with side groups based on hydrophobic quaternary ammonium functions can be considered as polymeric biocides.

The *biocidal polymers* preparation steps require the embodiment of the active principle in the whole macromolecule. It does not necessarily demand the use of antimicrobial repeating units. Microbial cells generally carry a negative net charge at the surface due to their membrane proteins. These charges are prepresented by teichoic acids in case of Gram-positive bacteria, and phospholipids at the outer membrane in case of Gram-negative bacteria. Therefore, polycations are attracted and if they have a proportionate amphiphilic character, they are able to destroy the cytoplasmic membrane, resulting in cell death. The most antimicrobial polyca‐ tions contain quaternary ammonium [21] and phosphonium [22], tertiary sulfonium [23], and guanidinium functions. Biocidal macromolecules that do not contain biocidal repeating units present antimicrobial activity that originates from the whole molecule. The biocidal repeating units are not required if the polymer backbone exhibits a hydrophobic character. On the other hand, polymers with a hydrophilic polymer backbone demand a hydrophobic region parallel to the backbone, which is provided by the hydrophobic side groups. Polymeric biocides are efficient when cationic groups are placed along the polymer backbone, but the good results are obtained also for polymers having only one biocidal end group. These polymers are obtained by cationic ring-opening polymerization of 2-alkyl-1,3-oxazolines and terminating the macromolecule with a cationic surfactant. The advantage of this preparation technique is the controlled introduction of a specific group at one end and another group at the opposite end of the macromolecules by selecting a suitable initiator and termination agent.

*Biocide-releasing polymers* do not act through the actual polymeric part, but the latter represents a carrier for biocides that are transferred through different mechanisms (like diffusion) to the infected area. Such polymers are usually the most active systems, because they can release their biocides close to the cell in high local concentrations. The biocide-releasing macromole‐ cules were prepared for the first time through polymerization of salicylic acid subjected to degradation, which enables the controlled releasing of salicylic acid. Several types of biocidal polymers have been designed to release chlorine, nitric oxide, phenols, or singlet oxygen. Another class of biocide-releasing polymers is the contact-active ones, like tributyltin esters of polyacrylates.

Natural polymers, such as collagen, can serve as antibacterial drug carrier. The latter can be complexed to the polymer through direct binding of the biocide to free amino or carboxylic groups of the collagen molecule [24]. The diffusion is the main process that assures the release of the drug after implantation or injection. The design of the sponge and the drug incorporation by colyophilization allow the uniform distribution of the drug within the spongy matrix. This also ensures an equal drug dose applied per square centimeter of the treated surface. Pore size of natural polymer sponges can be controlled by the lyophilization process [24].

On the other hand, synthetic copolymers, like epoxy-functional poly(dimethylsiloxane) can be processed to favor the attachment (i.e., tethering) of levofloxacin [25]. The reaction occurred via ring-opening of epoxy groups by the carboxylic acid group of levofloxacin, the tether produced was an ester-functional tether. Compared to a control coating generated by simply blending levofloxacin into a polysiloxane, the samples with tethered levofloxacin moieties presented uniform distribution of levofloxacin, higher initial kill, and sustained antimicrobial surface activity.

The antimicrobial agents can be introduced into polymer microparticles. The co-precipitation of CaCO3 and silver nanoparticles (SNPs) in the presence of poly(sodium 4-styrenesulfonate) leads to a system that enables sustained release of biocide [26]. Microbiological tests confirmed the effectiveness of these microparticles as an antibacterial agent. This designed material can be stored as a dry powder and subsequently re-suspended in water without the risk of losing its antimicrobial activity.

Plasma is widely used as a tool for polymer functionalization with biocide agents. SNPs-based antibacterial coatings can protect eukaryotic cells from SNPs-related toxic effects, while preserving antibacterial efficiency [27]. A system of SNPs containing n-heptylamine (HA) polymer matrix was deposited by plasma polymerization and covered by a second HA layer. Even so, the antibacterial activity is maintained to planktonic bacteria living in the near surroundings of the material. The SNPs-based materials also revealed antibacterial effect on adhered bacteria [28, 29]. Their number was significantly reduced compared to pure HA plasma polymer and the physiology of the bacteria was affected. The number of adhered bacteria is directly diminished with thickness of the second HA layer.

## **5.** *In Vivo* **and** *In vitro* **activity of antibacterial substances**

The *biocidal polymers* preparation steps require the embodiment of the active principle in the whole macromolecule. It does not necessarily demand the use of antimicrobial repeating units. Microbial cells generally carry a negative net charge at the surface due to their membrane proteins. These charges are prepresented by teichoic acids in case of Gram-positive bacteria, and phospholipids at the outer membrane in case of Gram-negative bacteria. Therefore, polycations are attracted and if they have a proportionate amphiphilic character, they are able to destroy the cytoplasmic membrane, resulting in cell death. The most antimicrobial polyca‐ tions contain quaternary ammonium [21] and phosphonium [22], tertiary sulfonium [23], and guanidinium functions. Biocidal macromolecules that do not contain biocidal repeating units present antimicrobial activity that originates from the whole molecule. The biocidal repeating units are not required if the polymer backbone exhibits a hydrophobic character. On the other hand, polymers with a hydrophilic polymer backbone demand a hydrophobic region parallel to the backbone, which is provided by the hydrophobic side groups. Polymeric biocides are efficient when cationic groups are placed along the polymer backbone, but the good results are obtained also for polymers having only one biocidal end group. These polymers are obtained by cationic ring-opening polymerization of 2-alkyl-1,3-oxazolines and terminating the macromolecule with a cationic surfactant. The advantage of this preparation technique is the controlled introduction of a specific group at one end and another group at the opposite

16 Concepts, Compounds and the Alternatives of Antibacterials

end of the macromolecules by selecting a suitable initiator and termination agent.

polyacrylates.

surface activity.

*Biocide-releasing polymers* do not act through the actual polymeric part, but the latter represents a carrier for biocides that are transferred through different mechanisms (like diffusion) to the infected area. Such polymers are usually the most active systems, because they can release their biocides close to the cell in high local concentrations. The biocide-releasing macromole‐ cules were prepared for the first time through polymerization of salicylic acid subjected to degradation, which enables the controlled releasing of salicylic acid. Several types of biocidal polymers have been designed to release chlorine, nitric oxide, phenols, or singlet oxygen. Another class of biocide-releasing polymers is the contact-active ones, like tributyltin esters of

Natural polymers, such as collagen, can serve as antibacterial drug carrier. The latter can be complexed to the polymer through direct binding of the biocide to free amino or carboxylic groups of the collagen molecule [24]. The diffusion is the main process that assures the release of the drug after implantation or injection. The design of the sponge and the drug incorporation by colyophilization allow the uniform distribution of the drug within the spongy matrix. This also ensures an equal drug dose applied per square centimeter of the treated surface. Pore size

On the other hand, synthetic copolymers, like epoxy-functional poly(dimethylsiloxane) can be processed to favor the attachment (i.e., tethering) of levofloxacin [25]. The reaction occurred via ring-opening of epoxy groups by the carboxylic acid group of levofloxacin, the tether produced was an ester-functional tether. Compared to a control coating generated by simply blending levofloxacin into a polysiloxane, the samples with tethered levofloxacin moieties presented uniform distribution of levofloxacin, higher initial kill, and sustained antimicrobial

of natural polymer sponges can be controlled by the lyophilization process [24].

Bacterial agents can cause both superficial and serious systemic diseases, generating infections anywhere, including in hospitals. Infections involve the formation of *in vitro* or *in vivo* bioclusters on implanted devices, such as catheters or prosthetic heart valves. These bacterial agents formed *in vitro* on different bio-materials consist of micro-colonies which are resistant to a range of antibacterial agents, through several mechanisms of resistance [30, 31]. Microor‐ ganisms can be organized as biofilms, including pathogens, thus offering a means to protect themselves against antimicrobial agents. Several mechanisms have been proposed to explain this phenomenon of resistance within biofilms, such as:

Implications of biofilm formation are that alternative control strategies must be devised both for testing the susceptibility of the organisms within the biofilm and for treating the established biofilm to alter its structure. A number of testing protocols have been developed. The effective treatment strategies include antimicrobials or other agents that can penetrate and kill the biofilm organisms, or treatments that can disrupt or target specific components of the biofilm matrix [32].

Recent studies on bacterial and fungal species suggest that extensive and striking interactions occur between the prokaryotic and eukaryotic cells [33]. Also, their possible mechanisms of resistance vary with the nature of the administered antimicrobial agent, are not fully under‐ stood, and are grouped in literature taking into account [34] the following parameters:

The methods of selection of drugs to be considerate in case of combined devices are provided by Venn diagram---a diagram (Figure 5) that shows all possible logical relations between finite collections of different sets, including the pharmaceutical device (pharmacokinetics, pharma‐ codynamics, biopharmaceutics, therapeutic dose), medical device (type and class of device, manufacturing process, testing requirements), and combination device perspective (local drug effects, controlled release combined manufactured methods, business drivers, clinical con‐ cerns) [33].

The considerable interest exists in combination devices that include the type of peripheral stents, orthopedics, indwelling catheters, dental implants, surgical meshes, wound dressings, ophthalmic implants, sutures, and even artificial organs [35, 36]. The physicochemical properties of the drugs used in combination devices, as well as their location in vivo or in vitro, include the knowledge of their antibacterial activity.

Table 1 presents the beneficial effects of treatment with antimicrobial agents against various types of bacteria, associated as biofilms.

However, besides the beneficial treatments, there are some secondary effects produced by antimicrobial drugs. The fluoroquinolone class of antibacterial drugs that determine adverse events include central nervous system toxicity, phototoxicity, and in some cases electrocar‐ diographic changes. Some side-effects of the quinolones are class effects, and cannot be modulated by molecular variation. These include gastrointestinal irritation and arthropathy.

**Table 1.** Response to antibiotics of different bacteria associated as biofilms

**•** Restricted penetration of drugs through the micro-colonies

18 Concepts, Compounds and the Alternatives of Antibacterials

**•** Nature of resistance genes induced by contact with a surface

cerns) [33].

device; and (c) combination device

include the knowledge of their antibacterial activity.

types of bacteria, associated as biofilms.

**•** Number of 'per-sister' cells considered responsible for resistance

**•** Phenotypic changes resulting from a decreased growth rate or nutrient limitation

The methods of selection of drugs to be considerate in case of combined devices are provided by Venn diagram---a diagram (Figure 5) that shows all possible logical relations between finite collections of different sets, including the pharmaceutical device (pharmacokinetics, pharma‐ codynamics, biopharmaceutics, therapeutic dose), medical device (type and class of device, manufacturing process, testing requirements), and combination device perspective (local drug effects, controlled release combined manufactured methods, business drivers, clinical con‐

**Figure 5.** The Venn diagram for perspective of devices and combined devices: (a) pharmaceutical device; (b) medical

The considerable interest exists in combination devices that include the type of peripheral stents, orthopedics, indwelling catheters, dental implants, surgical meshes, wound dressings, ophthalmic implants, sutures, and even artificial organs [35, 36]. The physicochemical properties of the drugs used in combination devices, as well as their location in vivo or in vitro,

Table 1 presents the beneficial effects of treatment with antimicrobial agents against various

However, besides the beneficial treatments, there are some secondary effects produced by antimicrobial drugs. The fluoroquinolone class of antibacterial drugs that determine adverse events include central nervous system toxicity, phototoxicity, and in some cases electrocar‐ diographic changes. Some side-effects of the quinolones are class effects, and cannot be modulated by molecular variation. These include gastrointestinal irritation and arthropathy. Moreover, gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recent investigations revealed that cisapride (a partial 5-HT4 receptor agonist) can generate dose-dependent cardiac adverse effects, including lengthening of the electrocardiographic QT interval, syncopal episodes, and ventricular dysrhythmias.

Determination of the minimum inhibitory concentration, based on the activities of antibiotics against planktonic bacteria, is the standard assay for antibiotic susceptibility testing. In this context, the Calgary Biofilm Device is well recognized as a technology for the rapid and reproducible assay of biofilm susceptibilities to antibiotics, for the rational selection of antibiotics effective against microbial biofilms, and for the finding of new effective antibiotic compounds [8]. On the other hand, the antibiotic tolerance is defined as the ability of bacteria to survive but not grow in the presence of antibiotics. It is known that adherent bacteria on solid surfaces already have tolerance to antibiotics and depend essentially on the different stress conditions on antibiotic tolerance [47]. The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery motivate recent studies to find new classes of antibacterial agents and novel drugs, in order to maintain the ability to treat infectious diseases---especially those caused by multidrug-resistant organisms [48]. Research concerning the activity and design of cationic antimicrobial peptides and their mimics has produced several antimicrobial compounds with good antibacterial activity and elucidated trends of increasing activity and specificity. Applications are numerous, including antimicro‐ bial surfaces [49] and conjugates in targeted therapy [50].

The interest in cationic antimicrobial peptides opens new perspectives in antimicrobial drug design. The Hunter-killer peptides represent a novel class of targeted peptides that have demonstrated remarkable efficacy in several basic proof-of-principle paradigms including therapeutics for cancer [51], arthritis [52], prostate reduction [53], and obesity [54]. There are also reported new hunter-killer "nanostructures/nanospheres" and second-generation Hunter-killer peptides derivatives, which are protected from proteolytic degradation and adjust their "modulation of the absorption, distribution, metabolism, and excretion" properties [55]. This technology uses similar way to encapsulate anticancer proteins, such as the small globular proteins. Development and evaluation of the next generation of Hunter-killer peptides with improved modulation of the absorption, distribution, metabolism, and excretion properties are studies currently underway.

Host-defense peptides are present components of the innate immune system across all organisms. These molecules have been widely studied for their activities, such as antimicro‐ bial, antitumor, mitogenic, and chemical signaling properties. It is known that oligo-acyl-lysyls are synthetic mimics of host-defense peptides known to exert antibacterial activity both in cultures and in animal models of disease [56]. Data obtained with representative bacteria, including the Gram-negative bacterium *Escherichia coli* and the Gram-positive bacteria *Listeria monocytogenes* and *Staphylococcus aureus*, shows that the oligo-acyl-lysyls potency is affected by pH changes and subsides essentially throughout a wide range of salt concentrations and temperature, whereas antistaphyloccocal activity is vulnerable. Also, in biomedical strategy concerning host-defense peptides, several short synthetic oligomers such as methacrylate, arylamide foldamers, and oligo-acyl-lysyls have attracted particular attention due to their lower cost and rapid structural optimization capabilities [57]. Although a number of com‐ pounds that demonstrate broad-spectrum antimicrobial activities *in vitro* have been identified, robust/safe *in vivo* activity has been a great challenge for most published peptidomimetics [58]. As a result of the appearance of multidrug-resistant bacteria, antimicrobial peptides have emerged as one of the leading prospects for drug development. Antimicrobial peptides are retained in a wide range of organisms as a defense mechanism against a broad array of microbial targets. These peptides vary in size, sequence, and efficacy, allowing a good interaction with the charged bacterial membrane [59]. In this context, to mimic the amphiphilic nature of antimicrobial peptides, arylamide foldamers were prepared, that demonstrated bactericidal activity against both Gram-negative and Gram-positive strains, without many of the drawbacks of natural antimicrobial peptides [60].

The emergence and spread of antibiotic resistance represent an alarming concern in clinical practice. From this reason, the antimicrobial agents are used to cover materials and medical devices as a prophylaxis to prevent bacteria from growing or for therapeutic uses. A range of silver-coated or impregnated dressings are commercially available for use. The antibacterial activities of silver-coated/impregnated dressings were compared against common burnwound pathogens, namely *Staphylococcus aureus*, *Enterococcus faecali*s, *Pseudomonas aeruginosa*, *Escherichia coli*, *Enterobacter cloacae*, *Proteus vulgaris*, *Acinetobacter baumannii.* The rapidity and extent of killing of these pathogens evaluated under *in vitro* conditions shows that silverimpregnated dressings exert bactericidal activity, particularly against Gram-negative bacteria, including *Enterobacter* species, *Proteus* species, and *Escherichia coli.* Therefore, the incorporation of silver for dressings or as coating on medical products plays an important role in the domain of antimicrobial agents [61].

On the other hand, it is known that infection is the most common cause of biomaterial implant failure in modern medicine [62]. Adhesion and subsequent surface growth of bacteria on biomedical implants and devices cause the formation of a biofilm, in which the so-called ''glycocalyx'' embeds the infecting bacteria offering protection against the host immune system and antibiotic treatment. Gram-positive *Staphylococcus aureus* and *Staphylococcus epidermidis* are the predominant infecting organisms, followed by Gram-negative bacilli like *Escherichia coli* and *Pseudomonas aeruginosa*. A possible approach to prevent biomaterialcentered infections is to render the biomaterial surface antimicrobial properties by function‐ alization with, e.g., quaternary ammonium groups, which are widely known as disinfectants. Quaternary ammonium-functionalized surfaces have a high positive surface charge, and thus exert a strong adhesive force on negatively charged bacteria which are proposed to inhibit surface growth of bacteria. The main mechanisms of action of antibacterial drugs (Figure 6) can be classified as follows:

**•** Inhibition of cell wall synthesis (amoxicillin, cefalexin, oxacilin)

solid surfaces already have tolerance to antibiotics and depend essentially on the different stress conditions on antibiotic tolerance [47]. The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery motivate recent studies to find new classes of antibacterial agents and novel drugs, in order to maintain the ability to treat infectious diseases---especially those caused by multidrug-resistant organisms [48]. Research concerning the activity and design of cationic antimicrobial peptides and their mimics has produced several antimicrobial compounds with good antibacterial activity and elucidated trends of increasing activity and specificity. Applications are numerous, including antimicro‐

The interest in cationic antimicrobial peptides opens new perspectives in antimicrobial drug design. The Hunter-killer peptides represent a novel class of targeted peptides that have demonstrated remarkable efficacy in several basic proof-of-principle paradigms including therapeutics for cancer [51], arthritis [52], prostate reduction [53], and obesity [54]. There are also reported new hunter-killer "nanostructures/nanospheres" and second-generation Hunter-killer peptides derivatives, which are protected from proteolytic degradation and adjust their "modulation of the absorption, distribution, metabolism, and excretion" properties [55]. This technology uses similar way to encapsulate anticancer proteins, such as the small globular proteins. Development and evaluation of the next generation of Hunter-killer peptides with improved modulation of the absorption, distribution, metabolism, and excretion

Host-defense peptides are present components of the innate immune system across all organisms. These molecules have been widely studied for their activities, such as antimicro‐ bial, antitumor, mitogenic, and chemical signaling properties. It is known that oligo-acyl-lysyls are synthetic mimics of host-defense peptides known to exert antibacterial activity both in cultures and in animal models of disease [56]. Data obtained with representative bacteria, including the Gram-negative bacterium *Escherichia coli* and the Gram-positive bacteria *Listeria monocytogenes* and *Staphylococcus aureus*, shows that the oligo-acyl-lysyls potency is affected by pH changes and subsides essentially throughout a wide range of salt concentrations and temperature, whereas antistaphyloccocal activity is vulnerable. Also, in biomedical strategy concerning host-defense peptides, several short synthetic oligomers such as methacrylate, arylamide foldamers, and oligo-acyl-lysyls have attracted particular attention due to their lower cost and rapid structural optimization capabilities [57]. Although a number of com‐ pounds that demonstrate broad-spectrum antimicrobial activities *in vitro* have been identified, robust/safe *in vivo* activity has been a great challenge for most published peptidomimetics [58]. As a result of the appearance of multidrug-resistant bacteria, antimicrobial peptides have emerged as one of the leading prospects for drug development. Antimicrobial peptides are retained in a wide range of organisms as a defense mechanism against a broad array of microbial targets. These peptides vary in size, sequence, and efficacy, allowing a good interaction with the charged bacterial membrane [59]. In this context, to mimic the amphiphilic nature of antimicrobial peptides, arylamide foldamers were prepared, that demonstrated bactericidal activity against both Gram-negative and Gram-positive strains, without many of

bial surfaces [49] and conjugates in targeted therapy [50].

20 Concepts, Compounds and the Alternatives of Antibacterials

properties are studies currently underway.

the drawbacks of natural antimicrobial peptides [60].

Several *in vitro* and *in vivo* studies show that methicillin-resistant *Staphylococcus aureus*(MRSA) remains a leading cause of bacterial infections worldwide, ranging from minor skin and soft tissue infections to more severe conditions such as bacteremia and infective endocarditis [63]. The molecules currently under pre-clinical and clinical investigation that are active against MRSA, with special emphasis on their mechanism of action are grouped as follows:

**Figure 6.** The main action mechanisms of antibacterial drugs

As can be seen here, drug discovery and development against MRSA is a highly active field. The wide-ranging clinical spectrum of infections is mirrored by the discovery of chemical classes active against it [63]. Literature offers the opportunity to obtain a new drug with antibacterial, antifungal, antiviral, and antiparasitic potential from natural products by extraction process. Cos et al. [64] presents a scheme of testing organisms for antibacterial, antifungal, antiviral, and antiparasitic screening *in vitro*. Irrespective of the adopted plant collection strategy, a critical step is the processing of the plant material that will be used in the process of screens. Infections caused by different species continue to increase in frequency and severity [65]. The number of enzymes and the number of organisms that exhibit crossresistance to some classes of antimicrobials is growing, generating an increase of researches in antibacterial substances domain.

## **6. Conclusion and future perspectives**

The treatment of infections caused by bacteria remains an actual problem that still raises problems and maintains a vivid interest of both scientists and pharmaceutical companies for finding new and innovative solutions. These health issues should be approached on multiple levels, starting from synthesis, design, and the mechanisms of action. The research directed towards the preparation of new antibacterial compounds must be based on deeper under‐ standing of the resistance mechanisms. More promising antibacterial drugs with novel mechanisms of action should be developed and new types of targets must emerge. There is a great need for enhancing the precision of targeting the pathogens and limit the misuse of antimicrobials and other practices that accelerate the emergence of novel resistance mecha‐ nisms. So, specific microbial target enzymes will continue to attract attention for novel antimicrobial discovery. A starting point is given by peptide deformylase, but its unstable character delays its utilization on industrial level. Advances in deciphering the genome of a several microbes will further help the discovery of agents against them by providing a wider selection of potential targets.

Another emerging trend for the future is the increasing correlation between infections and other diseases. For example, infection with *Chlamydia pneumoniae* is a determining factor in the pathogenesis of atherosclerosis. Administration of specific drugs was found to be protective against atherosclerosis complications, thus reducing the disease progression in as yet unspe‐ cified ways. This type of significant correlation will be taken into increasing account by antibacterial drug producers in the future, as the repercussions of infection, and therefore treatment, expand beyond the microbe itself.

On the other hand, although there is a major progress on designing scientifically sound and feasible clinical trials, more efforts must be made for making new therapies available to meet patient needs. On the other hand, novel strategies, like targeting host infection response pathways or anti-infective antibodies, offer an insight into the anti-infective drug discovery pipeline of the future.

## **Acknowledgements**

**•** DNA synthesis inhibitors (fluoroquinolones, dihydrofolate reductase inhibitors)

As can be seen here, drug discovery and development against MRSA is a highly active field. The wide-ranging clinical spectrum of infections is mirrored by the discovery of chemical classes active against it [63]. Literature offers the opportunity to obtain a new drug with antibacterial, antifungal, antiviral, and antiparasitic potential from natural products by extraction process. Cos et al. [64] presents a scheme of testing organisms for antibacterial, antifungal, antiviral, and antiparasitic screening *in vitro*. Irrespective of the adopted plant collection strategy, a critical step is the processing of the plant material that will be used in the process of screens. Infections caused by different species continue to increase in frequency and severity [65]. The number of enzymes and the number of organisms that exhibit crossresistance to some classes of antimicrobials is growing, generating an increase of researches in

The treatment of infections caused by bacteria remains an actual problem that still raises problems and maintains a vivid interest of both scientists and pharmaceutical companies for finding new and innovative solutions. These health issues should be approached on multiple levels, starting from synthesis, design, and the mechanisms of action. The research directed towards the preparation of new antibacterial compounds must be based on deeper under‐ standing of the resistance mechanisms. More promising antibacterial drugs with novel

**•** Fatty acid synthesis inhibitors

**Figure 6.** The main action mechanisms of antibacterial drugs

22 Concepts, Compounds and the Alternatives of Antibacterials

antibacterial substances domain.

**6. Conclusion and future perspectives**

This work was financially supported from PNII-ID-PCE-2011-3-0937 Project No. 302/5.10.2011.

## **Author details**

Andreea Irina Barzic and Silvia Ioan\*

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Physical Chemistry of Polymers, "Petru Poni" Institute of Macromolecular Chemistry, Iasi, Romania

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mother (Suppl A). 1997;39:103-108.

## **Perception and Resistance Mechanism of some Metaldrug Complexes and Their Roles as Antibacterial**

Joshua A. Obaleye, Nzikahyel Simon, Olufunso O. Abosede, Mercy O. Bamigboye, Abiodun A. Ajibola, Uche B. Eke and Elizabeth A. Balogun

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61033

#### **Abstract**

[59] Glukhov E, Burrows LL, Deber CM. Membrane interactions of designed cationic anti‐ microbial peptides: The two thresholds. Biopolymers. 2008;89:360-371. DOI: 10.1002/

[60] Mensa B, Kim YH, Choi S, et al. Antibacterial mechanism of action of arylamide fol‐ damers. Antimicrob Agents Chemother. 2011;55:5043-5053. DOI: 10.1128/AAC.

[61] Ip M, Lui SL, Poo VCM, Lung I, Burd A. Antimicrobial activities of silver dressings:

[62] Gottenbos B, van der Mei HC, Klatter F, Nieuwenhuis P, Busscher HJ. *In vitro* and *in vivo* antimicrobial activity of covalently coupled quaternary ammonium silane coat‐

[63] Kumar K, Chopra S. New drugs for methicillin-resistant Staphylococcus aureus: An update. J Antimicrob Chemother. 2013;68:1465-1470. DOI: 10.1093/jac/dkt045

[64] Cos P, Vlietinck AJ, Vanden Berghe DV, Maesa L. Anti-infective potential of natural products: How to develop a stronger in vitro 'proof-of-concept.' J Ethnopharm.

[65] Nemeth J, Oesch G, Kuster SP. Bacteriostatic versus bactericidal antibiotics for pa‐ tients with serious bacterial infections: Systematic review and meta-analysis. J Anti‐

An in vitro comparison. J Med Microbiol. 2006;55:59-63.

ings on silicone rubber. Biomaterials. 2002;23:1417-1423.

2006;106:290-302. DOI: 10.1016/j.jep.2006.04.003

microb Chemother. 2015;70:382-395.

bip.20917

28 Concepts, Compounds and the Alternatives of Antibacterials

05009-11.

Metal-based drugs have undergone much development and application for therapeutic and diagnostic purposes for many decades since the huge success of cisplatin and other successful metal-drug complexes in the clinical stages. Furthermore, this metal-based drug has come up with a lot of signs of resistance and side-effects in their uses. This re‐ view points to some of the resistance natures and mechanisms of previously synthesized complexes in the field of chemistry.

**Keywords:** metal-drug complexes, antibacterial, mechanism, therapeutics, properties, re‐ sistance

## **1. Introduction**

Anti-bacterial are agents that disturb and combat the growth and reproduction of bacteria. They are known as agents used to disinfect surfaces and eliminate potentially harmful bacteria. Some antibacterial agents are contraindicated while some required dosage modification in patients who have renal insufficiency. The use of metal complexes as antibacterial/chemo‐ therapeutic agents against some ailments is a very attractive potential. Some metal complexes including mixed ligand metal complexes have been prepared in our laboratory and that of others. Their effectiveness as antibacterial agents has been revealed. Different synthetic procedures were utilized.

Though development of metallo-pharmaceuticals is met with limitations because of the perception that metals (especially when regarded as heavy metals) are toxic and the relative

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

limited expertise of most pharmaceutical companies in Inorganic Chemistry, metals and their compounds are essential to many species of plants and animals. Metal complexes may be useful as research probes of biological function, as intermediary lead compounds in the development of non-metal-containing therapeutics, and as potential diagnostic and therapeu‐ tic agents. The unique properties of metal complexes,(e. g., hydrolytic and redox activity, valency, geometry, magnetic, spectroscopic, photo-physical, and radiochemical properties) can be used to measure and/or alter cellular functions. In the recent past, polypyridyl metal complexes are also being tested as chemotherapeutic agents following the first success of cisplatin and the need to discover new drugs to combat the problem of resistance to existing drugs [1-8].

The importance of metal in medicine has been in existence for many years and researchers have explored their uses and advantages to human health, animals and the environment. Some of these metals are content of our day-to-day diets and in varying quantities.

Many researchers have come up with the importance of metals in known drugs or synthesized drugs. Transition metals are involved majorly in the formation of complexes by coordinating with the ligands (i. e. the drugs).

Humans need several metal ions for many vital and important functions in the body in which the lack of some of these metal ions can lead to malfunctioning of the body and development of diseases. Iron deficiency can lead to pernicious anemia while copper deficiency in infants can cause lack of accurate function of the heart.

Medicinal bioinorganic chemistry considers, from a molecular level point of view, how to understand and recognize different diseases that originate from the deficiency of essential metal ions functionality in the body of a living system. This also includes ways of providing solution to these problems. Introduction of heavy metal ions (e. g., Pb and Hg) can be detri‐ mental to living systems [9].

The involvement of the metal ions in most of these potent synthesized complexes has increased their biological activities. In most cases the acceleration of the action of many drugs is mainly caused by metal ion chelation. Therefore many metals are involved in enhancing the efficacy in antimalarial, antitumor and anticancer therapy [10-13].

Drug resistance refers to a situation in which the drugs that usually destroy the bacteria can no longer perform its duty. It implies that the patient can no longer be effectively treated against the bacteria.

Therefore, people become sick for a long time and if the epidemics are extended without a possible solution it results in more people being at risk of becoming infected.

Antimicrobial resistance is the ability of a microorganism to survive at a given concentration of anantimicrobial agent at which the normal population of the microorganism would be killed.

## **2. Resistance of some metal-drug complexes of antimalarial**

## **2.1. Resistance to anti-malarials**

limited expertise of most pharmaceutical companies in Inorganic Chemistry, metals and their compounds are essential to many species of plants and animals. Metal complexes may be useful as research probes of biological function, as intermediary lead compounds in the development of non-metal-containing therapeutics, and as potential diagnostic and therapeu‐ tic agents. The unique properties of metal complexes,(e. g., hydrolytic and redox activity, valency, geometry, magnetic, spectroscopic, photo-physical, and radiochemical properties) can be used to measure and/or alter cellular functions. In the recent past, polypyridyl metal complexes are also being tested as chemotherapeutic agents following the first success of cisplatin and the need to discover new drugs to combat the problem of resistance to existing

The importance of metal in medicine has been in existence for many years and researchers have explored their uses and advantages to human health, animals and the environment. Some

Many researchers have come up with the importance of metals in known drugs or synthesized drugs. Transition metals are involved majorly in the formation of complexes by coordinating

Humans need several metal ions for many vital and important functions in the body in which the lack of some of these metal ions can lead to malfunctioning of the body and development of diseases. Iron deficiency can lead to pernicious anemia while copper deficiency in infants

Medicinal bioinorganic chemistry considers, from a molecular level point of view, how to understand and recognize different diseases that originate from the deficiency of essential metal ions functionality in the body of a living system. This also includes ways of providing solution to these problems. Introduction of heavy metal ions (e. g., Pb and Hg) can be detri‐

The involvement of the metal ions in most of these potent synthesized complexes has increased their biological activities. In most cases the acceleration of the action of many drugs is mainly caused by metal ion chelation. Therefore many metals are involved in enhancing the efficacy

Drug resistance refers to a situation in which the drugs that usually destroy the bacteria can no longer perform its duty. It implies that the patient can no longer be effectively treated

Therefore, people become sick for a long time and if the epidemics are extended without a

Antimicrobial resistance is the ability of a microorganism to survive at a given concentration of anantimicrobial agent at which the normal population of the microorganism would be

possible solution it results in more people being at risk of becoming infected.

of these metals are content of our day-to-day diets and in varying quantities.

drugs [1-8].

with the ligands (i. e. the drugs).

mental to living systems [9].

against the bacteria.

killed.

can cause lack of accurate function of the heart.

30 Concepts, Compounds and the Alternatives of Antibacterials

in antimalarial, antitumor and anticancer therapy [10-13].

Resistance to antimalarials could be defined as the tendency by which the parasite is able to thrive and even reproduce itself in the presence of accurate dosage of malaria drug [14].

In 2006, the World Health Organisation (WHO) stated that, resistance has arisen to all classes of anti-malarials except the artemisinins. This has increased the malaria burden globally and is a most important threat to malaria control. Extensive and indiscriminate uses of antimalarial drugs impose a strong selective stress on *Plasmodium falciparum* and other malaria parasites to acquire higher resistance levels. This can be prevented at its onset or mellowed down significantly, through combination therapies of the anti-malarial drugs with differing modes of actions thereby achieving maximum cure rates by strict adher‐ ence to proper drug prescriptions [13].

The data acquired can be of assistance in treatment choices and forecasts concerning future resistance patterns. The most difficult with drug resistance arises from *P. falciparum*. Resistance due to *P. falciparum* is of special interest since the huge burden of disease arises from this class, as well as its deadly potential, the tendency for epidemics, and the cost implication of replace‐ ment with candidate drugs in places with well-known drug resistance. Chloroquine resistance does occur in *P. vivax*, particularly in Western Oceania. However, there is very scanty infor‐ mation on resistance in *P. ovale* and *P. malariae* [14].

Malaria is a deadly disease that affect both children and adult and is mostly caused by the protozoan parasite *Plasmodium*, and is transmitted by an Anopheline mosquito vector [15]. The five Plasmodia species affecting humans are *Plasmodium falciparum*, *Plasmodium vivax*, *Plasmodium ovale*, *Plasmodium malariae*, and *Plasmodium knowlesi*. *Plasmodium falciparum* is a common species commonly affecting the population and therefore its resistance to many drugs. Today, the available therapeutic drugs for malaria are limited; new anti-malarial drugs, preferably with new structures and/or modes of action, are urgently needed [16, 17].

The emergence of resistance in *Plasmodium* depends on parasite mutation rate and their total parasite load. Treatment response and drug selection strength also contributed to these factors.

Increase in the rates of mutation enhances the speed of resistance emergence which subse‐ quently leads to harmful mutations [17].

## **3. Some metal-drug complexes resistance and their mechanism**

## **3.1. Metal complexes of antimalarial drugs**

Metal–drug synergism has been exploited to obtain effective antimalarial metal agents [18-20].

The use of chloroquine (CQ) as a major reference drug of all antimalarial drugs has enabled many scientists to develop more potent drugs in combating malaria. Resistance against CQ is leads to harmful mutations [17].

Metal Complexes of Antimalarial Drugs

now prominent. The incorporation of metals into CQ and similar drugs has been yielding more positive results with little or no toxicity. Some examples of synthesized metal- drug complexes including their various resistances are also cited in the table below: positive results with little or no toxicity. Some examples of synthesized metal- drug complexes including their various resistances are also cited in the table below:

Increase in the rates of mutation enhances the speed of resistance emergence which subsequently

SOME METAL-DRUG COMPLEXES RESISTANCE AND THEIR MECHANISM

Metal–drug synergism has been exploited to obtain effective antimalarial metal agents [18-20].

The use of chloroquine (CQ) as a major reference drug of all antimalarial drugs has enabled

now prominent. The incorporation of metals into CQ and similar drugs has been yielding more

For Ruthenium and Rhodium complexes of chloroquine: For Ruthenium and Rhodium complexes of chloroquine:

Where (COD: 1,5-Cyclooctadiene), Ru- Ruthenium, Rh= Rhenium,

Where (COD: 1,5-Cyclooctadiene), Ru- Ruthenium, Rh= Rhenium,

Compound CQ-Sensitive strains of P.berghei

6

CQ-Resistance strains of P.

Reference

falciparum

1. [Au(PMe3)(CQ)]PF6] F32 W2, K1, FcB1 23

2. [Au(PPh3)(CQ)]PF6 F32 FcB1, FcB2 22

3. [Au(PPh3)(CQ)]NO3 F32 W2, K1, FcB1 23

4. [Au(PEt3)(CQ)]PF6 F32 W2, K1, FcB1 22

diphosphate. The same complex also shows high ability to inhibit β-haematin formation.

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6 has been clearly defined [22].

Structural effects and increased drug lipophilicity enhance haem aggregation inhibition at

From the conclusion that was drawn from the mechanism of [Au(PPh3)(CQ)]PF6 and its

antimalarial action, [Au(PPh3)(CQ)]PF6 has high propensity to haem than chloroquine

lipid/water interfaces [24].

Perception and Resistance Mechanism of some Metal-drug Complexes and Their Roles as Antibacterial http://dx.doi.org/10.5772/61033 33

now prominent. The incorporation of metals into CQ and similar drugs has been yielding more positive results with little or no toxicity. Some examples of synthesized metal- drug complexes

Increase in the rates of mutation enhances the speed of resistance emergence which subsequently

SOME METAL-DRUG COMPLEXES RESISTANCE AND THEIR MECHANISM

Metal–drug synergism has been exploited to obtain effective antimalarial metal agents [18-20].

The use of chloroquine (CQ) as a major reference drug of all antimalarial drugs has enabled

many scientists to develop more potent drugs in combating malaria. Resistance against CQ is

now prominent. The incorporation of metals into CQ and similar drugs has been yielding more

positive results with little or no toxicity. Some examples of synthesized metal- drug complexes

5

Compound CQ-Sensitive strains of P.berghei

lipid/water interfaces [24].

Compound CQ-Sensitive strains CQ-Resistance strains Reference

[RuCQCl2]<sup>2</sup> RhCl(COD)CQ

FcB1 21

6

Rh-chloroquine

CQ-Resistance strains of P.

Reference

falciparum

1. [Au(PMe3)(CQ)]PF6] F32 W2, K1, FcB1 23

2. [Au(PPh3)(CQ)]PF6 F32 FcB1, FcB2 22

3. [Au(PPh3)(CQ)]NO3 F32 W2, K1, FcB1 23

4. [Au(PEt3)(CQ)]PF6 F32 W2, K1, FcB1 22

diphosphate. The same complex also shows high ability to inhibit β-haematin formation.

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6 has been clearly defined [22].

Structural effects and increased drug lipophilicity enhance haem aggregation inhibition at

From the conclusion that was drawn from the mechanism of [Au(PPh3)(CQ)]PF6 and its

antimalarial action, [Au(PPh3)(CQ)]PF6 has high propensity to haem than chloroquine

A P. berghei FcB1, FcB2 21

**Compound CQ-Sensitive strains CQ-Resistance strains Reference** A *P. berghei* FcB1, FcB2 [21] B Reduction of parasitemia by 73% FcB1 [21]

including their various resistances are also cited in the table below:

For Ruthenium and Rhodium complexes of chloroquine:

(A) (B)

of parasitemia by 73%

Where (COD: 1,5-Cyclooctadiene), Ru- Ruthenium, Rh= Rhenium,

Where (COD: 1,5-Cyclooctadiene), Ru- Ruthenium, Rh= Rhenium,

1. R = CH3, X= PF6 (Au-CQ)

2. R = C6H5, X = PF<sup>6</sup> 3. R = C6H5, X = NO<sup>3</sup> 4. R = C2H5, X = PF<sup>6</sup>

including their various resistances are also cited in the table below:

For Ruthenium and Rhodium complexes of chloroquine:

Ru-chloroquine

B Reduction

leads to harmful mutations [17].

32 Concepts, Compounds and the Alternatives of Antibacterials

Metal Complexes of Antimalarial Drugs

From the conclusion that was drawn from the mechanism of [Au(PPh3)(CQ)]PF6 and its antimalarial action, [Au(PPh3)(CQ)]PF6 has high propensity to haem than chloroquine diphosphate. The same complex also shows high ability to inhibit β-haematin formation.

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6 has been clearly defined [22]. Structural effects and increased drug lipophilicity enhance haem aggregation inhibition at lipid/water interfaces [24].

1. R1 = -CH3, R2 = -CH(CH3)2, X = Cl-

2. R1=R2 = H, X = Cl-

7 FcB1, 3D7, PFB, F32 W2, Dd2, K1 25 The description of CQ derivatives with Arene−metal complexes and half-sandwich complexes are shown above, where some of them showed high antiplamodial activity and some showed different modes of binding with CQ.

The description of CQ derivatives with Arene−metal complexes and half-sandwich complexes Ferroquine (FQ) shows higher biological and structural activity than any other antimalarial drugs in the market including chloroquine (CQ). The reaction of FQ and CQ against *P.*

different modes of binding with CQ.

Ferroquine

7

Ferroquine (FQ) shows higher biological and structural activity than any other antimalarial drugs

in the market including chloroquine (CQ). The reaction of FQ and CQ against P. falciparum

are shown above, where some of them showed high antiplamodial activity and some showed

resistant and chloroquine-sensitive P. falciparum strains[26-32].

1. R1 = -CH3, R2 = -CH(CH3)2, X = Cl-

2. R1=R2 = H, X = Cl-

strains is quite unique and different in which FQ reveal some high potency in chloroquine-

Compound CQ-Sensitive strains CQ-Resistance strains Reference

The description of CQ derivatives with Arene−metal complexes and half-sandwich complexes

are shown above, where some of them showed high antiplamodial activity and some showed

6 FcB1, 3D7, PFB, F32 W2, Dd2, K1 25

7 FcB1, 3D7, PFB, F32 W2, Dd2, K1 25

*falciparum* strains is quite unique and different in which FQ reveal some high potency in chloroquine-resistant and chloroquine-sensitive *P. falciparum* strains[26-32]. analogues of ferroquine were reported by Salas et.al. (2013) [35]. All the disubstituted bridged Ferroquine (FQ) shows higher biological and structural activity than any other antimalarial drugs

Indeed it has been observed that a number of drugs that are active against CQ-resistant strains, including metal-based CQ derivatives, such as the iron-containing ferroquine [21,28,33] and the gold-CQ complex [Au(CQ)(PPh3)]PF6 [34], are considerably more lipophilic than CQ and this could be an important factor in the reduction of resistance. ferrocenyl compounds were observed to be active against all the tested parasite strains. The activities of some of the compounds under investigation were observed to be sensitive to the drug resistance level of the parasite strains. It was noted that: 7 in the market including chloroquine (CQ). The reaction of FQ and CQ against P. falciparum

Antiplasmodial activity of the synthetic products of chloroquine-bridged ferrocenophane analogues of ferroquine were reported by Salas *et. al*. (2013) [35]. All the disubstituted bridged ferrocenyl compounds were observed to be active against all the tested parasite strains. FQ was twenty times or more potent or operative against chloroquine-resistant parasite

The activities of some of the compounds under investigation were observed to be sensitive to the drug resistance level of the parasite strains. It was noted that: strains than CQ;

ferrocene−pyrrolo[1,2-α]quinoxaline compounds

This drug has shown lower resistance than chloroquine, therefore making their derivatives a good contender for chloroquine-resistant malaria.[36]. The most potent of this derivative This drug has shown lower resistance than chloroquine, therefore making their derivatives a good contender for chloroquine-resistant malaria. [36]. The most potent of this derivative contains a methoxy group just like the above.

#### **4. Multiple drug resistance mechanisms in cancer** The process and system whereby resistance to one drug is accompanied by resistance to drugs

The process and system whereby resistance to one drug is accompanied by resistance to drugs whose structures and mechanisms of action may be completely different is called multiple drug resistance (MDR). [37-42] whose structures and mechanisms of action may be completely different is called multiple drug resistance (MDR). [37-42]

Compound CQ-Sensitive strains CQ-Resistance strains Reference

F F32 FcB1, PFB 36

#### **4.1. Platinum anticancer agents** PLATINUM ANTICANCER AGENTS

universally.

stand crosslinks.

Resistance

×

Reduce Pt Uptake

Resistance

*falciparum* strains is quite unique and different in which FQ reveal some high potency in

could be an important factor in the reduction of resistance.

resistant and chloroquine-sensitive P. falciparum strains[26-32].

different modes of binding with CQ.

1. R1 = -CH3, R2 = -CH(CH3)2, X = Cl-

2. R1=R2 = H, X = Cl-

strains is quite unique and different in which FQ reveal some high potency in chloroquine-

Compound CQ-Sensitive strains CQ-Resistance strains Reference

The description of CQ derivatives with Arene−metal complexes and half-sandwich complexes

are shown above, where some of them showed high antiplamodial activity and some showed

6 FcB1, 3D7, PFB, F32 W2, Dd2, K1 25

7 FcB1, 3D7, PFB, F32 W2, Dd2, K1 25

Indeed it has been observed that a number of drugs that are active against CQ-resistant strains,

including metal-based CQ derivatives, such as the iron-containing ferroquine [21,28,33] and the

gold-CQ complex [Au(CQ)(PPh3)]PF6 [34], are considerably more lipophilic than CQ and this

Antiplasmodial activity of the synthetic products of chloroquine-bridged ferrocenophane

analogues of ferroquine were reported by Salas et.al. (2013) [35]. All the disubstituted bridged

ferrocenyl compounds were observed to be active against all the tested parasite strains.

The activities of some of the compounds under investigation were observed to be sensitive to the

7

Ferroquine (FQ) shows higher biological and structural activity than any other antimalarial drugs

in the market including chloroquine (CQ). The reaction of FQ and CQ against P. falciparum

drug resistance level of the parasite strains. It was noted that:

FQ was twenty times or more potent or operative against chloroquine-resistant parasite

FQ also displayed high level of potency in vivo in some experiments against P. berghei,

Due to the different formulation and structure, there were no expected differences.

Indeed it has been observed that a number of drugs that are active against CQ-resistant strains, including metal-based CQ derivatives, such as the iron-containing ferroquine [21,28,33] and the gold-CQ complex [Au(CQ)(PPh3)]PF6 [34], are considerably more lipophilic than CQ and

Antiplasmodial activity of the synthetic products of chloroquine-bridged ferrocenophane analogues of ferroquine were reported by Salas *et. al*. (2013) [35]. All the disubstituted bridged ferrocenyl compounds were observed to be active against all the tested parasite strains.

The activities of some of the compounds under investigation were observed to be sensitive to

**•** FQ was twenty times or more potent or operative against chloroquine-resistant parasite

**•** FQ also displayed high level of potency *in vivo* in some experiments against *P. berghei*, *P.*

ferrocene−pyrrolo[1,2-α]quinoxaline compounds

This drug has shown lower resistance than chloroquine, therefore making their derivatives a good contender for chloroquine-resistant malaria. [36]. The most potent of this derivative

**Compound CQ-Sensitive strains CQ-Resistance strains Reference** F F32 FcB1, PFB [36]

8

This drug has shown lower resistance than chloroquine, therefore making their derivatives a

good contender for chloroquine-resistant malaria.[36]. The most potent of this derivative

**•** Due to the different formulation and structure, there were no expected differences.

contains a methoxy group just like the above.

contains a methoxy group just like the above.

chloroquine-resistant and chloroquine-sensitive *P. falciparum* strains[26-32].

Ferroquine

this could be an important factor in the reduction of resistance.

34 Concepts, Compounds and the Alternatives of Antibacterials

the drug resistance level of the parasite strains. It was noted that:

P. vinckei and P. yoeli;

strains than CQ;

strains than CQ;

*vinckei* and *P. yoeli;*

One of the most effectively used drugs in cancer and for its treatment is the family called Platinium (II) complexes. The following compounds have been clinically approved for treatment universally. One of the most effectively used drugs in cancer and for its treatment is the family called Platinium (II) complexes. The following compounds have been clinically approved for treatment

Consideration of the toxic reduction of platinum complexes in living cells has been of special interest over the years. This happened so as to have a wider range of cure over other types of Consideration of the toxic reduction of platinum complexes in living cells has been of special interest over the years. This happened so as to have a wider range of cure over other types of cancer that have come to light, hereby avoiding being stopped by some resistance. [43-45]

cancer that have come to light, hereby avoiding being stopped by some resistance.[43-45] The usefulness of Platinum complexes in the clinical stage is limited by:

Pt-SG

(iii)its high toxicity to some normal cells.

Some of the current thinking on the chemical basis for the mechanism of action of cisplatin as Some of the current thinking on the chemical basis for the mechanism of action of cisplatin as an anticancer drug is summarized below:

an anticancer drug is summarized below: In 2000, Pe´rez *et. al.* [46], were able to report the first crystal structure of a biologically active *trans*-platinum compound *trans*-[PtCl2(dimethylamine)(isopropylamine) containing different

10

In 2000, Pe´rez et.al. [46], were able to report the first crystal structure of a biologically active

Pt drug Active Pt

e.g. hydrolysis

GSH M T

Activation

Inactivation Resistance

Complex

A summary of some of the processes that are thought to be involved in the cytotoxicity of platinum anticancer agents

Pt

Shield from repair (HMG)

> Repair Excision

DNA Adduct

Resistance

Pt

Apotosis cell death

Not Repair

trans-platinum compound trans-[PtCl2(dimethylamine)(isopropylamine) containing different

aliphatic amines where trans-PtCl2(dimethylamine)-(isopropylamine)] readily form DNA inter-

Oxaliplatin

an anticancer drug is summarized below:

Pt

H3N HN

OCOCH<sup>3</sup>

JM216

AMD473

OCOCH<sup>3</sup> Cl Cl

platinum anticancer agents **Figure 1.** A summary of some of the processes that are thought to be involved in the cytotoxicity of platinum anticanc‐ er agents

A summary of some of the processes that are thought to be involved in the cytotoxicity of

aliphatic amines where *trans*-PtCl2(dimethylamine)-(isopropylamine)] readily form DNA inter-stand crosslinks. In 2000, Pe´rez et.al. [46], were able to report the first crystal structure of a biologically active trans-platinum compound trans-[PtCl2(dimethylamine)(isopropylamine) containing different

Transplatin traCC)(Cisopropy Transplatin lamincce)

11

In 2014, Obaleye and co-workers synthesized and characterized a novel –M–X–M–X– type

infinite chain 1D Cu(II) complex with eflornithine hydrochloride hydrate as ligand where their

biological evaluation were examined and the results of the antibacterial screening show

appreciable activity of the metal-drug complexes compared to the ligand when challenged with

But in the year 2003, Ramos-Lima et al, were able to replace two amine groups of transplatin with aliphatic amine and phosphane group, which resulted in circumvention of cisplatin But in the year 2003, Ramos-Lima *et al*, were able to replace two amine groups of transplatin with aliphatic amine and phosphane group, which resulted in circumvention of cisplatin resistance [47-48].

The synthesis pathway for the novel complexes is shown below;

resistance [47-48]. The synthesis pathway for the novel complexes is shown below; resistance [47-48]. Perception and Resistance Mechanism of some Metal-drug Complexes and Their Roles as Antibacterial http://dx.doi.org/10.5772/61033 37

But in the year 2003, Ramos-Lima et al, were able to replace two amine groups of transplatin

with aliphatic amine and phosphane group, which resulted in circumvention of cisplatin

The synthesis pathway for the novel complexes is shown below;

Trans-[PtCl2(dimethylamine)(isopropylamine)]

Transplatin traCC)(Cisopropy Transplatin lamincce)

In 2014, Obaleye and co-workers synthesized and characterized a novel –M–X–M–X– type infinite chain 1D Cu(II) complex with eflornithine hydrochloride hydrate as ligand where their biological evaluation were examined and the results of the antibacterial screening show In 2014, Obaleye and co-workers synthesized and characterized a novel –M–X–M–X– type infinite chain 1D Cu(II) complex with eflornithine hydrochloride hydrate as ligand where their biological evaluation were examined and the results of the antibacterial screening show appreciable activity of the metal-drug complexes compared to the ligand when challenged with test organisms at varying concentrations. Copper complex was effective at virtually all concentrations used except against *E. coli* and *P. aeruginosa* at 0. 0001 gL-1 [49]. test organisms at varying concentrations. Copper complex was effective at virtually all concentrations used except against E. coli and P. aeruginosa at 0.0001 gL-1 [49]. Highest susceptibility to Copper complex was recorded by S. aureus with clearance zone of 4.2 mm at 1.0 gL-1. The results show that the metal-drug complex possesses a measure of

appreciable activity of the metal-drug complexes compared to the ligand when challenged with Highest susceptibility to Copper complex was recorded by S. aureus with clearance zone of 4. 2 mm at 1. 0 gL-1. The results show that the metal-drug complex possesses a measure of antibacterial activity against all the organisms tested. The results also agree with the findings of other researchers [50-51] that antibacterial potency is usually concentration dependent. antibacterial activity against all the organisms tested. The results also agree with the findings of other researchers [50-51] that antibacterial potency is usually concentration dependent. The data also revealed that the activity of the Ligand EFL was bacteriostatic against all the

11 The data also revealed that the activity of the Ligand EFL was bacteriostatic against all the organisms tested, while the activity of the copper (II) complex was bacteriostatic against *E. coli* and *P. aeruginosa* but bactericidal against S. aureus at 0. 0001 g/L concentration. organisms tested, while the activity of the copper (II) complex was bacteriostatic against E. coli and P. aeruginosa but bactericidal against S. aureus at 0.0001 g/L concentration.

#### **The Scheme of the reaction is shown below:** The Scheme of the reaction is shown below:

For a couple of years now, some bacteria are becoming resistant to antibiotic drugs during this

#### era of chemotherapy. This has been the main cause of morbidity and mortality worldwide. Many **5. Conclusion**

Conclusion

aliphatic amines where *trans*-PtCl2(dimethylamine)-(isopropylamine)] readily form DNA

trans-platinum compound trans-[PtCl2(dimethylamine)(isopropylamine) containing different

aliphatic amines where trans-PtCl2(dimethylamine)-(isopropylamine)] readily form DNA inter-

In 2000, Pe´rez et.al. [46], were able to report the first crystal structure of a biologically active

**Figure 1.** A summary of some of the processes that are thought to be involved in the cytotoxicity of platinum anticanc‐

Pt drug Active Pt

e.g. hydrolysis

GSH M T

Activation

Inactivation Resistance

Complex

A summary of some of the processes that are thought to be involved in the cytotoxicity of platinum anticancer agents

Pt

Some of the current thinking on the chemical basis for the mechanism of action of cisplatin as

H3N HN

OCOCH<sup>3</sup>

JM216

Pt

Shield from repair (HMG)

> Repair Excision

DNA Adduct

Resistance

Pt

Apotosis cell death

AMD473

Not Repair

OCOCH<sup>3</sup> Cl Cl

Trans-[PtCl2(dimethylamine)(isopropylamine)]

10

Transplatin traCC)(Cisopropy Transplatin lamincce)

But in the year 2003, Ramos-Lima *et al*, were able to replace two amine groups of transplatin with aliphatic amine and phosphane group, which resulted in circumvention of cisplatin

The synthesis pathway for the novel complexes is shown below;

11

In 2014, Obaleye and co-workers synthesized and characterized a novel –M–X–M–X– type

infinite chain 1D Cu(II) complex with eflornithine hydrochloride hydrate as ligand where their

biological evaluation were examined and the results of the antibacterial screening show

appreciable activity of the metal-drug complexes compared to the ligand when challenged with

But in the year 2003, Ramos-Lima et al, were able to replace two amine groups of transplatin

with aliphatic amine and phosphane group, which resulted in circumvention of cisplatin

inter-stand crosslinks.

stand crosslinks.

Resistance

×

Reduce Pt Uptake

Resistance

er agents

an anticancer drug is summarized below:

36 Concepts, Compounds and the Alternatives of Antibacterials

Oxaliplatin

Pt-SG

resistance [47-48].

resistance [47-48].

The synthesis pathway for the novel complexes is shown below;

reasons had been attached to this drug resistance of the organism.Some of these proposed reasons are (i) the over-prescription of the drugs by physicians,(ii) self-medication, (iii) premature discontinuity of the medication by the patients as they start to regain strength and (iv) difficulty in affording the full course of the therapy. Other factors such as the transmission of the drug-resistant organism among patients through air or by direct contact with contaminated person or environment have been identified. It is also attested that a long period is usually For a couple of years now, some bacteria are becoming resistant to antibiotic drugs during this era of chemotherapy. This has been the main cause of morbidity and mortality worldwide. Many reasons had been attached to this drug resistance of the organism. Some of these proposed reasons are (i) the over-prescription of the drugs by physicians,(ii) self-medication, (iii) premature discontinuity of the medication by the patients as they start to regain strength and (iv) difficulty in affording the full course of the therapy. Other factors such as the trans‐ mission of the drug-resistant organism among patients through air or by direct contact with contaminated person or environment have been identified. It is also attested that a long period is usually needed to complete the treatment of individuals infected by the organisms. Modes

12

of action of some of the potent antibiotic drugs are sometimes tagged as unknown. Hence, there is urgent need for continuous research in the development of drugs in order to have more effective drugs than the already available less potent drugs that will combat these dangerous microbes.

Although several metal-drug complexes have been synthesized to date, there are few of them at the final clinical stage due to their resistance capacity. Many researches are ongoing to circumvent this drug resistance, from this review, it is clear that some of the existing organic ligands or their derivatives are observed to be more potent when complexed with metals. These metal-drug complexes are *in vitro* and *in vivo* efficient.

In the aspect of antimalarial, antitumor, and anticancer drugs, more profitable researches are gradually emerging, yielding positive products with decent potency, stability, and reduced side effects. In this review resistance mechanisms of some synthesized metal-drug complexes were highlighted based on the investigations of various researchers.

## **Acknowledgements**

The authors are grateful to Science and Technology Education Post–Basic Project (Step B) for their support and the University of Ilorin and for awarding of a Senate Rresearch grant.

## **Author details**

Joshua A. Obaleye1\*, Nzikahyel Simon2 , Olufunso O. Abosede1 , Mercy O. Bamigboye3 , Abiodun A. Ajibola1 , Uche B. Eke1 and Elizabeth A. Balogun4

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

2 Department of Chemistry, University of Uyo, Uyo, Akwa Ibom State, Nigeria

3 Department of Industrial Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

4 Department of Biochemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

## **References**

[1] Saeed, A.; Najma, S.; Urooj, H.; and Ahmed Mesaik, M. (2009) Synthesis, characteri‐ zation, antibacterial and anti-inflammatory activities of Enoxacin metal complexes. Bioinorganic chemistry and applications BioinorgChem Appl.,2009 : 6.

of action of some of the potent antibiotic drugs are sometimes tagged as unknown. Hence, there is urgent need for continuous research in the development of drugs in order to have more effective drugs than the already available less potent drugs that will combat these dangerous

Although several metal-drug complexes have been synthesized to date, there are few of them at the final clinical stage due to their resistance capacity. Many researches are ongoing to circumvent this drug resistance, from this review, it is clear that some of the existing organic ligands or their derivatives are observed to be more potent when complexed with metals. These

In the aspect of antimalarial, antitumor, and anticancer drugs, more profitable researches are gradually emerging, yielding positive products with decent potency, stability, and reduced side effects. In this review resistance mechanisms of some synthesized metal-drug complexes

The authors are grateful to Science and Technology Education Post–Basic Project (Step B) for their support and the University of Ilorin and for awarding of a Senate Rresearch grant.

, Olufunso O. Abosede1

and Elizabeth A. Balogun4

, Mercy O. Bamigboye3

,

metal-drug complexes are *in vitro* and *in vivo* efficient.

38 Concepts, Compounds and the Alternatives of Antibacterials

were highlighted based on the investigations of various researchers.

microbes.

**Acknowledgements**

**Author details**

Abiodun A. Ajibola1

**References**

Joshua A. Obaleye1\*, Nzikahyel Simon2

, Uche B. Eke1

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

2 Department of Chemistry, University of Uyo, Uyo, Akwa Ibom State, Nigeria

4 Department of Biochemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

3 Department of Industrial Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria

[1] Saeed, A.; Najma, S.; Urooj, H.; and Ahmed Mesaik, M. (2009) Synthesis, characteri‐ zation, antibacterial and anti-inflammatory activities of Enoxacin metal complexes.

Bioinorganic chemistry and applications BioinorgChem Appl.,2009 : 6.

[35] Biot, C.; Tarameli, D.; Forfar-Bares, I.; Maciejewski, L. A.; Boyce, M.; Nowogrocki, G.; Brocard, J. S.; Basilico, N.; Olliaro, P., Egan T. J. (2005) Mol. Pharm. 2:185–193. [PubMed: 15934779]

[18] Sanchez-Delgado, R. A.; and Anzellotti, A. (2004) Metal complexes as chemothera‐ peutic agents against tropical diseases: trypanosomiais, malaria and leishmaniasis.

[19] Sharma, V. (2005) Therapeutic drugs for targeting chloroquine resistance in malaria.

[20] Navarro, M. (2009) Gold complexes as potential anti-parasitic agents. Coord. Chem.

[22] Sánchez-Delgado, R. A.; Navarro, M.; Perez, H.; Urbina, J. A. (1996) J. Med. Chem.

[24] Navarro, M.; Vasquez, F.; Sánchez-Delgado, R. A.; Perez, H.; Sinou, V.; Schrevel, J.

[25] Navarro M.; Castro W.; Martínez A., Sánchez Delgado R. A. (2011); J. Inorg. Biochem.

 Agents Chemother.

 Chemother., 48, 179.

Smith, P. J.; Su, H. (2003) Dalton Trans., 15, 3046.

[34] Biot, C. (2004) Curr Med Chem Anti-Infect Agents; 3:135–147.

[23] Navarro, M.; Perez, H.; Sánchez-Delgado, R. A. (1997). J. Med. Chem. 40, 1937.

Mini Rev. Med. Chem. 4, 23–30

40 Concepts, Compounds and the Alternatives of Antibacterials

Mini Rev. Med. Chem. 5, 337–351

(2004). J. Med. Chem. 47, 5204.

Delgado, R. A. (2009) Inorg. Chem., 48, 1122.

[21] Rev. 253, 1619–1626

39, 1095.

105, 276–282

3715.

42, 540.

D. J. Med. Chem., 49, 4707.

Bioorg. Med. Chem., 15, 6510.

J. Chem. Soc., Dalton Trans., 23, 4426.

**Section 2**

## **The Compounds**

[49] Francisco, J.; Ramos-Lima, A.; Quiroga, G.; Pe´rez, J. M.; Font-Bardı´a M, Solans X.;

[50] Obaleye, J. A.; Tella, A. C.; Osunniran, W. A; Simon, N.; Omojasola, P. F; (2014). Syn‐ thesis, Characterization, Crystal Structure and Antimicrobial Evaluation of a Novel – M–X–M–X– Type Infinite Chain 1D Cu(II) Complex with Eflornithine Hydrochloride

and Navarro-Ranninger C. (2003) Eur. J. Inorg. Chem., 1591-1598.

[51] Ekwenye, U. N.; Elegalam, N. N. (2005), J. Mol. Med. Adv. Sci. 1(4), 410.

[52] Omojasola P. F.; and Awe S. (2004), Biosci. Res. Comm. 16, 25.

Hydrate as Ligand. 24: 827-835.

42 Concepts, Compounds and the Alternatives of Antibacterials

## **Quinolone Compounds with Activity Against Multidrug-Resistant Gram-Positive Microorganisms**

## Pintilie Lucia

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60948

#### **Abstract**

The emergence of resistance to antimicrobial agents is a global public health problem. Some microorganisms may develop resistance to a single antimicrobial agent (or related class of agent), while others develop resistance to several antimicrobial agents or classes. These organisms are often referred to as multidrug-resistant or MDR strains. Identification of new molecules that show activity against multidrug-resistant microorganisms and its development on a new antimicrobial drug, would be an important step in the fight against antimicrobial resistance. This paper presents experimental data regarding the synthesis of several quinolones. The novel com‐ pounds having quinolone structure were synthesized by Gould-Jacobs method. Their structure has been determined and confirmed by the following physicochemical methods: elemental analysis, IR spectral analysis, H-NMR, C-NMR, UV, thin layer chromatography. The new compounds have been evaluated for "in vitro" activity by determining minimum inhibitory concentration against a variety of bacteria Some of new quinolones, which showed a good activity, have been tested against 30 strains of methicillin resistant Staphylococcus aureus isolated in the Microbiology Laboratory of INBI Prof. "Dr. Matei Bals" during 2012 The minimum inhibitory concentration (MIC) of the isolates have been determined by agar plate Mueller Hinton (bioMerieux) dilution method using the reference strain Staphylococcus aureus ATCC 29213. The 30 strains of isolated have been also tested for susceptibility to ciprofloxacin, levofloxacin and imipenem by Etest method. Base on the "in vitro" studies, the quinolone FPQ-30 appears to be an promising compound, all strains isolates were inhibited at a concentration of 8 μg/ml.

**Keywords:** Quinolones, fluoroquinolones, antimicrobial agents, Methicillin-resistant Sthaphilococcus aureus

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

The emergence of resistance to antimicrobial agents is a global public health problem. Some microorganisms may develop resistance to a single antimicrobial agent (or a related class of agents), while others develop resistance to several antimicrobial agents or classes. These organisms are often referred to as multidrug-resistant or MDR strains. Identification of new molecules that show activity against multidrug-resistant microorganisms and its development into a new antimicrobial drug would be an important step in the fight against antimicrobial resistance.

The discovery of fluoroquinolones after 1980 represented a decisive step forward for chemical anti-infectious therapy. A large number of fluoroquinolones are used today in medical practices and some of them are deemed by leading pharmacologists to be of vital importance to anti-infectious therapy.

## **2. Tendencies and strategies in the field of quinolones**

The basic structure of quinolones (Figure 1) [9], is a bicyclic structure that contains a ring type A 4-pyridinone combined with an aromatic or heteroaromatic ring B. According to the nature of atoms symbolized by X, Y, Z, they can be defined as four subfamilies: naphthyridine 1-8, cinnoline, pyrido-2,3-pyrimidines, and quinolone.

naphthyridines : X=Z=H; Y=N cinnolin: X=N; Y=Z=H pyrido-2,3-pyrimidine: X=H; Y=Z=N quinolones : X=Y=Z= H

**Figure 1.** Basic structure of quinolones.

The structural modifications of the core of the quinolone influence the antimicrobial activity

#### **2.1. Position 1**

Research has been oriented in several directions:

**1. Introduction**

46 Concepts, Compounds and the Alternatives of Antibacterials

resistance.

to anti-infectious therapy.

naphthyridines : X=Z=H; Y=N cinnolin: X=N; Y=Z=H

quinolones : X=Y=Z= H

**2.1. Position 1**

pyrido-2,3-pyrimidine: X=H; Y=Z=N

**Figure 1.** Basic structure of quinolones.

Research has been oriented in several directions:

The emergence of resistance to antimicrobial agents is a global public health problem. Some microorganisms may develop resistance to a single antimicrobial agent (or a related class of agents), while others develop resistance to several antimicrobial agents or classes. These organisms are often referred to as multidrug-resistant or MDR strains. Identification of new molecules that show activity against multidrug-resistant microorganisms and its development into a new antimicrobial drug would be an important step in the fight against antimicrobial

The discovery of fluoroquinolones after 1980 represented a decisive step forward for chemical anti-infectious therapy. A large number of fluoroquinolones are used today in medical practices and some of them are deemed by leading pharmacologists to be of vital importance

The basic structure of quinolones (Figure 1) [9], is a bicyclic structure that contains a ring type A 4-pyridinone combined with an aromatic or heteroaromatic ring B. According to the nature of atoms symbolized by X, Y, Z, they can be defined as four subfamilies: naphthyridine 1-8,

O

R

The structural modifications of the core of the quinolone influence the antimicrobial activity

X N

3

2

1

CO2H

**2. Tendencies and strategies in the field of quinolones**

Z

6

7

Y

8

B A

5 4

cinnoline, pyrido-2,3-pyrimidines, and quinolone.

Usually, the most active compounds contain the ethyl substituent in position 1. Using a STERIMOL program, Fujita (1984), based on a set of five parameters that characterize the shape and size of a substituent and following a quantitative analysis of the relationship between chemical structure and biological activity on a set of N-1 allyl and alkyl derivatives have deduced the optimum length of the substituent in position 1 is 0.42 nm [9, 58], which corre‐ sponds to the ethyl substituent. In general, the most active components contain in position 1 an ethyl substituent. These studies have already been confirmed by the results achieved with quinolones that are used in therapeutic practice: nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, quinolones that have an ethyl substituent in N-1 position.

In Table 1 is presented the antimicrobial activity for the 1-substituted quinolones against gram positive and gram negative microorganisms. By comparison, data are entered for norfloxacin (R1 = ethyl) and ciprofloxacin (R1 = c-C3H5).

Replacing ethyl substituent with:

In series N-1 cyclopropyl (ciprofloxacin), the substituent from N-1 position has a larger volume than the ethyl. This is contrary to the concept of the steric volume. High antimicrobial activity of the ciprofloxacin may be caused by this hyperconjugation or self-association properties induced by the cyclopropyl. For compounds that present in this position, a cycloalkyl with a number of carbon atoms of more than 3 (cyclobutyl, cyclopentyl) the antimicrobial activity is much reduced compared to ciprofloxacin.

The following are relevant for the chemical structure–biological activity relationships:

Relevant for the chemical structure–biological activity relationships are to:

**Figure 2.** Quinolones with an aliphatic substituent in N-1 position.

**•** The nature of the substituent introduced in the alkyl moiety at N-1 position of quinolone:

**•** The position where the substituents are introduced in the alkyl moiety: substituents in

**•** The number of substituents placed on the alkyl moiety: increasing the number of substitu‐

**•** Presence of cis-trans stereoisomers: cis derivatives are more active against gram positive bacteria than the trans derivatives, while the activity is comparable against gram negative

**•** Nature of the substituent introduced in the alkyl moiety at N-1 position of quinolone: the

**•** The position where the substituents are introduced in the alkyl moiety: substituents in

**•** The number of substituents placed on the alkyl moiety: increasing the number of substitu‐

**•** Presence of cis-trans stereoisomers: cis derivatives are more active against gram positive bacteria than the trans derivatives, while the activity is comparable against gram negative

N

R1

**(μg/ml) Reference**

O

CO2HF

position 1 of the alkyl moiety have positive influence on antimicrobial activity;

N

**Minimum inhibitory concentration**

*S. aureus E. coli P. aeruginosa* -CH3 6.25 0.39 1.56 (Koga et al. 1980) -C2H5 (Norfloxacin) 0.39 0.05 0.39 (Koga et al. 1980) -CH=CH2 3.13 0.10 0.39 (Koga et al. 1980) n-C3H7 1.56 0.20 3.13 (Koga et al. 1980)

HN

**Figure 2.** Quinolones with an aliphatic substituent in N-1 position.

position 1 of the alkyl moiety have positive influence on antimicrobial activity;

the fluorine atom has benefic influence on the antimicrobial activity;

Relevant for the chemical structure–biological activity relationships are to:

fluorine atom has benefic influence on the antimicrobial activity;

ents leads to decreased antimicrobial activity;

48 Concepts, Compounds and the Alternatives of Antibacterials

ents leads to decreased antimicrobial activity;

bacteria.

bacteria.

**R1**

**Table 1.** MIC values (μg/ml) for quinolones with an aliphatic substituent in N-1 position