**1. Introduction**

Due to the global increase in aging, the elderly population is constantly growing [1]. During the period 2015–2030, the elderly population is expected to grow from 901 million to 1.4 billion people (by 56%), and the 2015 population is expected to double by 2050 [2].

This increase in the elderly population is already placing substantial extra strain on healthcare and support services [3], increasing the costs due to health-related complications [4].

Among the main concerns linked to age, malnutrition is a common health problem in people older than 65 [5]; in fact, nutritional fragility is a frequent condition in vulnerable elderly people and is related to an increased incidence of mortality in this population [6]. Moreover, it is often associated with a reduced adaptive response to physiological and pathological conditions [7]; for instance, the elderly population experiences a physiological loss of taste, which impacts the frailty condition. Assessment of nutritional status through

**Citation:** Liquori, G.; De Leo, A.; De Nuzzo, D.; D'Inzeo, V.; Arancio, R.M.; Di Simone, E.; Dionisi, S.; Giannetta, N.; Ricciardi, F.; Fabbian, F.; et al. Management Strategies and Nursing Activities for Nutritional Care in Hospitalized Patients with Cognitive Decline: A Scoping Review. *Nutrients* **2022**, *14*, 4036. https://doi.org/ 10.3390/nu14194036

Academic Editors: Alessandra Durazzo and Massimo Lucarini

Received: 9 August 2022 Accepted: 26 September 2022 Published: 28 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

anthropometric measurements in these patients is essential to ensure healthy aging and adequate food intake [8].

Malnutrition has a negative impact on both people living independently and, overall, on those admitted to healthcare facilities, affecting up to 60% of hospitalized older adults [9]. In fact, according to estimates, up to 50% of patients are undernourished when they are admitted, increasing their malnutrition while being treated in a hospital [10]. This issue is linked to lengthier hospital stays, increased morbidity (pressure ulcers, infections, and falls), and mortality, especially in patients affected by chronic diseases [11,12].

In elderly people with cognitive impairment, the phenomenon is also more serious, since malnutrition irreversibly worsens other health conditions [13].  The relationships between nutritional status, cognitive decline, and performance are complex and reciprocal: the presence or the risk of malnutrition may influence cognitive performance, and the presence of cognitive decline may affect the activities of daily living (ADL), also affecting food intake [16].

Unfortunately, malnutrition is also a frequently underdiagnosed entity, capable of subtly impacting patient outcomes, length of stay, hospital costs, and readmissions [9]. Recent studies suggest the crucial role of nurses in preventing, assessing, and treating malnutrition in this fragile population [2,7]. One of the possible key points could be implementing all known strategies to avoid worsening nutritional status, improving health status, and reducing mortality risk [17].

Therefore, this scoping review was targeted at evaluating the relationship between nursing activities and the identification, prevention, and management of malnutrition among hospitalized elderly individuals with cognitive impairment. In particular, our aims were collecting best practice and scientific evidence with regard to: (i) risk factors for developing low food intake in hospitalized older patients with cognitive impairment; (ii) prevalence of malnutrition in older patients with cognitive impairment; (iii) identify the nursing strategies to enhance clinical outcomes and care of patients with cognitive impairment in the hospital environments.


The term Solvent-less and solvent-free extraction have been used as synonymous with each other. Extraction of essential oil using these methods has a number of advantages such as fast action, cleanliness, green method, low energy output as compared to traditional extraction method. However, microwave extraction needs extra care before use as it may cause some negative effect on human health. There are many opportunities and modification possible in term of purification of essential oil by applying in combination with other extraction technique.

## **Author details**

Muhammad Shahzad Aslam1,2\*, Muhammad Syarhabil Ahmad1 and Sarwat Ali Raja3 [11] Nasshorudin D, Ahmad MS, Mamat AS. Novel closed system extraction of essential oil:

Solventless Extraction of Essential Oil http://dx.doi.org/10.5772/intechopen.72401 47

[12] Ahmad MS, Nasshorudin D, Mamat AS. Novel closed system extraction of essential oil: Impact on yield and physical characterization muhammad. 2nd International

[13] Nasshorudin D, Ahmad MS, Mamat AS, Rosli S. Optimization study of *Chromalaena odorata* essential oil extracted using solventless extraction technique. AIP Conference

[14] Lucchesi ME, Chemat F, Smadja J. An original solvent free microwave extraction of essential oils from spices. Flavour and Fragrance Journal. Mar. 2004;**19**(2):134-138 [15] Lucchesi ME, Chemat F, Smadja J. Solvent-free microwave extraction of essential oil from aromatic herbs: Comparison with conventional hydro-distillation. Journal of

[16] Wang Z et al. Improved solvent-free microwave extraction of essential oil from dried *Cuminum cyminum* L. and *Zanthoxylum bungeanum* maxim. Journal of Chromatography.

[17] Wang Z et al. Rapid analysis of the essential oils from dried Illicium Verum Hook. f. And Zingiber Officinale Rosc. By improved solvent-free microwave extraction with three types of microwave-absorption medium. Analytical and Bioanalytical Chemistry. Nov.

[18] Michel T, Destandau E, Elfakir C.Evaluation of a simple and promising method for extraction of antioxidants from sea buckthorn (*Hippophaë rhamnoides* L.) berries: Pressurised

solvent-free microwave assisted extraction. *Food Chemistry*. 2011;**126**(3):1380-1386 [19] Farhat A, Fabiano-Tixier AS, Visinoni F, Romdhane M, Chemat F. A surprising method for green extraction of essential oil from dry spices: Microwave dry-diffusion and grav-

[20] Lucchesi ME, Smadja J, Bradshaw S, Louw W, Chemat F. Solvent free microwave extraction of Elletaria cardamomum L.: A multivariate study of a new technique for the extrac-

[21] Qi XL et al. Solvent-free microwave extraction of essential oil from pigeon pea leaves [*Cajanus cajan* (L.) Millsp.] and evaluation of its antimicrobial activity. Industrial Crops

[22] Ma CH, Yang L, Zu YG, Liu TT. Optimization of conditions of solvent-free microwave extraction and study on antioxidant capacity of essential oil from *Schisandra chinensis*

[23] Uysal B, Sozmen F, Aktas O, Oksal BS, Kose EO. Essential oil composition and antibacterial activity of the grapefruit (*Citrus Paradisi*. L) Peel essential oils obtained by solventfree microwave extraction: Comparison with hydrodistillation. International Journal of

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\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
1 School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, Malaysia

#### **References**

[11] Nasshorudin D, Ahmad MS, Mamat AS. Novel closed system extraction of essential oil: A green approach. American Journal of Biochemistry. 2016;**6**(6):145-148

**Author details**

46 Green Chemistry

Malaysia

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Muhammad Shahzad Aslam1,2\*, Muhammad Syarhabil Ahmad1

2 Rashid Latif College of Pharmacy, Lahore, Pakistan

\*Address all correspondence to<EMAIL_ADDRESS>
3 Lahore Pharmacy College, (A project of LMDC), Lahore, Pakistan

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1 School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Arau, Perlis,

[1] Tongnuanchan P, Benjakul S. Essential oils: Extraction, bioactivities, and their uses for

[2] Cook CM, Lanaras T. The Encyclopedia of Food and Health. Chapter: Essential Oils: Isolation, Production and Uses. In: Cabballero B, Finglas P, Toldra F, editors. Academic

[3] Cavanagh HMA, Wilkinson JM. Biological activities of lavender essential oil. Phyto-

[4] Sharma PR et al. Anticancer activity of an essential oil from *Cymbopogon flexuosus*.

[5] Kumar Tyagi A et al. Eucalyptus essential oil as a natural food preservative: *In Vivo* and

[6] Gonçalves ND et al. Encapsulated thyme (*Thymus vulgaris*) essential oil used as a natural preservative in bakery product. Food Research International. 2017;**96**:154-160

[7] Tzortzakis NG, Economakis CD. Antifungal activity of lemongrass (*Cympopogon citratus* L.) essential oil against key postharvest pathogens. Innovative Food Science & Emerging

[8] Kedia A, Prakash B, Mishra PK, Dubey NK. Antifungal and antiaflatoxigenic properties of *Cuminum cyminum* (L.) seed essential oil and its efficacy as a preservative in stored

[9] Diao W-R, Hu Q-P, Zhang H, Xu J-G. Chemical composition, antibacterial activity and mechanism of action of essential oil from seeds of fennel (*Foeniculum vulgare* mill.). Food

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**Section 3**

**Pharmaceutical Green Chemistry**

**Pharmaceutical Green Chemistry**

[24] Riela S et al. Effects of solvent-free microwave extraction on the chemical composition of essential oil of *Calamintha nepeta* (L.) Savi compared with the conventional production

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[27] Chen X, Zhang Y, Zu Y, Fu Y, Wang W. Composition and biological activities of the essential oil from *Schisandra chinensis* obtained by solvent-free microwave extraction.

[28] Paroul N et al. Solvent-free production of bioflavors by enzymatic esterification of citronella (*Cymbopogon winterianus*) essential oil. Applied Biochemistry and Biotechnology.

[29] Filly A, Fernandez X, Minuti M, Visinoni F, Cravotto G, Chemat F. Solvent-free microwave extraction of essential oil from aromatic herbs: From laboratory to pilot and indus-

[30] Li Y, Fabiano-Tixier AS, Vian MA, Chemat F. Solvent-free microwave extraction of bioactive compounds provides a tool for green analytical chemistry. TrAC, Trends in

[31] Okoh OO, Sadimenko AP, Afolayan AJ. Comparative evaluation of the antibacterial activities of the essential oils of *Rosmarinus officinalis* L. obtained by hydrodistillation and solvent free microwave extraction methods. Food Chemistry. 2010;**120**(1):308-312

[32] Périno-Issartier S, Zill-e-Huma, Abert-Vian M, Chemat F. Solvent free microwaveassisted extraction of antioxidants from sea buckthorn (*Hippophae rhamnoides*) food by-

[33] Azar A, Torabbeigi, Sharifan, Tehrani. Chemical composition and antibacterial activity of the essential oil of lavandula angustifolia isolated by solvent free microwave assisted extraction and hydrodistillation. Journal of Food Biosciences and Technology.

products. Food and Bioprocess Technology. 2011;**4**(6):1020-1028

evaluation of antioxidant activity. Food Chemistry. 2012;**133**(2):437-444

method. Journal of Separation Science. 2008;**31**(6-7):1110-1117

LWT- Food Science and Technology. 2011;**44**(10):2047-2052

trial scale. Food Chemistry. May 2014;**150**:193-198

Analytical Chemistry. 2013;**47**:1-11

2016;**10**(2):213-218

48 Green Chemistry

2012;**166**(1):13-21

2011;**1**:19-24

**Chapter 4**

**Provisional chapter**

**Green Chemistry and Synthesis of Anticancer**

**Green Chemistry and Synthesis of Anticancer**

DOI: 10.5772/intechopen.70419

Green chemistry is a modern area of chemistry merged with chemical engineering methods. It highlighted the synthesis of molecules in a manner of using environment-friendly chemical reagents with low waste material for enhancing environmental performance which reduce the formation of hazard substances. Modern researches are trying to reduce the risk of human kind health and the environment of our world by doing magnificent work in the field of green chemistry. In the pharmaceutical field, green chemistry works very well with the formation of many drugs and it utilizes non-hazards, reproducible and environment-friendly solvents with low time and money costs by using catalyst, microwave, ultrasonic, solid phase and solvent-free synthesis. Until now, scientist has synthesized many anticancer molecules by using these modern green chemistry techniques. These compounds showed significant anticancer activities against many human cancer cell lines. In this chapter, we will cover different views and the recently published literature to summarize the role of green chemistry in the synthesis of anticancer

**Keywords:** green synthetic approaches, anticancer activity, synthesis of active molecules,

© 2016 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,

© 2018 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.

and reproduction in any medium, provided the original work is properly cited.

Green chemistry is a modern way for the synthesis of organic compounds and designed different drugs under facile protocols, efficient conditions, environmentally benign and high yielding method of molecules with advantages over traditional organic synthetic methods. It usually reduces waste by-products, costs and develops environmentally friendly procedures.

Shagufta Perveen and Areej Mohammad Al-Taweel

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Shagufta Perveen and Areej Mohammad

http://dx.doi.org/10.5772/intechopen.70419

**Molecules**

**Abstract**

compounds.

cancer cell lines

**1. Introduction**

Al-Taweel

**Molecules**

**Provisional chapter**

#### **Green Chemistry and Synthesis of Anticancer Molecules Molecules**

**Green Chemistry and Synthesis of Anticancer**

DOI: 10.5772/intechopen.70419

Shagufta Perveen and Areej Mohammad Al-Taweel Al-Taweel

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Shagufta Perveen and Areej Mohammad

http://dx.doi.org/10.5772/intechopen.70419

#### **Abstract**

Green chemistry is a modern area of chemistry merged with chemical engineering methods. It highlighted the synthesis of molecules in a manner of using environment-friendly chemical reagents with low waste material for enhancing environmental performance which reduce the formation of hazard substances. Modern researches are trying to reduce the risk of human kind health and the environment of our world by doing magnificent work in the field of green chemistry. In the pharmaceutical field, green chemistry works very well with the formation of many drugs and it utilizes non-hazards, reproducible and environment-friendly solvents with low time and money costs by using catalyst, microwave, ultrasonic, solid phase and solvent-free synthesis. Until now, scientist has synthesized many anticancer molecules by using these modern green chemistry techniques. These compounds showed significant anticancer activities against many human cancer cell lines. In this chapter, we will cover different views and the recently published literature to summarize the role of green chemistry in the synthesis of anticancer compounds.

**Keywords:** green synthetic approaches, anticancer activity, synthesis of active molecules, cancer cell lines

#### **1. Introduction**

Green chemistry is a modern way for the synthesis of organic compounds and designed different drugs under facile protocols, efficient conditions, environmentally benign and high yielding method of molecules with advantages over traditional organic synthetic methods. It usually reduces waste by-products, costs and develops environmentally friendly procedures.

© 2016 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. © 2018 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.

Cellulose-supported

copper nanoparticlecatalyzed click

in the presence of K2CO3

to yield 4-*O*-propargylated benzaldehyde. In the next

step, 4-*O*-propargylated benzaldehyde was reacted with

substituted acetophenones via base-catalyzed Claisen-

Schmidt condensation to yield chalcones

Functionalized pyrazolopyridine derivatives via

Novel pyrazolo, pyridine derivatives (**6**)

Human A549 lung

[6]

adenocarcinoma, MCF-7

breast carcinoma cell line,

HCT-116 colon cancer, PC-3

prostate cancer

copper-promoted cyclization of pyridyl acetates and

benzonitriles in DMSO under argon atmosphere,

converted to corresponding pyrazolo[1, 5-a]pyridines

from commercially available aromatic nitriles and

various pyridyl acetates

Quinolone derivatives were synthesized by reacting

Pyrazolo[4,3-c] quinoline (5a-i,

Human MCF-7 breast and

[7]

A549 lung cancer

7a-b) and pyrano[3,2-c] quinoline

derivatives (**7**)

2,3-dihydro-8-nitro-4-quinolones with aromatic

aldehydes by pyrrolidine base-catalyzed condensation

reaction and were treated with hydrazine derivatives

under MW condition, which afforded pyrazolo quinoline

Synthetic route to barbituric acid derivatives substituted

Pyrimidine-2,4,6-trione derivatives (**8**)

HeLa cervical cancer and

[8]

3T3 mouse fibroblast cancer

at C5-position. Addition of barbituric acid analogous

into nitrostyrene, in water mediated by diethylamine as

base gave the target 5-monoalkylbarbiturates in excellent

derivatives in high yields

Facile protocol,

efficient and

environmentally

benign

yield

Simple, eco-friendly

To synthesize α,β-unsaturated carbonyl-based

α,β-unsaturated carbonyl-based

PC12 cancer

[9]

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 53

compounds (**9**)

compounds, Claisen-Schmidt condensation was used

between different ketones and suitable aryl aldehydes in

the presence of NaOH in ethanol

and efficient method

Microwave

conditions

in dry acetone under reflux

reaction in water

Copper-mediated

synthesis

**Reaction condition**

4-hydroxybenzaldehyde treated with propargyl bromide

**Class of compounds synthesized**

Chalcone-linked 1,2,3-triazoles (**5**)

**Cancer cell lines**

Human MCF-7, MIA-Pa-Ca-2,A549, HepG2 cancer

[5]

Eco-friendly one-pot

synthesis

**Reaction condition**

Mixture of methyl ketone, aldehyde, active methylene

cyanoacetamide, malononitrile, ethylcyanoacetate and

2 mL of glycol/ammonium acetate was added to the

reaction vessel and placed into MW reactor then allowed

to react under MW irradiation at 200–400

and 120°C for 6–8

by filtration and recrystallized from ethanol/DMF to

give pure amino-cyanopyridine and oxo-cyanopyridine

A mixture consisting of methyl salicylate and sodium

Salicyloyloxy and

Human breast

[2]

adenocarcinoma ER+,

MCF-7, estrogen

receptor negative breast

adenocarcinoma ER+,

MDA-MB-231, prostate

cancer PC-3 and normal

fetal lung fibroblasts MRC-5

cancer

Human A549 lung

[3]

adenocarcinoma

epithelial, MCF-7 breast

adenocarcinoma, HepG2

hepatocellular liver

carcinoma, DU145 prostate

cancer

Human HT-29 colon cancer

[4]

and MDA-MB breast cancer

and MRP1 inhibitory

activity using the insect cell

membrane

2-methoxybenzoyloxy androstane and

stigmastane derivatives (**2**)

was heated to 110°C.

for 30

min at 160–200°C using a 200

Chromatographic separation of crude mixture on silica

gel column gave the pure products

One-pot synthesis

Reaction of 2-chloro-3-chloromethyl-quinoline

Quinoline, triazole and

dihydroquinoline (**3**)

with terminal alkyne in the presence of KI, NaN3

and precatalyst copper(II)sulfate in combination

with Na-ascorbate was examined in water at room

temperature

Microwave-assisted

Ethyl/methyl acetoacetate and an aldehyde were taken

4-alkyl/aryl-3,5-bis(carboethoxy/

carbomethoxy)-1,4-dihydro-2,6-

imethylpyridines (**4**)

into a beaker and dissolved in minimum quantity of

dimethylformamide. To this solution, ammonium

acetate was added. Reaction mixture was subjected to

rate of 60 s each in a microwave oven. After completion

of the reaction on TLC, the resultant product was filtered,

washed with chill water and recrystallized

W for 2–6 min, with a pulse

microwave irradiation at 480

synthesis

W MW source.

was completed after 5–10 min, mixture was irradiated

When the reaction with sodium

derivatives

Microwave-assisted

synthesis

min. The compound was collected

W power

**Class of compounds synthesized**

Novel cyanopyridine derivatives (**1**)

**Cancer cell lines**

Human liver HepG2, colon

[1]

52 Green Chemistry

HCT-116, breast MCF-7

cancer

Catalyst-free, green

approach

**Reaction condition**

Mixture of 2-(1H-pyrrol-1-yl) aniline and isatin in EtOH

was refluxed at 80°C for 6 h. The progress of reaction was

On the completion, it cooled to room

monitored by TLC.

temperature and then precipitated product was filtered,

washed with EtOH and dried by rotavapor to afford

Benzaldehyde was reacted with morpholine and

Morpholine-pyrazolidine

derivatives (**17**)

HepG2 liver, HeLa cervical and MCF-7 breast cancer

[17]

2,4-dinitrophenyl hydrazine in the presence of a

chiral pyrrolidine-based catalyst in EtOH.

step, compounds were reacted with cinnamaldehyde

in the presence of chiral catalyst in toluene at room

temperature for 5 h. Compounds were obtained in

excellent yields (88–96%)

A mixture of three components, thiosemicarbazide,

New bithiazolyl hydrazones (**18**)

cancers

MCF-7, HCT116 and THP-1

[18]

5-acyl thiazoles and phenacyl chlorides, was dissolved

in freshly prepared non-volatile organic solvent, DIPEAc

and the solution was stirred at room temperature for

min. Then, the products were isolated with excellent

30 yields, 82–96%

One-pot synthesis

Series of *N*-(aminosulfonyl)-4-podophyllotoxin

N-(aminosulfonyl)-4-podophyllotoxin

Human tumor HeLa, A-549,

[19]

HCT-8 and HepG2, human

fetal lung fibroblast WI-38

cancer cells

carbamates (**19**)

carbamates were synthesized with amines and

*N*-(chlorosulfonyl)-4-podophyllotoxin carbamate dry

CH2Cl2 via Burgess-type intermediate, which generated

in situ by reaction of PPT and chlorosulfonyl isocyanate

CSI in the presence of pyridine

Tryptamine, 2-hydroxy-4,6-dimethylpyrimidine and

Bacillamide analogues (**20**)

Human colorectal

[20]

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419

tumor HCT-116, breast

adenocarcinoma

MDA-MB-231 and immune

system JURKAT cancer

appropriate thiazole-4-carboxylate were homogenized

and then heated at 100–105°C for 5–6 h. The reaction

mixture was concentrated and the crude product so

obtained was crystallized from EtOH

Amine and ferulic acid were mixed together in 1:1 ratio

Ferulic acid amide derivatives (**21**)

Human breast

[21]

MDA-MB-231 and MCF-7,

cervical HeLa, lung A549

and liver HepG2

55

for mono-amide and 2:1 molar ratio for bisamide. The

reaction mixture was irradiated in microwave at 180–450

min. The reaction progress was monitored

Products were obtained and purified by

Watt for 3–7

by TLC. crystallization

Microwave-assisted

synthesis

One-pot solvent-free

synthesis

Novel one-pot

cyclocondensation

In the next

pure compound

Simple and

convenient one-pot

four-component

synthesis

**Class of compounds synthesized**

Pyrrolospirooxindole derivatives (1**6**)

DU-145

Human prostate cancer

[16]

**Cancer cell lines**

Synthesis by using

green solvents

**Reaction condition**

2,3-Dihydrophthalazine-1,4-dione, 5,5-dimethyl

clohexane-1,3-dione, aldehyde and p-sulfonic acid

calix[4]arene were dissolved in EtOAc. The mixture

was irradiated in a MW reactor for 10

reaction was cooled to room temperature and then water

was added. The mixture was placed in a freezer at 20°C

to form the product

One-pot reaction

Mixture of 2-thioxoimidazolidin-4-one and sodium

ethoxide in EtOH was refluxed for 30

CS2 was added and the reaction mixture was stirred at

room temperature for 1 h. After evaporation of solution,

the solid product was recrystallized from EtOH to give

compound in 70–75% yield

One-pot synthesis of 5-amino-2-(4-chlorophenyl)-

7-substituted phenyl-8,8a-dihydro-7H-3,4)

thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives

from three component reactions of 5-(4-chlorophenyl)-

1,3,4-thiadiazol-2 amine, aromatic aldehydes and

malononitrile in the presence of NaOH under reflux and

ultrasonic irradiation

Microwave irradiation of mixture of aldehyde and

1,2-phenylenediamine at 80°C, 150

 W for 5 Na2S2O5 for oxidation, the product 1H-benzo[d]

imidazol-2-yl)-6,7,8-trimethoxynaphthalen-1-ol was

isolated in excellent 95% yield

These reactions were carried out using catechol,

Novel pyrimidobenzothiazoles

Human HepG2 cancer

[14]

and catechol thioethers (**14**)

2,3-dihydro-2-thioxopyrimidin-4(1H)-ones and enzyme

laccase, phosphate buffer pH 6 and EtOH with nice

A solution of α-halocarbonyl derivative in dry acetone

Aryl-hydrazinyl-1,3-selenazole

Human leukemia cell lines

[15]

CCRF-CEM and HL60

and carcinoma cell lines

MDA-MB231, HCT116 and

U87MG

andaroyl-hydrazonyl-1,3-selenazoles

was added to the solution of benzylidene hydrazine

carboseleno amide derivative in DMF.

mixture was stirred at room temperature for 1 day and

then neutralized with NaHCO3. The precipitate was

filtered and then recrystallized from EtOH

The reaction

(**15**)

yields 95%

Microwave-assisted

Hantzsch type

condensation

reactions

Laccase-catalyzed

green synthesis

min using

2-quinolizinylbenzimidazole

Human breast MCF-7

[13]

cancer

and 2-naphthalylbenzimidazole

derivatives (**13**)

Microwave-assisted

synthesis

5-amino-2-(4-chlorophenyl)-

MCF-7, K562, HeLa and

[12]

PC-3 cancer

7-substituted phenyl-8,8adihydro-7H-(1,3,4)thiadiazolo (3,2-α)pyrimidine-6-carbonitrile

derivatives (**12**)

One-pot ultrasoundpromoted synthesis

min. After cooling,

Novel 2-thioxoimidazolidin-4-one

and benzothiazole thiolate salts (**11**)

min at 130°C.

  Anticancer molecules by green synthesis. This chemistry surrounds a series of modern techniques for synthesizing bioactive com

Cancer is a disease generated by uncontrolled cell growth in the body. There are many pro

gresses for cancer treatment but it remains mostly common cause of human death. The num

ber of cancer patients is increasing significantly worldwide, especially in developed countries. According to the global oncology trend report (2015), global spending on cancer medications rose 10.3% in 2014 to \$100 billion from \$ 75 billion in 2009. Therefore, there is a quick and urgent need of systematic approach to the development of new chemotherapeutic agents with superior efficacy, lower toxicity as well as better selectivity. The methods used in green chem

istry organic synthesis of molecules are playing wide role for designing the anticancer drugs. In this chapter, we discuss the most recent literature on green synthesis of different molecules

Green chemistry is one of the valuable concepts for the development of new, more effective, solvent-free less toxic, environmentally friendly and cost-efficient methods for the synthe

sis of different anticancer molecules. There are many developments for the environmentally friendly approaches for the synthesis of biologically active molecules such as microwaveassisted synthesis, one-pot synthesis, solvent-free synthesis, enzyme-catalyzed synthesis, solid phase synthesis, ultrasound promoted and catalyst-free synthesis. Herein, we are dis

cussing some recently published cytotoxic molecules, which have been synthesized by differ

**1**).

reduce environmental hazards and to minimize ecological risks.

and their anticancer potential on different human cancer cell lines (**Table**

**2. Green synthesis of different anticancer molecules**

ent green synthesis approaches (**Figure**

**Figure 1.** 3-cyano pyridine derivatives.

pounds, such as microwave-assisted synthesis, solid phase supported solvent-free synthesis, reaction with organocatalyst, one-pot multicomponent reactions and sonochemical synthesis, using ionic liquids techniques. Pharmaceutical companies are also improving chemicals to

57

**1**).

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 This chemistry surrounds a series of modern techniques for synthesizing bioactive compounds, such as microwave-assisted synthesis, solid phase supported solvent-free synthesis, reaction with organocatalyst, one-pot multicomponent reactions and sonochemical synthesis, using ionic liquids techniques. Pharmaceutical companies are also improving chemicals to reduce environmental hazards and to minimize ecological risks.

Cancer is a disease generated by uncontrolled cell growth in the body. There are many progresses for cancer treatment but it remains mostly common cause of human death. The number of cancer patients is increasing significantly worldwide, especially in developed countries. According to the global oncology trend report (2015), global spending on cancer medications rose 10.3% in 2014 to \$100 billion from \$ 75 billion in 2009. Therefore, there is a quick and urgent need of systematic approach to the development of new chemotherapeutic agents with superior efficacy, lower toxicity as well as better selectivity. The methods used in green chemistry organic synthesis of molecules are playing wide role for designing the anticancer drugs. In this chapter, we discuss the most recent literature on green synthesis of different molecules and their anticancer potential on different human cancer cell lines (**Table 1**).

#### **2. Green synthesis of different anticancer molecules**

Green chemistry is one of the valuable concepts for the development of new, more effective, solvent-free less toxic, environmentally friendly and cost-efficient methods for the synthesis of different anticancer molecules. There are many developments for the environmentally friendly approaches for the synthesis of biologically active molecules such as microwaveassisted synthesis, one-pot synthesis, solvent-free synthesis, enzyme-catalyzed synthesis, solid phase synthesis, ultrasound promoted and catalyst-free synthesis. Herein, we are discussing some recently published cytotoxic molecules, which have been synthesized by different green synthesis approaches (**Figure 1**).

**Figure 1.** 3-cyano pyridine derivatives.

**Method use** Catalyst under

solvent-free

conditions

15

**Reaction condition**

The aromatic aldehyde, 2-hydroxy-1,4-naphthoquinone

and 2-naphthol grinded in a mortar for 5

InCl3 was added and the reaction mixture was grinded

min again then placed in a sealed tube and kept in an

oven at 120°C for 3 h. The resulting crude was purified

by chromatography

**Table 1.**

Anticancer molecules by green synthesis.

min. Then,

**Class of compounds synthesized**

Dibenzo anthracenes (**22**)

**Cancer cell lines**

HEL human

erythroleukemia and

MCF7 breast cancer

**Refs.**

[22]

56 Green Chemistry

#### **2.1. One-pot synthesis of 3-cyano pyridine derivatives**

Novel series of 3-cyano pyridine type derivatives were synthesized and their cytotoxic activity was evaluated against many human MCF-7, HCT-116 and HepG-2 cancer cell lines. Most of the compounds showed good-to-moderate activity against HepG2 and HCT-116 cell lines, whereas only few compounds showed significant cytotoxic activity against MCF-7 breast cancer cell line (**Figure 1**) [1].

#### **2.2. Microwave-assisted solvent-free synthesis of stigmastane derivatives**

The microwave-assisted synthesis in most cases was more successful regarding to the reaction time and the yields of product. These reactions are more environmentally friendly too, compared to the conventional synthetic methods. In this research, a convenient simple microwave-assisted solvent-free synthesis of 2-methoxybenzoyloxy androstane, salicyloyloxy stigmastane derivatives from methyl salicylate and appropriate steroidal precursors has done. 2-Methoxybenzoyl ester exhibited significant cytotoxic activity against MDA-MB-231 cells. Most of the compounds strongly inhibited growth of PC-3 cells, whereas salicyloyloxy stigmastane derivative showed the best inhibition potency (**Figure 2**) [2].

**2.5. Cellulose-supported copper nanoparticle-catalyzed synthesis of chalcone derivatives**

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 59

Chalcone-linked 1,2,3-triazole derivatives were synthesized in water by cellulose-supported copper nanoparticle-catalyzed click reaction. All the products were subjected to MTT cytotoxicity assay against four human cancer cell lines A549, MCF-7, HepG2 and MIA-Pa-Ca-2 for testing their anticancer potential. Few compounds were found to be most active against all cancer cell lines and showed better activity when compared to reference drug (**Figure 5**) [5].

Some novel pyrazolo pyridine type compounds were synthesized by facile procedures and showed significant cytotoxic potential on different human cancer cell lines. They revealed various cancer cell lines (HCT-116, A549, MCF-7, PC-3) determined by SRB assay (**Figure 6**) [6].

A new class of pyrazolo[4,3-c]quinoline and pyrano[3,2-c]quinoline analogues was synthesized in good yields by microwave conditions. For enhancing the yield of products, multicomponent one-pot synthesis has been developed. The cytotoxicity of these compounds was also evaluated against MCF-7 and A549 cancer cell lines. Most of the compounds displayed

**2.6. Copper-mediated synthesis of pyrazolo pyridine derivatives**

**Figure 3.** Synthesis of polyazaheterocycles.

**2.7. Microwave-assisted synthesis of quinoline analogues**

**Figure 4.** Synthesis of carboethoxy/carbomethoxy derivatives.

moderate-to-good anticancer activity against these cell lines (**Figure 7**) [7].

#### **2.3. One-pot synthesis of polyazaheterocycles in water**

Synthesis of these polyazaheterocycles was carried out by green synthetic strategy that involved one-pot azidation and CuAAC under mild conditions in water. Many compounds were synthesized and evaluated for their cytotoxic effects against four human cancer cell lines, including A549 (lung), MCF-7 (breast), HepG2 (hepatocellular) and DU145 (prostate). Some of the compounds showed strong activities against A549 cancer cells (**Figure 3**) [3].

#### **2.4. Microwave irradiated one-pot synthesis of carboethoxy/carbomethoxy derivatives**

Fourteen carboethoxy/carbomethoxy derivatives have been synthesized by conventional and microwave irradiation method from a one-pot three-component reaction mixture, consisting of, alkyl acetoacetate, aldehyde and ammonium acetate. The synthesized products have been evaluated for their cytotoxic activity against MDA-MB (breast) and HT-29 (colon) human cancer cell lines. Few compounds exhibit some degree of cytotoxicity and it was low when compared with standard (**Figure 4**) [4].

**Figure 2.** Synthesis of stigmastane derivatives.

**Figure 3.** Synthesis of polyazaheterocycles.

**2.1. One-pot synthesis of 3-cyano pyridine derivatives**

the best inhibition potency (**Figure 2**) [2].

compared with standard (**Figure 4**) [4].

**Figure 2.** Synthesis of stigmastane derivatives.

**2.3. One-pot synthesis of polyazaheterocycles in water**

(**Figure 1**) [1].

58 Green Chemistry

Novel series of 3-cyano pyridine type derivatives were synthesized and their cytotoxic activity was evaluated against many human MCF-7, HCT-116 and HepG-2 cancer cell lines. Most of the compounds showed good-to-moderate activity against HepG2 and HCT-116 cell lines, whereas only few compounds showed significant cytotoxic activity against MCF-7 breast cancer cell line

The microwave-assisted synthesis in most cases was more successful regarding to the reaction time and the yields of product. These reactions are more environmentally friendly too, compared to the conventional synthetic methods. In this research, a convenient simple microwave-assisted solvent-free synthesis of 2-methoxybenzoyloxy androstane, salicyloyloxy stigmastane derivatives from methyl salicylate and appropriate steroidal precursors has done. 2-Methoxybenzoyl ester exhibited significant cytotoxic activity against MDA-MB-231 cells. Most of the compounds strongly inhibited growth of PC-3 cells, whereas salicyloyloxy stigmastane derivative showed

Synthesis of these polyazaheterocycles was carried out by green synthetic strategy that involved one-pot azidation and CuAAC under mild conditions in water. Many compounds were synthesized and evaluated for their cytotoxic effects against four human cancer cell lines, including A549 (lung), MCF-7 (breast), HepG2 (hepatocellular) and DU145 (prostate). Some of the compounds showed strong activities against A549 cancer cells (**Figure 3**) [3].

**2.4. Microwave irradiated one-pot synthesis of carboethoxy/carbomethoxy derivatives**

Fourteen carboethoxy/carbomethoxy derivatives have been synthesized by conventional and microwave irradiation method from a one-pot three-component reaction mixture, consisting of, alkyl acetoacetate, aldehyde and ammonium acetate. The synthesized products have been evaluated for their cytotoxic activity against MDA-MB (breast) and HT-29 (colon) human cancer cell lines. Few compounds exhibit some degree of cytotoxicity and it was low when

**2.2. Microwave-assisted solvent-free synthesis of stigmastane derivatives**

#### **2.5. Cellulose-supported copper nanoparticle-catalyzed synthesis of chalcone derivatives**

Chalcone-linked 1,2,3-triazole derivatives were synthesized in water by cellulose-supported copper nanoparticle-catalyzed click reaction. All the products were subjected to MTT cytotoxicity assay against four human cancer cell lines A549, MCF-7, HepG2 and MIA-Pa-Ca-2 for testing their anticancer potential. Few compounds were found to be most active against all cancer cell lines and showed better activity when compared to reference drug (**Figure 5**) [5].

#### **2.6. Copper-mediated synthesis of pyrazolo pyridine derivatives**

Some novel pyrazolo pyridine type compounds were synthesized by facile procedures and showed significant cytotoxic potential on different human cancer cell lines. They revealed various cancer cell lines (HCT-116, A549, MCF-7, PC-3) determined by SRB assay (**Figure 6**) [6].

#### **2.7. Microwave-assisted synthesis of quinoline analogues**

A new class of pyrazolo[4,3-c]quinoline and pyrano[3,2-c]quinoline analogues was synthesized in good yields by microwave conditions. For enhancing the yield of products, multicomponent one-pot synthesis has been developed. The cytotoxicity of these compounds was also evaluated against MCF-7 and A549 cancer cell lines. Most of the compounds displayed moderate-to-good anticancer activity against these cell lines (**Figure 7**) [7].

**Figure 4.** Synthesis of carboethoxy/carbomethoxy derivatives.

**2.8. Facile protocol, efficient and environmentally benign synthesis of cycloheximide**

activity against the standard cycloheximide (**Figure 8**) [8].

**Figure 8.** Synthesis of quinoline cycloheximide.

In this research, they describe a facile and efficient protocol and environmentally benign for the synthesis of C5-substituted barbiturate acid in water. The synthesized compounds tested for different assay and provided promising results against a-glucosidase inhibitor. The cytotoxic activity of compound against 3T3 cell resulted that compounds showed significant to weak

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 61

**2.9. Simple, eco-friendly and efficient synthesis of α,β-unsaturated carbonyl compounds**

showed strong protective effect against PC12 cell line (**Figure 9**) [9].

**Figure 9.** Synthesis of α,β-unsaturated carbonyl-based compounds.

A novel series of carbonyl compounds was synthesized by environment-friendly, simple and efficient method. Compounds were tested for cytotoxicity. All strong antioxidant compounds

**Figure 5.** Synthesis of chalcone derivatives.

**Figure 6.** Synthesis of pyridine derivatives.

**Figure 7.** Synthesis of quinoline analogues.

#### **2.8. Facile protocol, efficient and environmentally benign synthesis of cycloheximide**

In this research, they describe a facile and efficient protocol and environmentally benign for the synthesis of C5-substituted barbiturate acid in water. The synthesized compounds tested for different assay and provided promising results against a-glucosidase inhibitor. The cytotoxic activity of compound against 3T3 cell resulted that compounds showed significant to weak activity against the standard cycloheximide (**Figure 8**) [8].

#### **2.9. Simple, eco-friendly and efficient synthesis of α,β-unsaturated carbonyl compounds**

A novel series of carbonyl compounds was synthesized by environment-friendly, simple and efficient method. Compounds were tested for cytotoxicity. All strong antioxidant compounds showed strong protective effect against PC12 cell line (**Figure 9**) [9].

**Figure 9.** Synthesis of α,β-unsaturated carbonyl-based compounds.

**Figure 7.** Synthesis of quinoline analogues.

**Figure 5.** Synthesis of chalcone derivatives.

60 Green Chemistry

**Figure 6.** Synthesis of pyridine derivatives.

#### **2.10. Green methodology synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives**

**2.12. Green synthesis of pyrimidine-6-carbonitrile derivatives**

**2.13. Microwave-assisted synthesis of benzimidazole derivatives**

**Figure 13.** Synthesis of pyrimidine-6-carbonitrile derivatives.

pounds were found to be as active as standard Tamoxifen (**Figure 13**) [13].

and MCF-7 cancer cell lines (**Figure 12**) [12].

**Figure 12.** Synthesis of pyrimidine-6-carbonitrile derivatives.

This is a green synthetic approach for the formation of antitumor active 5-amino-2-(4 chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α) pyrimidine-6-carbonitrile. This protocol is extendable to a wide variety of many substrates. The advantages are the use of eco-friendly catalyst, reduced time, simple work-up process, ease of isolation and high yield of product. One compound was found to have the highest GI50 value for PC-3, HeLa, K562

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 63

Twelve 2-quinolizinylbenzimidazole and 2-naphthalylbenzimidazole type compounds have been synthesized under MW microwave condition. These compounds were tested for cytotoxicity against human breast cancer cell line MCF-7. The results showed that some com-

An efficient green method was used for the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives. Many compounds were obtained in good yields within 10 min. Among all tested cell lines, K562 leukemia cell line was most sensitive (**Figure 10**) [10].

**Figure 10.** Synthesis of phthalazine-trione derivatives.

#### **2.11. Green synthesis of thioxoimidazolidin and benzothiazole derivatives**

A series of 2-thioxoimidazolidin-4-one and benzothiazole thioglycosides were synthesized by one-pot reaction. The cytotoxic activity of compound was evaluated against MCF-7 breast cell and it showed high-to-moderate anticancer activities (**Figure 11**) [11].

**Figure 11.** Synthesis of thioxoimidazolidin and benzothiazole derivatives.

#### **2.12. Green synthesis of pyrimidine-6-carbonitrile derivatives**

**2.10. Green methodology synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives**

cell lines, K562 leukemia cell line was most sensitive (**Figure 10**) [10].

**2.11. Green synthesis of thioxoimidazolidin and benzothiazole derivatives**

and it showed high-to-moderate anticancer activities (**Figure 11**) [11].

**Figure 10.** Synthesis of phthalazine-trione derivatives.

62 Green Chemistry

**Figure 11.** Synthesis of thioxoimidazolidin and benzothiazole derivatives.

A series of 2-thioxoimidazolidin-4-one and benzothiazole thioglycosides were synthesized by one-pot reaction. The cytotoxic activity of compound was evaluated against MCF-7 breast cell

An efficient green method was used for the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives. Many compounds were obtained in good yields within 10 min. Among all tested This is a green synthetic approach for the formation of antitumor active 5-amino-2-(4 chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α) pyrimidine-6-carbonitrile. This protocol is extendable to a wide variety of many substrates. The advantages are the use of eco-friendly catalyst, reduced time, simple work-up process, ease of isolation and high yield of product. One compound was found to have the highest GI50 value for PC-3, HeLa, K562 and MCF-7 cancer cell lines (**Figure 12**) [12].

**Figure 12.** Synthesis of pyrimidine-6-carbonitrile derivatives.

#### **2.13. Microwave-assisted synthesis of benzimidazole derivatives**

Twelve 2-quinolizinylbenzimidazole and 2-naphthalylbenzimidazole type compounds have been synthesized under MW microwave condition. These compounds were tested for cytotoxicity against human breast cancer cell line MCF-7. The results showed that some compounds were found to be as active as standard Tamoxifen (**Figure 13**) [13].

**Figure 13.** Synthesis of pyrimidine-6-carbonitrile derivatives.

#### **2.14. Enzyme laccase-catalyzed green synthesis of pyrimidobenzothiazoles**

This is a newly developed method for the synthesis of pyrimidobenzothiazoles and catechol thioethers, and it addressed many of the principles of green chemistry. These reactions were catalyzed by laccase enzyme and transformations were completely safe and non-toxic aerial oxygen as the sole oxidant. This reaction delivers the products in an excellent yield. Among all tested compounds, few compounds showed moderate-to-good activity against HepG2 cell line (**Figure 14**) [14].

**2.17. One-pot four-component synthesis of morpholine-connected pyrazolidine**

showed significant cytotoxicity against tested cells (**Figure 17**) [17].

**2.18. Novel one-pot cyclocondensation**

**Figure 16.** Synthesis of spiro[indoline-3,4′-pyrrolo(1,2-a)quinoxalin.

**Figure 15.** Synthesis of 1,3-selenazole derivatives.

A simple and convenient one-pot four component reaction of morpholine connected with pyrazolidine derivatives was developed using metal-free catalysis. Cytotoxicity was evaluated using HeLa (cervical), HepG2 (liver) and MCF-7 (breast) cancer cell lines, and compounds

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 65

Bithiazolyl hydrazones have been synthesized by one-pot cyclocondensation reaction in freshly prepared ionic liquid at room temperature. Compounds have been evaluated for anti-

tubercular activity and showed potent antitubercular activity (**Figure 18**) [18].

**derivatives**

**Figure 14.** Synthesis of pyrimidobenzothiazoles.

#### **2.15. Microwave-assisted synthesis of 1,3-selenazole derivatives**

Synthesis of new 1,3-selenazole derivatives has been done by MW-assisted Hantzsch condensation reactions. Compound were screened for anti-proliferative effects against leukemia cell lines (HL60 and CCRF-CEM) and carcinoma cell lines (HCT116, MDA-MB231 and U87MG) and it gave moderate cytotoxicity against all tested cell lines (**Figure 15**) [15].

#### **2.16. Environment-friendly synthesis of 5′H-spiro[indoline-3,4′-pyrrolo(1,2-a) quinoxalin]-2-ones**

A very simple-to-perform, efficient, mild and environment-friendly benign formation of 5′H-spiro[indoline-3,4′-pyrrolo(1,2-a)quinoxalin]-2-ones has been developed without any catalysts. This method includes simplicity of operation, clean reaction, no side products and good yields. Purification of product is very simple, involving a filtration and washing. The synthesized compound with piperonyl substitution on 5-chloroisatin nitrogen showed highest cytotoxicity. Its IC50 values are comparable to that of the standard doxorubicin (**Figure 16**) [16].

**Figure 15.** Synthesis of 1,3-selenazole derivatives.

**2.14. Enzyme laccase-catalyzed green synthesis of pyrimidobenzothiazoles**

**2.15. Microwave-assisted synthesis of 1,3-selenazole derivatives**

and it gave moderate cytotoxicity against all tested cell lines (**Figure 15**) [15].

**2.16. Environment-friendly synthesis of 5′H-spiro[indoline-3,4′-pyrrolo(1,2-a)**

Synthesis of new 1,3-selenazole derivatives has been done by MW-assisted Hantzsch condensation reactions. Compound were screened for anti-proliferative effects against leukemia cell lines (HL60 and CCRF-CEM) and carcinoma cell lines (HCT116, MDA-MB231 and U87MG)

A very simple-to-perform, efficient, mild and environment-friendly benign formation of 5′H-spiro[indoline-3,4′-pyrrolo(1,2-a)quinoxalin]-2-ones has been developed without any catalysts. This method includes simplicity of operation, clean reaction, no side products and good yields. Purification of product is very simple, involving a filtration and washing. The synthesized compound with piperonyl substitution on 5-chloroisatin nitrogen showed highest cytotoxicity. Its IC50 values are comparable to that of the standard doxorubicin

line (**Figure 14**) [14].

64 Green Chemistry

**quinoxalin]-2-ones**

**Figure 14.** Synthesis of pyrimidobenzothiazoles.

(**Figure 16**) [16].

This is a newly developed method for the synthesis of pyrimidobenzothiazoles and catechol thioethers, and it addressed many of the principles of green chemistry. These reactions were catalyzed by laccase enzyme and transformations were completely safe and non-toxic aerial oxygen as the sole oxidant. This reaction delivers the products in an excellent yield. Among all tested compounds, few compounds showed moderate-to-good activity against HepG2 cell

#### **2.17. One-pot four-component synthesis of morpholine-connected pyrazolidine derivatives**

A simple and convenient one-pot four component reaction of morpholine connected with pyrazolidine derivatives was developed using metal-free catalysis. Cytotoxicity was evaluated using HeLa (cervical), HepG2 (liver) and MCF-7 (breast) cancer cell lines, and compounds showed significant cytotoxicity against tested cells (**Figure 17**) [17].

#### **2.18. Novel one-pot cyclocondensation**

Bithiazolyl hydrazones have been synthesized by one-pot cyclocondensation reaction in freshly prepared ionic liquid at room temperature. Compounds have been evaluated for antitubercular activity and showed potent antitubercular activity (**Figure 18**) [18].

**Figure 16.** Synthesis of spiro[indoline-3,4′-pyrrolo(1,2-a)quinoxalin.

**2.19. One-pot synthesis of carbamates**

**2.20. Eco-friendly synthesis of bacillamide**

**Figure 19.** Synthesis of N-(aminosulfonyl)-4-podophyllotoxin carbamates.

doxorubicin (**Figure 20**) [20].

One-pot synthesis of N-(aminosulfonyl)-4-podophyllotoxin carbamates has been done and it showed promising cytotoxic activities. Most effective compound induced HeLa cells cycle arrest in G2/M phase, leading to apoptosis, and activation of cdc2, cyclinB1, p53 and ROS and inhibits polymerization of tubulin and microtubule. These results suggest that these synthesized compounds have strong potential for development as cytotoxic agents (**Figure 19**) [19].

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 67

It is an efficient, advanced and eco-friendly route for synthesis of bacillamide analogues through a two-step solvent-free synthesis. Compounds exhibit potent cytotoxic activity against three HCT-116, MDA-MD-231 and JURKATs cancer cell lines and compared with

**Figure 17.** Synthesis of morpholine-connected pyrazolidine.

**Figure 18.** Synthesis of bithiazolyl hydrazones.

#### **2.19. One-pot synthesis of carbamates**

One-pot synthesis of N-(aminosulfonyl)-4-podophyllotoxin carbamates has been done and it showed promising cytotoxic activities. Most effective compound induced HeLa cells cycle arrest in G2/M phase, leading to apoptosis, and activation of cdc2, cyclinB1, p53 and ROS and inhibits polymerization of tubulin and microtubule. These results suggest that these synthesized compounds have strong potential for development as cytotoxic agents (**Figure 19**) [19].

#### **2.20. Eco-friendly synthesis of bacillamide**

It is an efficient, advanced and eco-friendly route for synthesis of bacillamide analogues through a two-step solvent-free synthesis. Compounds exhibit potent cytotoxic activity against three HCT-116, MDA-MD-231 and JURKATs cancer cell lines and compared with doxorubicin (**Figure 20**) [20].

**Figure 19.** Synthesis of N-(aminosulfonyl)-4-podophyllotoxin carbamates.

**Figure 18.** Synthesis of bithiazolyl hydrazones.

**Figure 17.** Synthesis of morpholine-connected pyrazolidine.

66 Green Chemistry

**2.22. One-pot synthesis of** *o***-quinonic adducts**

**3. Conclusion**

**Acknowledgements**

**Figure 22.** Synthesis of *o*-quinonic adducts.

**Author details**

Saudi Arabia

cytotoxicity against MCF-7 and HEL tumoral cell lines (**Figure 22**) [22].

Dibenzo[a,h]anthracene derivatives were synthesized via a one-pot synthetic protocol with threecomponent reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and 2-naphthol using InCl3 as catalyst under solvent-free condition. These *o*-quinonic adducts showed strong

Green Chemistry and Synthesis of Anticancer Molecules http://dx.doi.org/10.5772/intechopen.70419 69

The data of this chapter could be very helpful to identify the recently published approaches of

This book chapter was supported by a grant from the "Research Center of the Female Scientific

anticancer molecules synthesized via different green chemistry approaches.

and Medical Colleges," Deanship of Scientific Research, King Saud University.

Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh,

Shagufta Perveen\* and Areej Mohammad Al-Taweel

\*Address all correspondence to<EMAIL_ADDRESS>
#### **2.21. Solvent-free microwave-assisted synthesis of amide derivatives of ferulic acid**

In this research work, different amide derivatives of ferulic acid have been synthesized under solvent-free conditions by microwave-assisted reaction. These compounds were found to exhibit noticeable in vitro anticancer activity against breast (MDA-MB-231 and MCF-7), cervical (HeLa), lung (A549) and liver (HepG2) human cancer cell lines (**Figure 21**) [21].

**Figure 21.** Synthesis of ferulic acid derivatives.

#### **2.22. One-pot synthesis of** *o***-quinonic adducts**

Dibenzo[a,h]anthracene derivatives were synthesized via a one-pot synthetic protocol with threecomponent reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and 2-naphthol using InCl3 as catalyst under solvent-free condition. These *o*-quinonic adducts showed strong cytotoxicity against MCF-7 and HEL tumoral cell lines (**Figure 22**) [22].

**Figure 22.** Synthesis of *o*-quinonic adducts.

### **3. Conclusion**

**2.21. Solvent-free microwave-assisted synthesis of amide derivatives of ferulic acid**

**Figure 20.** Synthesis of bacillamide analogues.

68 Green Chemistry

**Figure 21.** Synthesis of ferulic acid derivatives.

cal (HeLa), lung (A549) and liver (HepG2) human cancer cell lines (**Figure 21**) [21].

In this research work, different amide derivatives of ferulic acid have been synthesized under solvent-free conditions by microwave-assisted reaction. These compounds were found to exhibit noticeable in vitro anticancer activity against breast (MDA-MB-231 and MCF-7), cervi-

> The data of this chapter could be very helpful to identify the recently published approaches of anticancer molecules synthesized via different green chemistry approaches.

#### **Acknowledgements**

This book chapter was supported by a grant from the "Research Center of the Female Scientific and Medical Colleges," Deanship of Scientific Research, King Saud University.

#### **Author details**

Shagufta Perveen\* and Areej Mohammad Al-Taweel

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

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70 Green Chemistry

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[2] Katarina MPG, Evgenija AD, Mihaly S, Janos G, Janos JC. Microwave assisted synthesis and biomedical potency of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives. Steroids 2015;**94**:31-40. DOI: 10.1016/j.steroids.2014.12.008 [3] Koduru SSP, Edupuganti VVSR. Design of new hybrid template by linking quinoline, triazole and dihydroquinoline pharmacophoric groups: A greener approach to novel polyazaheterocycles as cytotoxic agents. Bioorganic & Medicinal Chemistry Letters

[4] Srinivas NA, Mahendar P, Sadanandam A, Achaiah G, Malla RV. Synthesis, anticancer and MRP1 inhibitory activities of 4-alkyl/aryl-3,5-bis(carboethoxy/carbomethoxy)-1, 4-dihydro-2, 6-dimethylpyridines. Medicinal Chemistry Research 2013;**22**:147-155. DOI:

[5] Pinki Y, Kashmiri L, Ashwani K, Santosh KG, Sundeep J. Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles. European Journal of Medicinal Chemistry

[6] Chitrakar R, Arem Q, Darapaneni CM, Shashank KS. Design, synthesis and cytotoxicity studies of novel pyrazolo[1, 5-a] pyridine derivatives. European Journal of Medicinal

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2017;**126**:944-953. DOI: 10.1016/j.ejmech.2016.11.030

Chemistry 2017;**126**:277-285. DOI: 10.1016/j.ejmech.2016.11.037

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press. DOI: 10.1016/j.arabjc.2016.04.007

10.1007/s00044-012-9994-0

bmcl.2017.02.042

biological and computational studies. Medicinal Chemistry Research 2016;**25**:1175-1192. DOI: 10.1007/s00044-016-1562-6

**Chapter 5**

**Provisional chapter**

**The Role of Green Solvents and Catalysts at the Future**

Green chemistry is getting extended in many researches and industry areas. Not only pharmaceutical companies but also the other chemical industries started to take a step for green chemistry due to its advantages such as decreasing of waste and cost. With this respect, we have already witnessed that pharmaceutical companies searched out for green protocol when manufactured the pharmaceuticals. Green chemistry strategies can be seen in solvents, catalysts, and the others. So, we have briefly discussed the green solvents and nanocatalysts in this chapter. We hope that this chapter gives a brief consid-

**Keywords:** nanocatalyst, pharmaceutical company, green chemistry, environment

The demand of green chemistry for applying in the pharmaceutical and the other chemical industries is increasingly vital due to the fact that our world faces the environmental challenges of the twenty-first century. US Environmental Protection Agency (EPA) has suggested green chemistry for innovative technologies that reduce toxic, undesired waste, and environmental impact. Green chemistry is thus getting grew as an open light to afford a huge scientific area. After EPA, 12 principles of green chemistry have been gotten more attention and these principles have been considered more seriously by pharmaceutical companies since 1998. Pharmaceutical companies declared that they should improve the environmental performance by utilizing green chemistry. Not only pharmaceutical companies but also the other chemical industries started to take a step for green chemistry due to its advantages such as decreasing of waste and cost. It is assumed that green chemistry can save the industry an

**The Role of Green Solvents and Catalysts at the Future**

DOI: 10.5772/intechopen.71018

© 2016 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,

© 2018 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.

and reproduction in any medium, provided the original work is properly cited.

**of Drug Design and of Synthesis**

**of Drug Design and of Synthesis**

Additional information is available at the end of the chapter

eration of importance of green chemistry.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71018

Nurettin Menges

**Abstract**

**1. Introduction**

Nurettin Menges

[22] Idaira HF, Angel A, Patricia M, Matias L, Leandro F, Ana E. Indium catalyzed solventfree multicomponent synthesis of cytotoxic dibenzo[*a,h*]anthracenes from aldehydes, 2-hydroxy-1,4-naphthoquinone, and 2-naphthol. Tetrahedron 2014;**70**:8480-8487. DOI: 10.1016/j.tet.2014.09.076

**Provisional chapter**

## **The Role of Green Solvents and Catalysts at the Future of Drug Design and of Synthesis of Drug Design and of Synthesis**

**The Role of Green Solvents and Catalysts at the Future**

DOI: 10.5772/intechopen.71018

Nurettin Menges Nurettin Menges Additional information is available at the end of the chapter

biological and computational studies. Medicinal Chemistry Research 2016;**25**:1175-1192.

[22] Idaira HF, Angel A, Patricia M, Matias L, Leandro F, Ana E. Indium catalyzed solventfree multicomponent synthesis of cytotoxic dibenzo[*a,h*]anthracenes from aldehydes, 2-hydroxy-1,4-naphthoquinone, and 2-naphthol. Tetrahedron 2014;**70**:8480-8487. DOI:

DOI: 10.1007/s00044-016-1562-6

10.1016/j.tet.2014.09.076

72 Green Chemistry

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71018

#### **Abstract**

Green chemistry is getting extended in many researches and industry areas. Not only pharmaceutical companies but also the other chemical industries started to take a step for green chemistry due to its advantages such as decreasing of waste and cost. With this respect, we have already witnessed that pharmaceutical companies searched out for green protocol when manufactured the pharmaceuticals. Green chemistry strategies can be seen in solvents, catalysts, and the others. So, we have briefly discussed the green solvents and nanocatalysts in this chapter. We hope that this chapter gives a brief consideration of importance of green chemistry.

**Keywords:** nanocatalyst, pharmaceutical company, green chemistry, environment


*3.1. Identifying the Factors Affecting Indigenous Knowledge of the Optimal Use of Water in the Agricultural Sector*

According to Table 2, it is observed that in the matrix of pairwise comparison of indices of factors affecting indigenous knowledge in optimal water consumption in the agricultural sector of Sistan, according to experts of Jihad Keshavarzi, the area of relations with neighbors regarding the use of indigenous knowledge, membership in the aquifer organization, farmers' incomes, and drought loans (11, 13, 19, and 23) are superior to other indicators. Meanwhile, visitation programs for farmers on indigenous knowledge, training classes on the use of indigenous knowledge, practical projects around indigenous knowledge projects, and the provision of specialized human resources in terms of indigenous knowledge projects (1, 2, 3, and 14) have a weak advantage over other indicators.


**6.1.1 Specific measures for livestock animals**

are available (Cuny et al., 2010). In this respect, further research is needed to address these gaps, as well as to better understand the evolution of these strains in humans and animals.

All studies on animal MRSA have helped establish critical measures for its control. Numerous reports on MRSA control in humans have been published and many of the principles may also be applied to control in animals. However, caution is necessary for extrapolating these human guidelines to animals, as disease epidemiology can differ

It has been observed that exposure to antimicrobials is a risk factor for the acquisition and dissemination of MRSA in humans and also most probably in animals. In this respect, strategies for prevention and management of MRSA in animals should be, as much as possible, related to the use of antimicrobials. If the antimicrobial treatment is necessary in individual cases for the sake of animal welfare, the risk of the emergence of wider resistance in MRSA strains colonizing animals needs to be managed, especially considering zoonotic aspects. Options to manage this risk include the non-use of antimicrobials except as a last resort strategy, decolonization in humans, isolation of animals during treatment, and monitoring the effects of treatment in strain resistance through selective culture and

Good hygiene is an important general preventive and control measure, both in homes and human and animal healthcare environments, because environmental contamination with MRSA acts as a reservoir for infection. Known MRSA-positive animals should be nursed apart from other animals, with strict washing of the hands, gloves and gowns if in close contact. Recording the history of contact with human or animal MRSA, as well as an early culture of a wound non-responsive to first-line therapy allows for earlier recognition of MRSA and its appropriate management. Furthermore, when faced with repeated and inexplicable failure of human decolonization, clinicians can investigate nearby exposure to

Reduction of antimicrobial selective pressure in livestock by avoiding routine mass

Prevention of transmission of MRSA between and within the farms with sanitary

Use of contact precautions such as protective outerwear, overalls, aprons or coats and

Protective outerwear and all the items handled during the treatment of MRSA-positive

Hands can be hygienically cleaned with alcohol gel pouches, which are essential but

Identification and isolation of animals to minimize the risk for zoonotic infection

**6. MRSA prevention and control in animals**

significantly (Leonard & Markey, 2008).

susceptibility tests (CATRY et al., 2010).

**6.1 General preventive and control measures**

**6.1.1 Specific measures for livestock animals**

boots or overshoes that are not worn elsewhere

animals should be considered potentially contaminated

medication

need to be used correctly

animals and birds that could be the reservoirs (Morgan, 2008).

Below, are some precolonized specific measures cited from (Catry et al., 2010).

measures of control between herds and during transportation

#### **<IP_ADDRESS> Reducing carriers on MRSA-positive livestock farms**

Control and/or treatment of colonized and infected animals with or without antimicrobials is necessary for the reduction of carriers.

Th1e affected animals need to be immediately separated from healthy animals. In extreme cases culling of infected animals is a further option. Milk of animals with mastitis by MRSA must be destroyed, and in some cases the infected quarter must be prematurely dried-off.

If the antimicrobial treatment is chosen, it is necessary to evaluate its risk-benefit compared with other alternatives. The choice of antimicrobials should always be based on a susceptibility test, and all precautions should be taken that the drug reaches the infected site with appropriate concentrations.