*Article* **Clinical Impact of Nutritional Status and Sarcopenia in Pediatric Patients with Bone and Soft Tissue Sarcomas: A Pilot Retrospective Study (SarcoPed)**

**Alberto Romano 1,†, Silvia Triarico 1,†, Emanuele Rinninella 2,3,\*, Luigi Natale 4,5, Maria Gabriella Brizi 4,5, Marco Cintoni 2, Pauline Raoul 3, Palma Maurizi 1,6, Giorgio Attinà 1, Stefano Mastrangelo 1,6, Antonio Gasbarrini 3,7, Maria Cristina Mele 2,3,‡ and Antonio Ruggiero 1,6,‡**

	- † These authors contributed equally to this work (co-first).
	- ‡ These authors contributed equally to this work (co-last).

**Abstract:** Background: We evaluated nutritional and sarcopenia status and their clinical impact in pediatric patients affected by bone and soft tissue sarcomas. Methods: Body mass index (BMI), prognostic nutritional index (PNI), and total psoas muscle area (tPMA) at diagnosis and after 12 months were analyzed. tPMA was measured from single cross-sectional computed tomography (CT) images at L4–L5. Age-specific and sex-specific tPMA Z-scores were retrieved from an online calculator. Results: A total of 21 patients were identified between February 2013 and December 2018. Twelve patients (57.1%) experienced sarcopenia at diagnosis, although not statistically associated with overall survival (OS) (*p* = 0.09). BMI Z-score, PNI, and tPMA Z-score significantly decreased between diagnosis and after 12 months of treatment (*p* < 0.05). Univariate analysis showed significant associations between poor OS and the presence of metastasis (*p* = 0.008), the absence of surgery (*p* = 0.005), PNI decrease (*p* = 0.027), and the reduction in tPMA > 25% (*p* = 0.042) over the 12 months. Conclusions: Sarcopenia affects more than half of the patients at diagnosis. Decreased PNI during 12 months of treatment has significant predictive value for OS. The role of tPMA derived from CT scan among pediatric patients with sarcoma should be investigated in further prospective and larger studies.

**Keywords:** soft tissue sarcoma; bone sarcoma; pediatric patients; chemotherapy; psoas muscle area (PMA); sarcopenia; personalized medicine

**Citation:** Romano, A.; Triarico, S.; Rinninella, E.; Natale, L.; Brizi, M.G.; Cintoni, M.; Raoul, P.; Maurizi, P.; Attinà, G.; Mastrangelo, S.; et al. Clinical Impact of Nutritional Status and Sarcopenia in Pediatric Patients with Bone and Soft Tissue Sarcomas: A Pilot Retrospective Study (SarcoPed). *Nutrients* **2022**, *14*, 383. https://doi.org/10.3390/nu14020383

Academic Editors: Silvia Scaglioni, Alessandra Mazzocchi and Valentina De Cosmi

Received: 22 December 2021 Accepted: 14 January 2022 Published: 17 January 2022

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**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/).

#### **1. Introduction**

Nutritional status plays a key role in the growth, response to treatment, related complications, quality of life, cost of care, and hospital stay of pediatric patients admitted for various types of illness [1]. In 2013, the Academy of Nutrition and Dietetics of the American Society of Parenteral and Enteral Nutrition (ASPEN) defined pediatric malnutrition status as "an imbalance between nutritional needs and nutrient intake, resulting in a cumulative deficit of energy, protein, or micronutrients that may adversely affect growth, development, and other clinical outcomes" [2].

Pediatric hospital malnutrition is still an underestimated problem, although it results in significant morbidity and mortality among hospitalized children. Several studies have reported a prevalence of 6–51% of this condition among hospitalized pediatric patients [3,4]. The European Society for Clinical Nutrition and Metabolism at Risk (ESPEN) and the European Society for Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommend screening for nutritional risk in hospitalized children on admission to the ward to facilitate the identification of nutritionally at-risk children and to allow the physician to prepare an appropriate nutritional support plan [5–7].

In children hospitalized for cancer, malnutrition constitutes a very common complication, and it is influenced by the type and extent of disease, the intensity of treatment, and the patient's living conditions [8]. In these patients, the inflammatory response of the underlying disease induces high-energy expenditure and protein catabolism with a net lean body mass loss. In addition, gastrointestinal symptoms such as nausea, vomiting, and lack of appetite (caused by the therapy and/or the tumor) further aggravate the state of protein-energy malnutrition, sometimes exacerbating the toxic effects of therapy and susceptibility to complications [9].

Early identification of the risk and presence of malnutrition, coupled with rapid and personalized nutritional intervention, could, in turn, enhance treatment adherence, reduce treatment complications, and improve patients' quality of life [10–12].

The prognostic nutritional index (PNI) is calculated using the serum albumin concentration and peripheral blood lymphocyte count. PNI has been recognized as a valid indicator of the nutritional and immune status among cancer patients and as an independent prognostic indicator of various malignant tumors [13–16].

Numerous studies have tried to quantify the effect of malnutrition on the survival of pediatric cancer patients, showing a close relationship between the body mass index (BMI) and mortality [17]. However, the BMI is a nutritional indicator based on the weight and height of the patient, without taking into account the real body composition and the proportions of fat and lean tissue. On the other hand, the loss of muscle tissue and the alteration of body composition may occur as an effect of malnutrition, regardless of weight changes [18]. In pediatric patients with neoplasms, sarcopenia may coexist in the context of malnutrition, amplifying its negative impact on the patients' prognosis. Sarcopenia is a pathological condition, characterized by a progressive and generalized reduction in the quantity, quality, and strength of muscle mass, more or less associated with reduced physical performance. It is a major cause of physical disability, poor quality of life, loss of self-sufficiency, and death [19,20]. Despite that sarcopenia is generally associated with aging (primary sarcopenia) [21], there are many inflammatory conditions (such as chronic inflammatory diseases and cancer) yielding its occurrence even at a young age as an effect of the catabolic state (secondary sarcopenia) [22]. The development of sarcopenia in adult cancer patients is closely linked to an increase in mortality and morbidity, independently from the BMI variation [23,24]. In the pediatric age, the presence of sarcopenia has been linked to the mortality and morbidity of numerous chronic diseases and in patients with aggressive and disabling malignant pathologies, even if the evidence is still scarce [25,26].

There are several ways to assess muscle mass and possible sarcopenia status in clinical practice [27]. In adults, the skeletal muscle mass index (SMI) is calculated from the skeletal muscle area (SMA) (cm2) divided by the square of the patient's height (m2) [28–30]. SMI is indicative of sarcopenia if less than 55 cm2/m2 in males and 39 cm2/m2 in females [31,32]. This method has been widely adopted for the analysis of muscle mass in adult patients with neoplasia, as well as in patients with liver disease, patients in intensive care units, and patients undergoing surgery [33–36]. Recently, Lurz et al. generated age- and sex-specific curves related to total psoas muscle area (tPMA) derived at L3–L4 or L4–L5, which can be used for pediatric patients aged 1 to 16 years. From them, the Z-scores of the PMA can be derived through a calculator available online (https://ahrc-apps.shinyapps.io/sarcopenia/ (accessed on 15 December 2021)) and easily identify the presence of sarcopenia [37]. Although Lurz et al. analyzed tPMA at both L3–L4 and L4–L5 levels, tPMA at L4–L5 seems to be more relevant in the pediatric age group, because at this level the psoas muscle shape is also rounder than at L3–L4, allowing for more accurate contour drawing. In addition, L4–L5 is the reference level for the assessment of visceral adipose tissue, so an analysis at this level is a reliable measure of both skeletal muscle and adipose tissue [38,39]. Bone and soft tissue sarcomas of childhood are highly aggressive pathologies, which require intensive chemotherapy treatments and can be burdened by a high rate of immobilization resulting from surgical procedures or pain. Prolonged immobilization further causes a reduction in muscle mass and strength, with a consequent possible worsening of the state of sarcopenia [40].

In the present study, we evaluate body composition changes, sarcopenia assessed by the evaluation of PMA obtained from computed tomography (CT) scans, and their impact on the survival and prognosis of pediatric patients with bone and soft tissue sarcomas.

#### **2. Materials and Methods**

#### *2.1. Study Endpoints*

The primary endpoint was:

The secondary endpoints were:

#### *2.2. Study Design, Patients' Characteristics, Ethical Approval, Inclusion, and Exclusion Criteria*

In this observational pilot study, data from twenty-two pediatric patients with a new diagnosis of bone and soft tissue sarcoma, admitted at the Pediatric Oncology Unit of the Fondazione Policlinico Agostino Gemelli IRCCS from February 2013 to December 2018, were retrospectively analyzed.

The ethical approval was obtained from the Ethics Committee of our institution (Protocol ID 4211, Approval Letter Number 36155/21). Informed consent was obtained from the parents or the legal guardians of the enrolled patients. The study was carried out following the Helsinki Declaration of Human Rights.

Inclusion criteria were: diagnosis of bone or soft tissue sarcomas (Ewing sarcoma, rhabdomyosarcoma, desmoplastic tumor), age between 1 and 16 years, and staging of the disease by CT scan of the abdomen at diagnosis and after 12 months of treatment.

The exclusion criterion was the absence of CT images available at the time of data analysis.

#### *2.3. Clinical Data and Nutritional Assessment*

For each patient, the following data were collected:

For each patient, the assessment of nutritional status was performed according to the following variables: BMI, BMI Z-score, PNI, and tPMA at diagnosis and after 12 months.

The BMI was calculated with the formula: weight (kg)/height (m2). The BMI Z-score was calculated with "PediTools-Clinical tools for pediatric providers", available on the internet (https://peditools.org/, last (accessed on 20 September 2021)). The change in BMI (ΔBMI) over the 12 months was calculated with the formula: ((BMI after 12 months—BMI at diagnosis)/(BMI at diagnosis)) × 100.

The PNI, as an indicator of the nutritional and inflammatory status, was calculated according to the formula: (10 × serum albumin (g/dL)) + (0.005 × number of lymphocytes/μL). The change in the PNI (ΔPNI) over the 12 months was calculated with the formula: ((PNI after 12 months − PNI at diagnosis)/(PNI at diagnosis)) × 100.

To evaluate the presence of sarcopenia, tPMA was measured from single cross-sectional abdominal CT images at the level of L4–L5 at diagnosis and after 12 months of treatment. The tPMA expressed in mm2 was obtained using the SliceOmatic software v5.0 (Tomovision, Montreal, QC, Canada) and was measured at the level of L4–L5 because most clinically relevant and useful according to Lurz et al. [37]. A calculator available online (https://ahrcapps.shinyapps.io/sarcopenia/) (accessed on 15 December 2021) was used to obtain the tPMA Z-scores in relation to sex and age of the patient. The degree of sarcopenia was defined by the following parameters: mild for <−1 Z-score, moderate for <−2 Z-score, severe for <−3 Z-score. The change in tPMA (ΔtPMA) over the 12 months was calculated with the formula: ((tPMA after 12 months—tPMA at diagnosis)/(tPMA at diagnosis)) × 100.

#### *2.4. Sample Size and Statistical Analysis*

Given the lack of data on the presence and degree of sarcopenia in the population of interest, we set the sample size for this pilot study at *n* = 22 patients. This number intercepts various expected proportions, with a confidence level of 95% and a margin of error ranging from a minimum of 4.16% (for an expected proportion of 1%) to a maximum of 20.89 (for an expected proportion of 50%).

Continuous data are given as median and interquartile range (IQR: 25–75◦ percentile) and were compared using Mann–Whitney U tests. Categorical data are presented as absolute and percentage frequencies and were compared using the Chi-squared test or Fisher Exact Test, where appropriate. The study of the correlations was carried out using Pearson's test.

OS was estimated by the Kaplan–Meier method and was tested with the log-rank test. OS was defined as the time between diagnosis and death, expressed in months. A Cox regression proportional hazards model was constructed to assess the prognostic significance of covariates. The hazard ratio (HR) with 95% CI was reported as an estimate of the risk of death. All statistical analyses were performed using XLSTAT version 2021.3.1 by Addinsoft. Values of *p* < 0.05 were considered statistically significant.

#### **3. Results**

#### *3.1. Clinical Characteristics, Nutritional Status, Sarcopenia at Diagnosis and 12 Months*

A total of 22 patients diagnosed with a bone or soft tissue sarcoma and treated at our center were included between February 2013 and December 2018. Only one patient was excluded, due to the impossibility of obtaining the CT images at12 months after diagnosis. Table 1.

**Table 1.** Clinical characteristics, nutritional status, and sarcopenia at diagnosis (*n* = 21).

Demographic and clinical characteristics of the enrolled population are reported in

Abbreviations: tPMA, total area of the psoas muscle; BMI, body mass index; IQR, interquartile range; PNI, prognostic nutritional index.

Eleven (52.4%) patients were male, and ten (47.6%) were female, with a median age of 125.6 (78.7; 181.5) months. There were 14 (66.6%) diagnoses of Ewing sarcoma, 6 (28.6%) of rhabdomyosarcoma, and 1 (4.8%) of desmoplastic tumor.

At diagnosis, no patient could undergo complete resection of the primitive mass. As per EpSSG RMS 05 protocol, all patients with rhabdomyosarcoma or desmoplastic tumor who did not have metastases at diagnosis and who could not undergo complete resection of the mass were classified as stage III, while those with metastases were classified as stage IV. Similarly, all patients with Ewing's sarcoma without metastases at diagnosis and who could not undergo complete resection of the mass were classified as stage III, and those with metastases were classified as stage IV.

At diagnosis, the median of the BMI Z-score was −0.23 (−0.89; 0.85), the median of PNI was 48.1 (45.2; 53.2), and the median of the tPMA Z-score was −1.01 (−1.71; −0.35). At diagnosis, 12 (57.2%) were sarcopenic, 8 (38.1%) mild, and 4 (19.1%) moderate sarcopenic. None were diagnosed with severe sarcopenia.

Patients with Ewing sarcoma were treated according to the EURO-EWING99 protocol: 4 (28.6%) of them received high-dose chemotherapy with busulfan and melphalan, followed by autologous stem cell transplantation, 3 (21.4%) underwent radiotherapy, and 13 (92.9%) underwent surgical excision of the primary residual mass. Patients with rhabdomyosarcoma and desmoplastic tumor were treated according to the EpSSG RMS 05 protocol. None received high-dose chemotherapy or radiotherapy. One patient with rhabdomyosarcoma and desmoplastic tumor required primary tumor surgery, followed by chemotherapy according to the EpSSG NRSTS 05 protocol.

At the time of the analysis, 11 patients (52.4%) were dead, and 13 patients (61.9%) had disease progression.

Table 2 shows the comparison of nutritional variables at diagnosis and 12 months after the beginning of treatment. The differences in terms of presence of sarcopenia at diagnosis and after 12 months of treatment were not statistically significant, whereas significant differences were observed for the BMI Z-score, the PNI, and the tPMA Z-score.

**Table 2.** Comparison of nutritional status variables and sarcopenia status rates at diagnosis and after 12 months of treatment.

Abbreviations: tPMA: total area of the psoas muscle; BMI: body mass index; PNI prognostic nutritional index.

Figure 1 represents the change of tPMA, measured from single cross-sectional abdominal CT images at the level of L4–L5 in the same patient at diagnosis and after 12 months of treatment.

**Figure 1.** tPMA (in red color) measured from single cross-sectional abdominal CT images at the level of L4–L5 in the same patient, at diagnosis, and after 12 months of treatment.

*3.2. Association between Clinical Characteristics, Nutritional Status, Sarcopenia, and Overall Survival*

Among the sarcopenic patients at diagnosis, seven (58.3%) were affected by Ewing sarcoma and five (41.7%) by rhabdomyosarcoma (*p* = 0.16).

Table 3 describes the potential associations between clinical and nutritional variables and OS, as a result of Cox proportional hazards analysis. The presence of mild or moderate sarcopenia at diagnosis was not statistically associated with OS (HR = 3.19 (0–82–12.36); *p* = 0.09). In the univariate analysis, the presence of metastasis, the absence of surgery

during the 12 months, the ΔPNI, and a reduction of PMA greater than 25% over 12 months were significantly associated with poor OS.

**Table 3.** Univariate analysis of clinical characteristics, nutritional status, and sarcopenia for overall survival.

Abbreviations: tPMA: total area of the psoas muscle; BMI: body mass index; PNI prognostic nutritional index; ΔBMI (the change of BMI over the 12 months of treatment); ΔPNI (the change of PNI over the 12 months of treatment); ΔtPMA (the change of PMA over the 12 months); ΔtPMA L4–L5 > −25% (reduction of PMA greater than 25% over 12 months).

#### *3.3. Association between Sarcopenia and Infectious Complications*

The median number of febrile neutropenic episodes that require hospitalization and intravenous antibiotic therapy was 3 (IQR = 3–7) in nonsarcopenic patients, 2.5 (IQR = 0.5–4.5) in mild sarcopenic patients, and 5 (IRQ 1–5.5) in moderate sarcopenic patients. The comparison between the median number of febrile neutropenic episodes that require hospitalization and intravenous antibiotic therapy was not statistically different among the nonsarcopenic, mild sarcopenic, and moderate sarcopenic groups at diagnosis, as shown in Figure 2a. Additionally, the median number of febrile neutropenic episodes that require hospitalization and intravenous antibiotic therapy was 2 (IQR = 2–5.75) in patients with ΔtPMA L4–L5 < −25% and 2 (IQR = 3.5–5) in patients with ΔtPMA L4–L5 > −25%. The comparison between the median number of febrile neutropenic episodes that require hospitalization and intravenous antibiotic therapy was not statistically different among the patients with ΔtPMA L4–L5 < −25% and patients with ΔtPMA L4–L5 > −25%, as shown in Figure 2b. The study of correlations using Pearson's test showed that there was no association between Δ tPMA L4–L5 and the number of febrile neutropenic episodes (*r* = −0.25; *p* = 0.06) and between ΔBMI and the number of febrile neutropenic episodes (*r* = −0.3; *p* = 0.1). A weak association was observed between ΔPNI and the number of febrile neutropenic episodes (*r* = 0.1; *p* = 0.01).

**Figure 2.** (**a**) Number of febrile neutropenic episodes in nonsarcopenic, mildly sarcopenic, and moderately sarcopenic patients at diagnosis. (**b**) Number of febrile neutropenic episodes in the patients with ΔtPMA L4–L5 < −25% and patients with ΔtPMA L4–L5 > −25%.

#### **4. Discussion**

This is a pilot retrospective study investigating sarcopenia and nutritional status at diagnosis among inpatient children affected by cancer and their potential clinical impact. The recently published study of Lurz et al. defining pediatric reference curves for tPMA allowed us to diagnose sarcopenia in children using CT scan [37]. Indeed, by using the reference curves we observed that sarcopenia in children with cancer at diagnosis is a greatly more widespread condition than we might have expected. We can speculate that the cause of this phenomenon could be found in the pathogenetic mechanisms of sarcopenia. Secondary sarcopenia is caused by the coexistence of multiple pathogenic mechanisms involving the increase in apoptotic activity in muscle cells, the production of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, the presence of oxidative stress, and accumulation of oxygen radicals, low energy and protein intake [41]. Even before the tumor diagnosis, it is possible that these mechanisms, especially the

neoplastic, inflammatory, microenvironmental (TNF, IL-1, proteolysis-inducing factor), and physical inactivity [42], play a role in the pathogenesis of sarcopenia. In our opinion, such a high rate of sarcopenia at diagnosis in children with soft tissue and bone sarcomas could also be related to the diagnostic delay of these tumors [43].

By comparing the mean value of tPMA at diagnosis and after 12 months, we observed a statistically significant reduction in the tPMA Z-score. This change during treatment may probably be caused by an inadequate intake of energy or proteins (due to anorexia, nausea, vomiting, malabsorption related to the oncologic treatments), already associated with the inflammatory state and hypomobility [42]. A reduced intake of nutrients during cancer treatment can be associated with sarcopenia diagnosis or can worsen its severity if already present before initiating treatment. As observed by Chindapasirt et al., sarcopenia may produce a vicious circle, causing the worsening of the patient's inflammatory status [44]. In our population, this resulted in the fact that after 12 months of treatment only 23% of the patients did not develop sarcopenia. A previous report also showed an increased rate of pediatric sarcopenia status during treatment of acute lymphoblastic leukemia, but the authors assessed the skeletal muscle mass using dual-energy X-ray absorptiometry scans without exactly defining sarcopenia status at diagnosis [45]. In our study, the incidence of sarcopenia in children with cancer and its variations during treatment have been precisely defined from the analysis of CT scan routinely used at diagnosis for the staging of sarcomas. This means that the diagnosis of sarcopenia was easily made without the need for supplementary procedures and additional costs.

Furthermore, BMI Z-score and PNI significantly decreased from diagnosis to 12 months after treatment. The mechanisms underlying the reduction of BMI Z-score and PNI could be similar to those of the reduction in muscle mass in children with cancer. PNI is a nutritional and inflammatory marker associated with survival in numerous studies of cancer patients. It is calculated on the basis of albumin values, which are compromised both by the inflammatory status and the reduced protein intake and by lymphocytes, whose values may also be affected by myelotoxic chemotherapy [14].

The univariate analysis showed that metastatic disease, the absence of surgery during the 12 months, the ΔPNI and ΔtPMA L4–L5 > −25% adversely affected the prognosis of the population studied. This has not been shown for the change in BMI. Indeed, BMI is not a marker of muscle mass, especially in inflammatory conditions. The decline in visceral and muscle proteins generally occurs with an increase in extracellular volume, so body weight and BMI may vary little until cachexia becomes evident [46]. It has also been observed that pediatric patients with poor prognosis frequently have a high BMI due to an excess of fat or edema. In recent decades, sarcopenic obesity has emerged as a pathological condition with a loss of muscle tissue associated with an increase in adipose tissue and body weight [47]. The presence of sarcopenic obesity may adversely affect the prognosis of adult patients with cancer [47,48]. The lack of significance of the variation of the BMI Z-score as a negative prognostic factor in our population is probably the result of this mechanism.

As we have observed in children with soft tissue and bone sarcomas, a relationship between tPMA and survival has also been demonstrated in children with hepatoblastoma and neuroblastoma [49,50]. Ritz et al. observed that tPMA in children with hepatoblastoma was significantly lower than in healthy controls, even in the presence of normal body weight and height. Moreover, children with tPMA under the fifth percentile showed an increased risk of relapse and liver transplant [49]. Finally, Kawakubo et al. analyzed the rate of change in the tPMA of L3 level on CT images before and after treatment in fifteen children with high-risk neuroblastoma. They found shorter progression-free survival (PFS) and OS in the group of patients who presented a reduced skeletal muscle mass during the treatment [50].

Unlike the study conducted by Rayar et al. in children with acute lymphoblastic leukemia, the presence of sarcopenia at diagnosis and the reduction of tPMA during treatment seem not to influence the number of infectious episodes recorded during the observation [45]. However, Rayar et al. conducted their studies among children with leukemia during the induction treatment when infections are very frequent due to the intensity of the treatment to leukemia itself, which compromises the immune system [45]. Moreover, during treatment, children with leukemia undergo a modification of the gut microbiome, which can affect the nutritional status of the patients, causing an increase in infectious episodes [51]. In soft tissue and bone sarcomas, the treatment has a decisively lower myeloablative effect compared to the induction phase of leukemia with a consequent lower incidence of infectious episodes.

Our results failed to show a significant reduction in skeletal muscle mass during treatment as a prognostic value. It could be due to the small sample size of the population studied, representing the main limitations of this pilot study. However, we showed a significant reduction in tPMA between diagnosis and 12 months after treatment at an age in which muscle mass and weight should physiologically increase. Moreover, this is the first study that used tPMA measurement in the clinical setting as a marker of sarcopenia in childhood cancer. We acknowledge that tPMA is easy to use and can be determined through a routinely abdominal CT. Since all patients with soft tissue and bone sarcoma undergo numerous disease stages with abdominal CT, tPMA can be simply performed also during the treatment and the follow-up visits. Further studies with a more robust design and higher sample size are warranted to confirm or rebut our results.

#### **5. Conclusions**

Sarcopenia may occur in pediatric patients with soft tissue and bone sarcoma already at diagnosis. The diagnosis of sarcopenia can be easily performed by measuring the tPMA from single cross-sectional abdominal CT images at the level of L4–L5, according to tPMA Z-scores specific for the sex and age of the patients. Our study showed a reduction of tPMA Z-scores between diagnosis and at 12 months of treatment. This could be crucial for OS, tolerance, and the response to the treatment; therefore, careful surveillance should be performed, to allow the implementation of nutritional and physical rehabilitation measures. Furthermore, significant differences in BMI Z-scores and PNI may be observed after 12 months of treatment, and consequently, nutritional and immune status should be closely monitored throughout the treatment.

Prospective and larger studies may help to better investigate the role of tPMA derived from CT scan in this particular setting of patients, to implement their use in the clinical practice, allowing a therapeutic approach as personalized as possible.

**Author Contributions:** Conceptualization, S.T., E.R., M.C.M. and A.R. (Antonio Ruggiero); methodology, S.T. and M.C.; software, E.R., P.R., L.N. and M.G.B.; validation, A.G. and M.C.M.; formal analysis, E.R. and M.C.; investigation, S.T. and M.C.; resources, A.R. (Alberto Romano), G.A. and P.M.; data curation, L.N. and M.G.B.; writing—original draft preparation, A.R. (Alberto Romano) and S.T.; writing—review and editing, S.T. and E.R.; visualization, L.N. and S.M.; supervision, E.R. and A.G.; project administration, E.R. and M.C.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of our institution (Protocol ID 4211, Approval Letter Number 36155/21).

**Informed Consent Statement:** Informed consent was obtained from all subjects' parents involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author for any academic use upon citation of this article. The data are not publicly available due to privacy and permission restricted to the publication of this article only.

**Acknowledgments:** The authors thank "Sara un angelo con la bandana ONLUS" for their dedicated patient care and scientific support.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**RECENT INSIGHTS IN PETROLEUM SCIENCE AND ENGINEERING**

Edited by **Mansoor Zoveidavianpoor**

#### **Recent Insights in Petroleum Science and Engineering**

http://dx.doi.org/10.5772/65538 Edited by Mansoor Zoveidavianpoor

#### **Contributors**

Naga Raju Maddela, Laura Scalvenzi, Tatjana Paulauskiene, Galba Maria Campos-Takaki, Marcos Antonio Babosa Lima, Luciana De Oliveira Franco, Manfred Schwartz, Kaoru Okada, Aline Elesbão Do Nascimento, Carlos Alberto Alves Da Silva, Patricia Mendes Souza, Thayse Alves De Lima E Silva, Ian Garrard, Elias B Tambourgi, Nabil Mohammed Al-Areeq, Nohra Violeta Gallardo Rivas, Ernestina Elizabeth Banda Cruz, Ulises Paramo-Garcia, Ana María Mendoza-Martínez, José Aarón Melo Banda, Oscar E. Vázquez-Noriega, Javier Guzmán-Pantoja, Maria Yolanda Chavez-Cinco, Reinaldo David Martínez-Orozco, Luciano Aguilera-Vázquez, Luis A. Alcazar-Vara, Ignacio R. Cortés-Monroy, Reda Abdelazim, Sara Faiz, Nour Al Obaidi, Ahmed Al Bagir, Bing Wei, Lezorgia Nekabari Nwidee, Ahmed Barifcani, Stefan Iglauer, Mohammad Sarmadivaleh, Mouna Mahjoubi, Simone Cappello, Yasmine Souissi, Ameur Cherif, Yongtu Liang, Haoran Zhang, Jing Ma, Pengwei Di, Xiaohan Yan, Zhongliang Huang, Adolfo Pires, Rafael Scardini, Viatcheslav Priimenko, David Lacerda, Andre Vinhal, Igor Evdokimov, Aleksey Fesan, Aleksandr Losev, Abiodun Olagoke Adeniji, Omobola Okoh, Anthony Okoh, Muftah El-Naas, Taghreed Al-Khalid, Pradip Mandal, Mitsuru Sasaki, Dmitry Borisov, Dmitry Milordov, Svetlana Yakubova, Makhmut Yakubov

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**1. Introduction**

The Finnish education system offers an interesting and internationally recognised example of a high-performing system that successfully combines high quality with widely spread equity and social cohesion through reasonable public financing [1, 2]. The Finnish system differs in several ways from most other European countries and the US.

example of a teacher education programme. Finally, an analysis of teacher education reform will be offered, concentrating on how the pursuit of this goal has been supported through

Educating Professional Teachers in Finland through the Continuous Improvement of Teacher…

http://dx.doi.org/10.5772/intechopen.77979

5

A key goal of teacher education in all countries is to educate high-quality, *professional teachers* through a high-quality post-secondary programme and then support teachers through their career in professional development. However, different definitions and interpretations have been offered concerning teacher professionalism. Several other terms, including effective, competent, expert, or ideal teachers are used in a similar way as a *professional teacher* [8–10]. Teacher quality is typically approached by analysing (1) the knowledge base of a professional teacher (input approach), (2) the process or the interaction that occurs in the classroom between the teacher and students (process approach) or (3) the outcomes of the teaching and learning process, such as students' learning outcomes measured by national tests or graduation rates (output approach) [10]. In the first case, teachers reaching high levels of quality are typically

According to the 'input approach', a professional teacher is supposed to have a versatile knowledge base, allowing him or her to act as an autonomous professional. The term 'knowledge' is interpreted broadly in this context and is close in meaning to 'competence' or 'skill'. This knowledge base is supportive for the planning, organising and evaluation of teachers' own teaching, students' learning and their learning outcomes. Planning, broadly conceived, includes all steps from the planning of the local curriculum to the planning of a single lesson. Finland has followed this input type of orientation in the education of professional teachers.

Teacher professionalism does not only refer to the competence of individual teachers but also to their status. Overall professionalism depends on factors operating at the school level and on cultural and education policy as well as such individual characteristics as their knowledge base, teaching philosophy and interaction and collaboration skills [11]. Important school-level factors include the nature of school leadership, the culture of collaboration and the structure of networks and school-society-family partnerships. Cultural and education policy factors include the state-level context, including whether the country is following a more accountability-oriented educational policy or whether it trusts teachers without relying heavily on practices of inspection and testing.

To characterise teacher professionalism, a description of their knowledge base is the logical starting point. One well-known approach for describing this knowledge base is Shulman's work [12, 13], in which he made the distinction between different domains of knowledge for teaching, including content (subject matter) knowledge, pedagogical content knowledge and curricular knowledge [14, 15]. The level and depth of teachers' knowledge in these domains

**2. Teacher professionalism as an aim in teacher education**

called professional teachers and in the third case, referred to as effective teachers.

**2.1. Shulman's model of teachers' professional knowledge**

are the basis of professionalism [16, 17].

collaborative strategies.

The quality of Finnish education has been promoted through a decentralised approach since the 1990s, in all areas of governance. Following this decentralisation, only basic guidelines are prepared at a national level, such as framework curricula and teacher education strategies. Finland has never based its educational system on standardised testing, as have many countries that follow an outcome-based educational model. Providers of education, typically municipalities, have been responsible for quality assurance and the preparation of local curricula, in collaboration with local stakeholders and families.

Teachers in Finland are highly educated. All teachers at the elementary, middle and high school levels are required to have a Master's degree. In fact, the education of elementary teachers (Grades 1–6) at the Master's level has been entrenched for 35 years, while secondary teachers (Grades 7–12) have been trained at Master's-level programmes for more than 100 years. An essential characteristic of teacher education in Finland has been its emphasis on research [3]. Following this perspective, student teachers learn both how to consume and how to produce educational knowledge. This research knowledge is needed for local curriculum planning and the development of teaching and school practices, as well as for the assessment of teaching and learning. Consequently, quality is assured primarily at the teachers' level. Over recent decades, studies have indicated that local curriculum processes have inspired and empowered teachers and principals to develop the local curriculum and their own work processes and, moreover, to increase the quality of education overall. Education authorities and national-level education policymakers trust professional teachers [4, 5].

The teaching profession in Finland has always enjoyed great public respect and appreciation [6]. There are several reasons why teaching is an attractive occupation in Finland. In addition to the academic status of teachers, they enjoy collaboration with and receive support from school leaders and communities. Moreover, national education policy and its practical implementation, including the strong culture of quality and the key role of teachers in assessment activities, support the professional ethos of teachers [7]. Decentralisation allows teachers to consider local contexts and to address diversity among the students they teach. Decentralisation in education is strongly linked to the Finnish way of interpreting teacher professionalism and the status of teachers in Finnish society.

The aim of this chapter is to analyse *how professional teachers are educated in the Finnish educational context and how teacher education has improved to position the teaching profession for new and challenging contexts in the future*. First, a short overview of the research on teacher professionalism and effectiveness is introduced. Then, the successes and challenges of the Finnish educational context and the role of teachers in this environment are discussed. Third, primary and secondary teacher education at the University of Helsinki is shortly introduced as an example of a teacher education programme. Finally, an analysis of teacher education reform will be offered, concentrating on how the pursuit of this goal has been supported through collaborative strategies.


Synthesis of Quinazoline and Quinazolinone Derivatives

*Heba E. Hashem*

#### **Abstract**

Active heterocyclic compounds are one of the main topics of interest for the medicinal chemists as they display a number of pharmacological activities. Nitrogen, sulfur, and oxygen containing five- and six-membered heterocyclic compounds have occupied enormous significance in the field of medicinal chemistry. The most important six-membered heterocyclic compounds are quinazoline and quinazolinone derivatives for their biological activities. The current chapter outlined the different methods for synthesis of quinazoline and quinazolinone derivatives that possess broad spectrum of biological activities.

**Keywords:** quinazoline, quinazolinone synthesis, six-membered heterocycles, biological activity

#### **1. Introduction**

Quinazoline (1,3-diazanaphthalene or 5,6-benzopyrimidine) and 4(3H) quinazolinone derivatives have a great interest in organic synthesis and medicinal chemistry fields as they possess a broad range of pharmacological activities. They exhibit antimicrobial [1], antimalarial [2], antioxidant [3], anti-inflammatory [4], anticonvulsant [5], antihypertensive [6], antidiabetic [7], and antitumor activities [8–10].

Many quinazolinone derivatives occurred naturally in various classes of the plant kingdom, microorganisms, and different animals (**Figure 1**). The first discovery of quinazolinone alkaloid is *febrifugine* which possesses antimalarial potential, extracted from the Chinese plant *aseru* (*Dichroa febrifuga* Lour) [11].

Quinazoline is a heterocyclic compound of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. It is a yellow-colored compound, found usually in crystalline form. Its oxo-derivative (quinazolinone) is classified into three types according to the position and number of carbonyl group: 2(1H) quinazolinones, 4(3H)quinazolinones, and 2,4(1H,3H)quinazolinedione (**Figure 2**).

#### **2. Chemistry of quinazoline**

Quinazoline is a compound made up of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. The properties of the pyrimidine ring were affected by the presence of fused benzene ring. The two nitrogen atoms are not equivalent, and the marked polarization of the 3,4-double bond is reflected

O-aminobenzaldehyde, ammonia, and formic acid. Quinazoline derivative can be easily oxidized in acidic medium at room temperature to give 3,4-dihydro-4-oxo quinazoline, while in alkaline medium using potassium permanganate will afford

The spectroscopic analysis of some synthesized quinazoline and quinazolinone derivatives was studied to investigate their structures including infrared, mass

Quinazoline derivatives found to give mainly three absorption bands in IR

correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680–1700 and 1640–1660 cm1 corresponding to C=O and C=N groups [13, 14].

HNMR, and elemental analysis. The resulted data could be taken as

; these represented bands are

**3. Spectral characterization of quinazoline and quinazolinone**

standard for the new synthesized quinazoline analogue [13].

spectra: 1478–1517, 1566–1581, and 1612–1628 cm1

3,4-dihydro-6 4-oxo quinazoline (cf. **Figure 3**).

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*Oxidation reaction of quinazoline at different medium.*

**derivatives**

**Figure 3.**

spectroscopy, 1

**43**

**3.1 Infrared spectra**

**Figure 1.** *Structure of different quinazolinone alkaloids.*

#### **Figure 2.**

*Structure of quinazoline and different quinazolinone compounds.*

in the reactions of quinazoline. The properties of quinazoline derivatives depend on the following three factors:

The first synthesized quinazoline in laboratory was achieved by Gabriel in 1903 [12]. Most of quinazoline derivatives are stable in cold acidic or basic medium but can be destroyed at high temperature and undergo ring opening reaction, affording *Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

**Figure 3.** *Oxidation reaction of quinazoline at different medium.*

O-aminobenzaldehyde, ammonia, and formic acid. Quinazoline derivative can be easily oxidized in acidic medium at room temperature to give 3,4-dihydro-4-oxo quinazoline, while in alkaline medium using potassium permanganate will afford 3,4-dihydro-6 4-oxo quinazoline (cf. **Figure 3**).

## **3. Spectral characterization of quinazoline and quinazolinone derivatives**

The spectroscopic analysis of some synthesized quinazoline and quinazolinone derivatives was studied to investigate their structures including infrared, mass spectroscopy, 1 HNMR, and elemental analysis. The resulted data could be taken as standard for the new synthesized quinazoline analogue [13].

#### **3.1 Infrared spectra**

Quinazoline derivatives found to give mainly three absorption bands in IR spectra: 1478–1517, 1566–1581, and 1612–1628 cm1 ; these represented bands are correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680–1700 and 1640–1660 cm1 corresponding to C=O and C=N groups [13, 14].

in the reactions of quinazoline. The properties of quinazoline derivatives depend on

b. The presence of substituent whether they are in the pyrimidine ring or in the

The first synthesized quinazoline in laboratory was achieved by Gabriel in 1903 [12]. Most of quinazoline derivatives are stable in cold acidic or basic medium but can be destroyed at high temperature and undergo ring opening reaction, affording

the following three factors:

**Figure 2.**

**42**

**Figure 1.**

benzene ring

a. The nature of the substituents

*Structure of different quinazolinone alkaloids.*

*Quinazolinone and Quinazoline Derivatives*

*Structure of quinazoline and different quinazolinone compounds.*

c. The presence of conjugation in the pyrimidine ring

The 1 HNMR spectra of quinazoline and quinazolinone derivatives are different from each other according to the presence of acidic proton and its position in the presented compound. In general the 1HNMR spectrum of the main quinazoline (I) represents multiple signals in the aromatic region δ 7–8 and two singlet signals for the two CH=N protons at δ 9–9.5 ppm, while quinazolinone (II) will show also signals of aromatic protons in the same region as well as one singlet signal for CH=N proton and one broad singlet signal at the down-field region for the NH proton at δ 12–13 ppm [13, 14].

On the other hand, the 13C NMR spectrum for quinazoline and quinazolinone derivatives is nearly the same, as it shows signals at δ 100–160 ppm region.

### **4. Synthesis of quinazoline and quinazolinone derivatives**

The synthesis of various quinazoline compounds is largely based on the substitution patterns of the 1,3-diazine moiety of the system. The first quinazoline derivative (2-cyano-3,4-dihydro-4-oxoquinazoline) was synthesized in 1869 by the reaction of cyanogens with anthranilic acid [15]. Many years later quinazoline was obtained by decarboxylation of the 2-carboxy derivative (quinazolinone) which can be synthesized more easily by a different method.

*<IP_ADDRESS> Reaction with different aromatic amines*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

(4) [18].

to the reaction medium [19].

*<IP_ADDRESS> Reaction with hydrazine hydrate*

(10) [13].

**45**

It was stated by several authors that 2-substituted benzoxazinone reacted easily with primary aromatic amines, giving the corresponding quinazolones

On the other hand, reaction of benzoxazinone (5) with o-phenylenediamine gave quinazolinone derivative (6) or the fused quinazoline derivative (7) according

It was reported that benzoxazinone (8) reacted with hydrazine hydrate in ethanol and has the corresponding quinazolinone (9), while carrying out the same reaction in boiling acetic acid glacial afforded the fused quinazoline

#### **4.1 Synthesis of quinazolinone**

#### *4.1.1 Niementowski's synthesis*

From anthranilic acid and formamide.

#### *4.1.2 Grimmel, Guinther, and Morgan's synthesis*

From the reaction of o-amino benzoic acid with amine in the presence of phosphorus trichloride in toluene.

*4.1.3 From 3,1,4-benoxazones (acylanthranils) and amines*

Various quinazoline and quinazolinone derivatives can be synthesized from the reaction of benzoxazinone and different amine compounds in different media.

#### *<IP_ADDRESS> Reaction with ammonium hydroxide*

When ammonium hydroxide reacted with benzoxazinone (1) over 1–3 h, it produced anthranilamides (2) which cyclizes to 4-quinazolones (3) under thermal conditions (240–280°C) or on heating with acetic anhydride [16, 17].

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

The 1

*Quinazolinone and Quinazoline Derivatives*

12–13 ppm [13, 14].

HNMR spectra of quinazoline and quinazolinone derivatives are different

from each other according to the presence of acidic proton and its position in the presented compound. In general the 1HNMR spectrum of the main quinazoline (I) represents multiple signals in the aromatic region δ 7–8 and two singlet signals for the two CH=N protons at δ 9–9.5 ppm, while quinazolinone (II) will show also signals of aromatic protons in the same region as well as one singlet signal for CH=N proton and one broad singlet signal at the down-field region for the NH proton at δ

On the other hand, the 13C NMR spectrum for quinazoline and quinazolinone

derivatives is nearly the same, as it shows signals at δ 100–160 ppm region.

The synthesis of various quinazoline compounds is largely based on the substitution patterns of the 1,3-diazine moiety of the system. The first quinazoline derivative (2-cyano-3,4-dihydro-4-oxoquinazoline) was synthesized in 1869 by the reaction of cyanogens with anthranilic acid [15]. Many years later quinazoline was obtained by decarboxylation of the 2-carboxy derivative (quinazolinone) which

From the reaction of o-amino benzoic acid with amine in the presence of

Various quinazoline and quinazolinone derivatives can be synthesized from the reaction of benzoxazinone and different amine compounds in different media.

When ammonium hydroxide reacted with benzoxazinone (1) over 1–3 h, it produced anthranilamides (2) which cyclizes to 4-quinazolones (3) under thermal

conditions (240–280°C) or on heating with acetic anhydride [16, 17].

**4. Synthesis of quinazoline and quinazolinone derivatives**

can be synthesized more easily by a different method.

From anthranilic acid and formamide.

*4.1.2 Grimmel, Guinther, and Morgan's synthesis*

*4.1.3 From 3,1,4-benoxazones (acylanthranils) and amines*

*<IP_ADDRESS> Reaction with ammonium hydroxide*

**44**

phosphorus trichloride in toluene.

**4.1 Synthesis of quinazolinone**

*4.1.1 Niementowski's synthesis*

#### *<IP_ADDRESS> Reaction with different aromatic amines*

It was stated by several authors that 2-substituted benzoxazinone reacted easily with primary aromatic amines, giving the corresponding quinazolones (4) [18].

On the other hand, reaction of benzoxazinone (5) with o-phenylenediamine gave quinazolinone derivative (6) or the fused quinazoline derivative (7) according to the reaction medium [19].

#### *<IP_ADDRESS> Reaction with hydrazine hydrate*

It was reported that benzoxazinone (8) reacted with hydrazine hydrate in ethanol and has the corresponding quinazolinone (9), while carrying out the same reaction in boiling acetic acid glacial afforded the fused quinazoline (10) [13].

#### *<IP_ADDRESS> Reaction with different carbohydrazide*

Treatment of 2-substituted-3,1-benzoxazin-4-ones (11) with semicarbazide hydrochloride in dry pyridine is a good way to construct a third heterocyclic ring condensed with quinazoline (12) [18].

It was also reported that refluxing an equimolar amount of the benzoxazinone (8) with thiocarbonohydrazide in ethanol and in the presence of few drops of glacial acetic acid furnished quinazolinone (20) in the two isomers of thione and thiol form [13].

Isobutyrylanilides with urethane and phosphorus pentoxide in xylene gave 2-

propyl- and 2-isopropyl-3,4-dihydro-4-oxoquinazolines.

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*4.1.4 Sen and Ray's synthesis*

**47**

The reaction of benzooxazinone (8) with 2-benzamido-3-phenylacrylohydrazide (13) glacial acetic acid in the presence of fused sodium acetate gave quinazoline derivative (14). In contrast, their reaction in pyridine afforded pyrazoloquinazoline derivative (15) [13].

Reaction of benzoxazinone (8) with cyanoacetohydrazide gave the corresponding cyano quinazolinone (16) which was reacted with different nucleophiles to give fused quinazoline and annulated quinazolinone derivatives (17–19) [13].

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

It was also reported that refluxing an equimolar amount of the benzoxazinone (8) with thiocarbonohydrazide in ethanol and in the presence of few drops of glacial acetic acid furnished quinazolinone (20) in the two isomers of thione and thiol form [13].

*4.1.4 Sen and Ray's synthesis*

Isobutyrylanilides with urethane and phosphorus pentoxide in xylene gave 2 propyl- and 2-isopropyl-3,4-dihydro-4-oxoquinazolines.

*<IP_ADDRESS> Reaction with different carbohydrazide*

condensed with quinazoline (12) [18].

*Quinazolinone and Quinazoline Derivatives*

derivative (15) [13].

**46**

Treatment of 2-substituted-3,1-benzoxazin-4-ones (11) with semicarbazide hydrochloride in dry pyridine is a good way to construct a third heterocyclic ring

The reaction of benzooxazinone (8) with 2-benzamido-3-phenylacrylohydrazide (13) glacial acetic acid in the presence of fused sodium acetate gave quinazoline derivative (14). In contrast, their reaction in pyridine afforded pyrazoloquinazoline

Reaction of benzoxazinone (8) with cyanoacetohydrazide gave the corresponding cyano quinazolinone (16) which was reacted with different nucleophiles to give fused

quinazoline and annulated quinazolinone derivatives (17–19) [13].

#### *4.1.5 From 2-aminobenzylamine*

Reaction of 2-aminobenzylamine with butyrolactone further condensed with benzaldehyde afforded 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-quinazoline.

### **5. Biological importance of quinazoline derivatives**

As we mentioned above, the important biological activity of quinazoline and quinazolinone skeletons in various fields depends mainly on the substituents of quinazoline compounds. Different substituted quinazoline compounds are found to be active as antihypertensive, antineoplastic, antidepressant, and antipsychotic, and others are effective against analgesic, antipsychotic, antiarrhythmic, cancer, and other activities [20–22].

#### **5.1 Anticancer**

It was reported that 3-substituted quinazolin-4(3H)-ones and 3,4-dihydroquinazolin-2-(1H)-one derivatives possess broad spectrum antitumor activities toward different cell (**Figure 4**) [23].

Also, different quinazoline derivatives containing thiosemicarbazide moiety possess antitumor activity (**Figure 5**) [24].

#### **5.2 Antibacterial activity**

It was reported that some novel substituted iodoquinazoline derivatives possess remarkable activity toward Gram-negative bacteria *E. coli* (**Figure 6**) [25].

#### **5.3 Antiviral agents**

A series of Schiff bases of some 2-phenyl quinazoline-4(3)H-one derivatives have shown great activity as antiviral agents (**Figure 7**) [26].

**5.4 Antimutagenic activity**

*Quinazoline derivatives with antibacterial activity.*

**Figure 5.**

**Figure 6.**

**Figure 7.**

**49**

**5.5 Antioxidant activity**

The (S)-4-aminoquinazoline alcohols performed great antimutagenic activity when tested by using *Salmonella typhimurium* and *E. coli* WP2uvrA tester strains at

Some novel thiazoloquinazoline derivatives are investigated for antioxidant activity by DPPH radical assay, nitric oxide scavenging activity, and hydrogen

0.01, 0.1, and 1 lg/plate concentrations (**Figure 8**) [27].

*Different schiff base of quinazolinone with antiviral activity.*

*Quinazoline derivatives bearing thiosemicarbazide possess anti-tumor activity.*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

**Figure 4.** *Anti-tumor quinazolinone derivatives.*

*Synthesis of Quinazoline and Quinazolinone Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89180*

*4.1.5 From 2-aminobenzylamine*

*Quinazolinone and Quinazoline Derivatives*

other activities [20–22].

**5.2 Antibacterial activity**

**5.3 Antiviral agents**

**Figure 4.**

**48**

*Anti-tumor quinazolinone derivatives.*

toward different cell (**Figure 4**) [23].

possess antitumor activity (**Figure 5**) [24].

**5.1 Anticancer**

Reaction of 2-aminobenzylamine with butyrolactone further condensed with benzaldehyde afforded 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-quinazoline.

As we mentioned above, the important biological activity of quinazoline and quinazolinone skeletons in various fields depends mainly on the substituents of quinazoline compounds. Different substituted quinazoline compounds are found to be active as antihypertensive, antineoplastic, antidepressant, and antipsychotic, and others are effective against analgesic, antipsychotic, antiarrhythmic, cancer, and

It was reported that 3-substituted quinazolin-4(3H)-ones and 3,4-dihydroquinazolin-2-(1H)-one derivatives possess broad spectrum antitumor activities

Also, different quinazoline derivatives containing thiosemicarbazide moiety

It was reported that some novel substituted iodoquinazoline derivatives possess

A series of Schiff bases of some 2-phenyl quinazoline-4(3)H-one derivatives

remarkable activity toward Gram-negative bacteria *E. coli* (**Figure 6**) [25].

have shown great activity as antiviral agents (**Figure 7**) [26].

**5. Biological importance of quinazoline derivatives**

**Figure 5.** *Quinazoline derivatives bearing thiosemicarbazide possess anti-tumor activity.*

**Figure 6.** *Quinazoline derivatives with antibacterial activity.*

**Figure 7.**

*Different schiff base of quinazolinone with antiviral activity.*

#### **5.4 Antimutagenic activity**

The (S)-4-aminoquinazoline alcohols performed great antimutagenic activity when tested by using *Salmonella typhimurium* and *E. coli* WP2uvrA tester strains at 0.01, 0.1, and 1 lg/plate concentrations (**Figure 8**) [27].

#### **5.5 Antioxidant activity**

Some novel thiazoloquinazoline derivatives are investigated for antioxidant activity by DPPH radical assay, nitric oxide scavenging activity, and hydrogen

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**Figure 8.** *Antimutagenic activity of amino quinazoline derivative.*

**Figure 9.** *Antioxidant activity of different quinazoline.*

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