Letters in Drug Design & Discovery - Volume 15, Issue 10, 2018

Background: A number of novel fluorinated 4,5-dihydropyrazolo [4,3-f][1,2,3] triazolo diazepines (9-11) have been accomplished starting from 1-phenyl-3-trifluoromethyl pyrazole-5-one (3) in a multistep synthesis. Thus obtained compound 9 was converted into corresponding 5-aryl / alkyl fluorinated 4,5-dihydropyrazolo [4,3-f][1,2,3]triazolo diazepinones 10a-j and also 3,5-diaryl / dialkyl fluorinated 4,5-dihydropyrazolo [4,3-f][1,2,3]triazolo diazepinones 11a-c and all the compounds 9-11 were evaluated for in vitro cytotoxic activities. The outcome of the study showed that compounds 9, 10c, 11a showed very promising activity against MCF7, HeLa, Neuro2a and A549 cell lines. Further, compound 10g showed good activity against HeLa, Neuro2a and A549 cell lines whereas 10f and 11c showed good activity against A549 cell line. Methods: Synthesis of 1,4-benzodiazepines considered as privileged structures owing to their pharmacological, medicinal and clinical importance. Among the 1,4-benzodiazepine heterocycles 1,4-benzodiazepin-5-ones are well recognized for their wide range of biological activities. In view of the biological importance of 1,4-benzodiazepines, more specifically when fused with different heterocycles i.e. pyrroles, imidazoles, triazoles and pyrimidines, we envisaged the construction of tricyclic 1,4-benzodizepinone ring system having pyrazole and triazole units may become better candidates from cytotoxicity point of view. Because, pyrazole and triazole compounds gained enormous interest owing to their broad spectrum pharmaceutical and therapeutic applications. Additionally, it is well documented that presence of a trifluoromethyl functional group in an organic molecule at a specified position can lead to profound changes in physical, chemical, and especially biological properties of the molecule. With this background we accomplished synthesis of a number of novel fluorinated 4,5-dihydropyrazolo [4,3-f][1,2,3] triazolo diazepines starting from 1-phenyl-3-trifluoromethyl pyrazole-5-one in a multistep synthesis and evaluated for in vitro cytotoxic activities. Results & Conclusion: A series of novel fluorinated 4,5-dihydropyrazolo [4,3-f][1,2,3] triazolo diazepines (9-11) have been synthesized in a multistep synthesis and all the compounds were screened for in vitro cytotoxicity against a panel of different human tumor cell lines. The outcome of the study showed that, three compounds 9, 10c and 11a showed a very potent activity and the data is helpful to further exploit these compounds for anticancer activity mechanistic studies and also helpful to design and synthesize more such derivatives in order to take-up for further studies.

Background: PI3K/Akt/mTOR was an important signal transduction pathway, activated in tumor cells. The dual inhibitors of mTORC1 and mTORC2 could suppress the tumor growth and angiogenesis by inhibiting the abnormal signal pathway. To deeply understand the structure-activity relationship of urea-morpholinopyrimidine analogues as inhibitors of mTOR, molecular modeling studies include Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) and molecular docking was carried out. Methods: CoMFA CoMSIA and Topomer CoMFA methods created by 3D-QSAR were used to build stable model, and significant correlation coefficients for dual inhibitors (q2 = 0.750, r2 = 0.931 for CoMFA model; q2 = 0.745, r2 = 0.927 for CoMSIA model; q2 = 0.780, r2 = 0.950 for Topomer CoMFA model) were obtained. At the same time, the generated models were validated using the test sets (external predictive correlation coefficient rpred 2 = 0.696 for CoMFA; rpred 2 = 0.794 for CoMSIA). Result: These correlation coefficients confirmed that these models were correct and could be used to predict new compounds. Afterward, molecular docking study was performed to study the molecular interactions between these analogues and the receptor protein. Conclusion: In this study, the selected urea-morpholinopyrimidine compounds were docking into the active site. Some key amino acid residues such as Lys802, Ser806, Lys808 and Val882 were determined. The satisfactory results from this study may aid in the research and can be used to design novel dual inhibitors.

Background: Novel bis(1,4-dihydropyridine) derivatives linked to arene core via ester 5- 7 as well as ether linkages 10-12 were prepared, and their structures were confirmed by several spectral tools. They were evaluated as anticancer agents on A549 and MCF7 cell lines by SRB assay and as antibacterial agents on two gram-positive and two gram-negative bacterial strains by disc diffusion method. Methods: SRB assay shows that the novel compounds are more effective against lung carcinoma than human breast cancer. Compound 7 was found to be the most active compound toward A549 cell line with an IC50 value (30.7μM), while compound 12 showed great efficiency against MCF7 cell line recording an IC50 value (46.3μM). The computational studies enabled us to understand the mechanism of action of these compounds. Compound 7 was chosen for molecular docking studies on xIAP and cIAP1 proteins using MOE-2009.10 software, and the results obtained show that compound 7 bound to xIAP and cIAP1 with good energy score (S = -22.0356 Kcal/mol and -21.3381Kcal/mol), respectively. Results: With respect to the antibacterial activity, compound 12 exhibited great efficiency against the bacterial strains and hence it was used in the docking study on β-ketoacyl-ACPsynthaseIII (fabH). Conclusion: The results showed good interaction of compound 12 with fabH (with energy score S = -22.8975 kcal/mol).

Background: Chronic Myelogenous Leukemia (CML) is a kind of blood and bone marrow cancer. Tyrosine Kinase Inhibitors (TKIs) play an important role in the treatment of Chronic Myelogenous Leukemia (CML). Objective: The aims of this study are to demonstrate the different binding mode of Benzothiazole- Based analogues with T315I mutant Bcr-Abl and wild-type Bcr-Abl. Methods: In this paper, Self-Organizing Molecular Field Analysis (SOMFA), a simple Three- Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) analysis was performed on these 49 benzothiazole-based derivatives. Results: In this paper, highly predictive SOMFA models ( r2 = 0.748, rcv 2 = 0.720, F value = 124.9, and SEE = 0.761 for T315I mutant Bcr-Abl, r2 = 0.676, rcv 2 = 0.616, F value = 52.98, and SEE = 0.767 for wild-type Bcr-Abl) were obtained, and the generated models were validated using test sets. Conclusion: We obtained the best models of the training set and the statistical results for SOMFA model had a high predictive ability. The contour maps of potent compounds 9b was constructed by SOMFA method and some useful information was obtained for further designing new structures with high activity.

Background: Despite availability of variety of antibacterial agents, re-emergance of pathogenic bacteria is still a serious medical concern. Identification of new, safer, and selective antibacterial agents is the key interest in the medicinal chemistry research. Methods: A library of synthetic arylidene nicotinic and isonicotinic hydrazones (1-63) were investigated for antimicrobial activities. Results: A number of derivatives showed significant to moderate antimicrobial activities against Gram positive and Gram negative bacterial cultures. Few compounds also showed antifungal activity against fungal cultures. Minimum Inhibitory Concentration (MIC) was calculated for the most active compounds 1, 7, 11, 19, 34, 46, 50, 51, and 55 against gram positive and gram negative cultures. Conclusion: Newly identified compounds may serve as lead for future research in order to get the more powerful antibacterial agents.

Background: Going through several difficulties in crystallizing GPCRs, deeper understanding of these proteins could be understood through homology modeling and mutational studies. Due to the unavailability of experimentally solved structures, in silico models could gain insights. CCR5 is a pharmaceutically significant GPCR and it has been well-characterized even before its xtal structure. Mutagenesis studies were carried out to designate the binding pockets of CCR5 with the help of homology models. This prompted us to bring out the indispensable nature of homology modeling with CCR5 as a case study. Result: In this paper, we pointed out the advantages and limitations of homology modeling approaches through the comparison of previously reported in silico models of CCR5 with the recently emerged crystal structure. From our extensive literature studies, we found that homology modeling and associated mutagenesis studies shall provide greater understanding towards any receptor-ligand interaction and the amino acid residues involved in it. Adding a structural characteristic of the selected templates to make a multi-template model gave a new insight into homology modeling having its own merits and demerits. Conclusion: Through our observations, we emphasize that homology modeling can be a valuable tool to understand those structurally unsolved, yet clinically important drug design and discovery targeting proteins such as GPCRs.

Background: Lack of specificity and occurence of resistance to current antibacterial and antifungal agents are major shortcomings for the treatment of microbial diseases. Finding novel antimicrobial agents is therefore highly needed to develop more potent drugs. Within this framework, several indole derivatives were designed and reported in the literature. Methods: In vitro antibacterial and antifungal activities of previously synthesized novel indole compounds containing 4-substituted piperazine moieties were tested against Staphylococcus aureus (ATCC 25923), Methicilline resistant Staphylococcus aureus (MRSA, ATCC 43300), Escherichia coli (ATCC 25922), Bacillus subtilis (ATCC 6633) and Candida albicans (ATTC 10231). Sultamicillin T, ampicillin, ciprofloxacin and fluconazole were used as positive controls. Molecular docking was used to study the interaction of active compounds with their receptor. Results: Fifteen compounds were synthesized and their antibacterial activities were similar to that of the reference drugs used as controls. Compounds 4 and 15 were more active (MIC 25 μg/ml) than ampicillin (MIC 50 μg/ml) against MRSA, while they showed the same activity as sultamicillin T (MIC 25 μg/ml). All compounds showed lower activity than ciprofloxacin (MIC 25 μg/ml) against the tested microorganisms. However, none of the compounds showed remarkable antifungal activity against C. albicans. Conclusion: Compound 6 showed the best interaction with the amino acid residues of the targeted cofactor NAD+.

Background: Tuberculosis (TB), a contagious airborne disease caused by pathogen Mycobacterium tuberculosis (M. tb) is the second leading cause of death world-wide among the transferable diseases. It is therefore necessary to devote continuing effort for the identification and development of New Chemical Entities (NCEs) as potential antimicrobial agents to address this serious health problem. Methods: A series of new compounds containing fluoroquinolone ring linked to a 4-thiazolidinone moiety were synthesized and evaluated for their potential pharmacological properties. The ZnCl2 mediated construction of 4-thiazolidinone ring via the condensation/cyclization of Schiff bases with thioglycolic acid was used as a key step for the multi-step synthesis of this class of compounds. Results: When tested for antibacterial, antifungal, antitubercular activities in vitro and antioxidant activities several of these compounds showed good activities. Two compounds showed activities against both gram-(+) and gram-(-) strains and Mycobacterium smegmatis H37Rv ATCC 27294 (MTB) with MIC 16.28 and 27.86 μM, respectively. They also showed free radical scavenging properties with IC50 values in the range 23-33 μM and are appeared to be promising. Conclusion: Our study revealed that the molecular framework presented here could be a useful template for the identification of novel small molecules as promising antimicrobial / amtitubercular agents.

Background: The past decade has witnessed a significant increase in the prevalence of resistance to antibacterial and antifungal agents. To overcome this problem it is desirable to devote continuing effort in evaluating new series of chemical entities for the identification of new antimicrobial agents. Methods: The alkynyl substituted 2-amino-1,4-dihydropyrimidine framework has been explored for the identification of potential antimicrobial / cytotoxic agents. Compounds derived from this framework were synthesized using a multi-step method involving the Biginelli reaction, followed by chlorination and subsequent displacement of the chloro group by various amines and finally alkynylation via a Cu-free Sonogashira coupling. Results: Several of these compounds showed promising antimicrobial / antifungal activities and cytotoxicity against cancer cell lines indicating their potential in reducing the danger of bacterial infections in the immunocompromised cancer patients. Conclusion: We have shown that the current framework could be an attractive template for the design and generation of diversity based library of small molecules leading.

Background: Free radicals are unstable molecules with one or more unpaired electrons that can associate and oxidize the biological macromolecules causing damage. The human organism is endowed with antioxidant defenses; however, an imbalance between these defenses and the oxidative stress, derived from excess of free radicals, can trigger the development of diseases. The fighting against free radicals can receive the reinforcement of endogenous and exogenous antioxidant molecules. Plants constitute a valuable source of antioxidant compounds, thus, this review explains the activity of the main enzymatic and non-enzymatic antioxidants of plants functioning as exogenous antioxidants for humans. Methods: Works were searched through electronic databases according to article titles, abstract text, and relevance in the field of plant antioxidant compounds. Articles were analyzed and selected by the authors (WFO and PMSS) and were approved by the other authors (LCBBC and MTSC). Results: Some pathological conditions can be initiated or exacerbated by free radicals that cause cellular and molecular damages. Plants can produce constitutively antioxidant molecules, with enzymatic or non-enzymatic action; and such synthesis can be increased in certain situations when the plants are exposed to some stressors. These compounds with antioxidant action can be identified in plant extracts and even be purified with elucidation of their chemical structure. Different in vitro methodologies can be useful for screening the antioxidant action of these molecules, for example, by evaluating the reducing power of such compounds on commercially available free radicals. Nanotechnology can be used to promote local delivery of antioxidant molecules, for example, by loading such compounds into nanotubes or encapsulating them in nanoemulsions. Conclusion: Some isolated compounds approached can be used for the design of new drugs. In addition, this article reports new nanotechnological systems that promote the delivery of plant antioxidant molecules, becoming a future perspective for the elaboration of more effective formulations with these compounds.

Purpose: The aim of this study was to synthesize a series of symmetrical 2,6- diarylidenecyclohexanones (1-6) and their 6-amino-1,3-dimethyluracil monoadducts (7-10) to evaluate their cytotoxicity in a panel of cell lines. Secondly, to evaluate the effect of the most potent compound on the cell cycle of HeLa cells. Methods: The 2,6-diarylidenecyclohexanones (1-6) were synthesized by the Claisen-Schmidt condensation using cyclohexanone and the corresponding aromatic aldehyde. Monoadducts (7-10) were obtained relying in a one-pot procedure, involving a 1,4-addition of 6-amino-1,3-dimethyluracil followed by self-condensation. The cytotoxicity assay was performed using the MTT assay. The IC50 value was obtained from the dose-response curve at 48 h of treatment. HeLa cell cycle analysis was performed by flow cytometry using propidium iodide to quantify the DNA content. Results: Four of the synthesized 2,6-diarylidenecyclohexanones displayed moderate cytotoxicity in HeLa, K562, MCF7, SW480 and C33 human cell lines ranging from 15.5 to 63.2 μM. Compound 5 was the most potent in K562 (IC50 15.5 μM), C-33 (IC50 16.6 μM) and HeLa (19.0 μM) cell lines. In contrast, when a 6-amino-1,3-dimethyluracil group was added to the 2,6-diarylidenecyclohexanones, the activity was lost. In addition, we showed that compound 5 produces disruption in the cell cycle of HeLa cells, producing an increment in both the sub-G0/G1 and the G0/G1 phase population with a concomitant decrease in the S phase. Conclusion: Compound 1-3 and 5, which are 2,6-diarylidenecyclohexanone derivatives, are cytotoxic on human cell lines. The formation of monoadducts of 6-amine-1,3-dimethyluracil (7-10) was detrimental for the cytotoxic potency. The appearance of a Sub G0/G1 cell population peak, on HeLa cells treated with compound 5, suggests this compound possibly induces an apoptotic cell death.