Letters in Drug Design & Discovery - Volume 15, Issue 9, 2018

Background: Tuberculosis is global health threat caused by infectious bacillus called Mycobacterium tuberculosis. To develop newer antitubercular agents against bacterial resistance, we have designed new quinoline derivatives 6a-6f and 7a-7f by molecular hybridization approach and evaluated for antitubercular, antioxidant and cytotoxicity studies along with molecular docking study. Methods: The designed molecules were synthesized by multi-step synthetic protocol and structures of compounds were confirmed by NMR, Mass and Elemental analysis. The synthesized derivatives were screened for antitubercular activity against Mycobacterium tuberculosis using Microplate Alamar Blue Assay (MABA). The antioxidant activity and cytotoxicity were also evaluated using 1,1-Dipheny-1-picrylhydrazyl (DPPH) radical scavenging and Sulforhodamine B (SRB) assay, respectively. The molecular docking studies were performed in Glide v5.6 (Schrodinger). Results: Among the synthesized derivatives, the compounds 6d and 7d displayed promising antitubercular activity, with MIC value of 18.27 and 15.00 μM respectively and are relatively nontoxic to HeLa cell line. The synthesized compounds were found to have potential antioxidant activities with IC50 range of 73.47-123.46 μM. The molecular docking study, physicochemical and pharmacokinetic properties prediction study suggested that the synthesized derivatives have potential for development of good drug candidate. Conclusion: Herein, we designed and synthesized a series of new quinoline pharmacophores appended with isoniazid and linezolid-like fragment as a promising strategy for the development of quinoline derivatives with potent biological activities.

Background: Dyslipidemia is a serious threat to human health. The objective of our research was to develop effective FXR antagonists against dyslipidemia. Methods: Herein we describe the design, synthesis of 37 N-(5-(2,5-dimethylphenoxy)-2,2- dimethylpentyl)-benzamide derivatives and evaluated for their FXR inhibition ability compared to GS and SIPI-7623. Results: Structure–activity relationship analyses indicated that compounds containing hydroxyl on the right side of the phenyl were more effective than those without hydroxyl. Compound BI-24 was identified to have the most potent antagonic activity with an IC50 value of 10.8 μM for FXR, exhibited no cytotoxicity on HepG2 cells and reduced levels of TC, TG, LDL-C for 36%, 69%, and 32% on serum, respectively. Conclusion: Compound BI-24 may be developed to a potential agent for the treatment of dyslipidemia.

Background: Drug resistance and reservoirs of latent viral infection have prevented total eradication of the HIV-virus which underlines the need for continuous efforts in the discovery of new anti-HIV agents. The present study deals with the synthesis of novel compounds based on naturally occurring scaffolds and their evaluation as potential anti-HIV agents. Objective: Design and synthesis of styrylquinoline scaffold based new molecules and evaluation of their anti-HIV-1 activity. Methods: A series of forty three new styrylquinolines (SQLs) was designed and synthesized. The newly synthesized compounds were tested for anti-HIV-1 activity against HIV-1VB59 and HIV- 1UG070 primary isolates in TZM-bl cell lines. Results: The most active compounds 9 and 34 (IC50 = 0.5-4.0 μM), also exhibited significant inhibition activity against HIV-1VB51 primary isolate in PBMCs (IC50 = 7.3 μM). Compounds 9 and 34 were also found to inhibit HIV-1 entry into host cells and fusion inhibitory activities. The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents. Conclusion: The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents.

Background: Ester and amide derivatives of shikonin were synthesized to improve the chemical stability of shikonin. Methods: All synthesized compounds were evaluated for their antiproliferative activity against A549 cell line by SRB assay, and five of them demonstrated comparable cytotoxicity to shikonin. Results and Conclusion: The most potent compound, 22d, was more stable and potent than shikonin.

Background: Aedes aegypti is the main mosquito vector for the transmission of several serious diseases, including Japanese encephalitis, yellow fever, Zika, and dengue virus. Increasing resistance to the limited number of public health chemicals requires the evaluation of new chemicals as potential control products. Methods: Pyrimidine-based compounds have shown some efficacy for agricultural uses and as mosquitocidal products. In this paper, a series of novel pyrimidine acyl-hydrazone derivatives were synthesized. Their structures were elucidated by 1H NMR and HRMS. Results: Mosquitocidal activity was assessed against immature and adult Ae. aegypti to determine efficacy and to guide further synthetic efforts. Bioassay using 1st instar Ae. aegypti produced about 33% mortality for compounds 4b and 4l but determined that most of the compounds exhibited minimal larvicidal activity at 1ug/ul after 24 hours of exposure. Conclusion: Compound 4m (N'-(4-bromobenzylidene)-2-((2-(diethylamino)-6-methylpyrimidin-4- yl)oxy)acetohydrazide) was the most effective adulticide in this synthetic group and exhibited 40% mortality at a concentration of 3.125μg/mosq.

Background: Due to high demand of developing new compounds to solve the health issues, paracetamol resembling 4-acetamidobenzaldehyde was derivatized into different new compounds including important pharmacophores (benzimidazole, benzothiazole). The synthesized compounds were investigated for anti-Alzheimer, antioxidant and DNA binding abilities. Methods: The new compounds were synthesized by the well-established synthetic routes. All synthesized compounds were analysed by H-NMR, 13C-NMR, Mass spectrometry and FTIR. Spectrophotometric method was applied for determination of inhibition potency against AChE and BChE. DPPH free radical scavenging method was used to check the antioxidant ability and the spectrophotometric titration was utilized to study the binding ability of synthesized derivatives with DNA. Results: 4-Acetamdiobenzaldehyde based derivatives were synthesized and characterised by HNMR, 13C-NMR, Mass spectrometry and FTIR. The synthesized compounds were analysed for anti-Alzheimer activity and results were compared by docking showed that 18 and 2 are good inhibitors of AChE and BChE. The results of DPPH radical scavenging activity explored most of the synthesized compounds as good antioxidants, out of these 18 showed maximum scavenging activities. Furthermore, compound 2 exhibited maximum intrinsic binding constant (K= 9.64 × 105M-1) for DNA. Conclusion: A new series of 4-Acetamidobenzaldehyde derivatives (1-20) were synthesized, characterized and studied for their antioxidant, anti-Alzheimer and DNA binding abilities. The results of anti-Alzheimer activity were compared by docking. Most of the synthesized compounds showed very significant antioxidants, anti-cholinesterase activities. All the compounds showed weak interaction with the DNA. These compounds are suitable for further pharmacological investigations.

Objects: Three compounds, 2-phenyl-2,3-dihydrochromen-4-one (1), 2-4-(benzyloxy-3- methoxyphenyl)-2-3-dihydrochromen-4-one (2), basilmoside 24-ethyl-25-methylcholesta-5,22- dien-3-β-O-D-glucoside (3) along with Compound 4 formed by the acetylation of Compound 3 from Ocimum basilicum were isolated and structures were elucidated through spectroscopic methods including EI-Mass, 1D and 2D NMR followed by biological evaluation for the modulatory effect on insulin secretion and β-cell function. Design: An in vitro and in vivo pharmacology study. Subjects and Study Interventions: For in vitro, freshly isolated islets from Balb/c mice were incubated for 60 min with glucose supplemented with Compound(s) 1-4. For in vivo, overnight fasted Wistar rats were orally challenged with glucose (3 g/kg) 60 min after administration of compound 1 (30 mg/kg). cAMP content was measured with ELISA kit. βTC-6, MIN6 and 3T3 cells were cultured for toxicity study. Outcome Measurements: Glucose-stimulated insulin secretion, fasting blood glucose, fasting plasma insulin, insulinogenic index, immunohistochemistry and cell viability. Results: Compounds 1, 2 and 3 induced glucose-stimulated insulin secretion from mice islets and maximum stimulation was found by compound 1 comparable to standard drug tolbutamide (12.3 ± 0.375 ng/islet/hr vs. 9.99 ± 1.005 ng/islet/hr; p < 0.001). Compound 1 induced insulin secretion which was significantly inhibited by verapamil, Ca2+ channels blocker (1.59 ± 0.29 ng/islet/hr vs. 14.26 ± 1.48 ng/islet/hr). Compound 1 also enhanced significantly the intracellular cAMP contents. Compound 1 reduced blood glucose (7.13 ± 0.47 mM vs. 9.25 ± 0.67 mM; p < 0.05) and enhanced glucose-stimulated plasma insulin compared to vehicle (443.76 ± 44.72 pM vs. 304.44 ± 29.24 pM; p < 0.01). Insulinogenic index, a frequently used index of beta-cell function, was 3-fold higher (p <0.01) in compound 1-treated group compared to vehicle. Immunohistochemistry of rat pancreas revealed that compound 1 has insulin degranulation role. Fluorescence intensity analysis showed less fluorescence in compound 1-treated rat pancreas. Conclusion: Among Compounds 1-3, compound 1 modulates glucose-stimulated insulin secretion in vitro and lowers the blood glucose, enhances plasma insulin in vivo which suggests Ocimum basilicum as an effectual source of anti-diabetic management for traditional use.

Background: Mitotic kinesin Eg5, a member of the kinesin superfamily, plays an essential role in cell proliferation while the regulated cell proliferation is essential for survival, but uncontrolled cell proliferation increases the risk of cancer. Therefore development of new efficient Eg5 inhibitors is very important in cancer chemotherapy. S-trityl-L-cysteine (STLC) and their analogues are known as potent allosteric inhibitors for Eg5. In the present work, we try to develop some 3D-QSAR techniques including CoMFA and COMSIA methods to modeling and prediction of the Eg5 inhibitory activities for new STLC analogues. The result of this study not only can use to predict the Eg5 inhibitory activities of untested chemicals but also to design more active chemicals. Method: The 3D-QSAR methods including CoMFA, CoMSIA, and H-QSAR methods were performed to study the structure anti-cancer activity relationship of STLC analogues. The analysis of the contour maps from CoMFA was used for design more active Eg5 inhibitors. Results: The constructed CoMFA and CoMSIA models produced statistically significant results with the cross-validation correlation coefficients Q2 of 0.608 and 0.5, noncross-validation correlation coefficients R2 of 0.988 and 0.943, standard errors SE of 0.0937 and 0.2, and predicted correlation coefficients R2pred of 0.925 and 0.761, respectively. The analysis of the steric contour maps from CoMFA showed sterically bulky groups (R1) in para position have a favorable effect on inhibitory activity. Also, the electrostatic contour map of CoMFA model suggests that the presence electron negative substituent in the meta and para position can increase the inhibitory activity. Conclusion: Based on the result of COMFA model newly compounds with good predictive activity have been designed and predicted. Our finding in design represents both factors affinity to Eg5 and physicochemical properties of inhibitor should be considered in design and synthesis.

Background: Dipeptides and their analogs have multiple biological functions, such as bitter taste, angiotensin-converting enzyme (ACE) inhibition, etc. That design and modification of dipeptides guided by theoretical models are of great significance for research and development on drug, especially in discovery and optimization of lead compound, which can reduce the experimental expenditure and improve the hit rate. Methods: We used conventional 3D-QSAR methods, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA), and Topomer CoMFA to construct Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models for four catalogues of dipeptides and their derivatives, which were bitter-tasting dipeptides, ACE-inhibitory dipeptides, anti-cryptococcal and anti-microtubule dipeptide derivatives. The CoMFA and CoMSIA models based on a training set were optimized through varying the force fields and their combination. Topomer CoMFA experientially completed identification and alignment of pose of the fragments. Results and Conclusion: We have achieved theoretical 3D-QSAR models with good reliability of prediction for correspondingly novel samples, which had good statistically significance with excellent cross-validated correlation coefficients (Q2 >0.5) and conventional correlation coefficients (R2 >0.9). The counter maps from the CoMFA and CoMSIA models could provide the direct information about contributions of the force fields for activity, aiding the design and modification of novel bioactive dipeptides and by which relationships between bitter dipeptides with ACEinhibitory dipeptides were explored briefly and a set of novel anti-cryptococcal dipeptide derivatives with predicted activities were designed. Topomer CoMFA models for bitter dipeptides, ACEinhibitory dipeptides and anti-cryptococcal dipeptidomimetics were ideal, proved the above results and could provide a tool for virtual screening.

Background: Epigenetics has proven to be a missing link to understand different diseases. However, the full understanding of chemical modifications of histones is still challenging. Initial research was focused on the ‘editing’ (writing/erasing) processes in the epigenome. More recently, the modulation of ‘reader’ enzymes has shown therapeutic potential. Bromodomains and Extra Terminal domain (BET) proteins have been related to chronic diseases such as diabetes and cancer. Different inhibitors of the BET family are known but, to date, none of them has reached approval for clinical use. Herein we discuss the insights of a structure-based analysis of the enzyme active site and searching of new BRD4 inhibitors. Methods: The search for novel inhibitors was based-on a multi-step approach using 2D and 3D similarity searching followed by molecular docking. Results: Among the most promising hits, one has a novel chemical scaffold. Other hit has a molecular scaffold with experimental report of activity. The later result supported the proof-of-concept of the computational approach. Receptor mapping provided additional insights into the pharmacophoric characterization of BET-inhibitors as well as on the haptophoric features required for optimal inhibition and ligand recognition. Conclusions: Finasteride and amentoflavone are promising candidates for BET inhibition. Amentoflavone has a molecular scaffold with experimental report of activity. Receptor mapping showed that the pocket size of BETs accounts for selectivity, which agreed with previous findings.

Background: Sulfur Mustard (SM), a chemical agent that is fat soluble with garlic-like or mustard odor and it needs moisture for activation. The mustard agent has alkylating, blistering and vesicating properties. Various cellular and molecular mechanisms of different signaling pathways are responsible for these acute and delayed cutaneous complications in the SM-exposed victims. The aim of this study is to review these mechanisms and signaling pathways. Methods: Published articles, books, and conference papers were searched in PubMed, Scopus and Google Scholar using relevant keywords to find studies describing the mechanisms of SM-induced dermatotoxicity. Results: Ninety percent of the SM-exposed victims show cutaneous lesions. Erythema, small vesicle, large blisters, erosion and partial or complete skin loss, are an acute sign of cutaneous SM exposure. Burning, dry skin, hypo and hyperpigmentation, pain, pruritus, redness are the most common chronic complications of SM-exposure. Various cellular and molecular mechanisms such as DNA adduct formation, inflammation, oxidative stress, and apoptosis are responsible for these acute and delayed cutaneous complications in the SM-exposed victims. Conclusion: Inflammation and formation of blister, ulcer and pseudomembrane are consequences of SM exposure in the skin. Cellular infiltration, separation of cell layers and cell death are responsible for these complications.