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Item Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives(Elsevier Masson SAS infos@masson.fr 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.; Yogeeswari, P.; Sriram, D.; Peethambar, S.K.; Achur, R.; Santosh Kumar, H.S.S.In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by 1H NMR, 13C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 ?g/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line. © 2015 Elsevier Masson SAS.Item New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies(Elsevier Ltd, 2015) Panathur, N.; Gokhale, N.; Udayakumar, U.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 ?M, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. © 2015 Elsevier Ltd. All rights reserved.Item One-pot synthesis of new triazole - Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity(Elsevier Ltd, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.; Yogeeswari, P.; Sriram, D.A new series of triazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a-s, 7a) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were characterised using spectral methods and one of the target compounds (6c) was analysed by the single crystal XRD study. The derivatives were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 6f and 6n, demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of 3.125 ?g/mL. The presence of chloro substituent on the imidazo[2,1-b][1,3,4]thiadiazole ring and ethyl, benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general cellular toxicity of these compounds. © 2015 Elsevier Ltd. All rights reserved.Item New INH-pyrazole analogs: Design, synthesis and evaluation of antitubercular and antibacterial activity(Elsevier Ltd, 2015) Nayak, N.; Ramprasad, J.; Udayakumar, U.With the aim of developing promising antitubercular and antibacterial leads, we have designed and synthesized a new series of isonicotinohydrazide based pyrazole derivatives (5a-r). All new derivatives (4a-b and 5a-r) were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) strain. Four compounds 5j, 5k, 5l and 4b emerged as promising antitubercular agents with MIC of ?4.9 ?M which is much lower than the MIC of the first line antitubercular drug, ethambutol. The 3-chlorophenyl substituent at position-3 of the pyrazole ring enhanced the antiTB activity of the molecules. Three derivatives 5b, 5k and 4b exhibited promising antibacterial activity against the tested bacterial strains. The active molecules were nontoxic to normal Vero cells and showed high selectivity index (>160). The structure and antitubercular activity relationship was further supported by in silico molecular docking study of the active compounds against enoyl acyl carrier protein reductase (InhA) enzyme of M. tuberculosis. © 2015 Published by Elsevier Ltd.Item Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents(Elsevier Masson SAS 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 ?g/mL (?1.9 ?M). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 ?g/mL), and compounds 5j, 5k and 5o (MIC = 3.125 ?g/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121. © 2015 Elsevier Masson SAS. All rights reserved.Item Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino[4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity(Birkhauser Boston, 2016) Panathur, N.; Gokhale, N.; Udayakumar, U.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.A series of pyridazino[4,5-b]indole derivatives containing alkyl-, benzyl- and phenacyl-substituted 1,2,3-triazolylmethyl units was synthesized using click chemistry approach. All 30 compounds of the series were screened in vitro against four cancer cell lines, viz. breast cancer cells MDA-MB-231 and MCF 7, human primary glioblastoma U-87 and human neuroblastoma IMR-32 cell lines. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. The IC50 value of compounds 7v and 7x against human neuroblastoma IMR-32 cell line is 0.07 and 0.04 ?M, respectively. Among the tested compounds, ten compounds showed IC50 value less than 1 ?M against MDA-MB-231 cells, whereas against IMR-32 cells, nine compounds and, against U-87 cells, six compounds showed similar inhibition activity. Further, these molecules exhibited prominent binding affinity and docking scores in the molecular simulation study with the target enzyme PI3 kinase. Graphical Abstract: This paper illustrates the synthesis of new fused indole-pyridazinone derivatives containing substituted 1,2,3-triazoles via click chemistry approach. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. [Figure not available: see fulltext.] © 2015 Springer Science+Business Media New York.Item Design, Synthesis, and Biological Evaluation of New 8-Trifluoromethylquinoline Containing Pyrazole-3-carboxamide Derivatives(HeteroCorporation, 2017) Nayak, N.; Ramprasad, J.; Udayakumar, U.The article describes the design, synthesis, and characterization of a new series of 8-trifluoromethylquinoline substituted pyrazole-3-carboxamides (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) derived from different primary and secondary amines. The intermediate and target compounds were characterized using spectroscopic methods. The structures of intermediate 7 and target molecule 9d were evidenced by the single crystal X-ray study. All the synthesized target compounds (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) and three intermediates (6, 7, 8) were screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 9k and 9t, showed significant inhibition activity with MIC of 3.13 µg/mL, which is comparable with the activity of standard drug, ethambutol. The carboxamides derived from benzylamine derivatives were more active than their aniline analogs. In general, the hybrid amides with a N-methylene linkage (-CONHCH2-) exhibited enhanced antitubercular activity. In the antibacterial screening, intermediate 3-hydrazinyl-2-methyl-8-(trifluoromethyl)quinoline (6) displayed remarkable activity against the tested bacterial strains. Further, the active anti-TB derivatives were non-toxic to benign NIH 3T3 cells, which demonstrate the lack of general cellular toxicity and hence signifies their suitability for further lead development. © 2015 HeteroCorporationItem Structural modification of zolpidem led to potent antimicrobial activity in imidazo[1,2-: A] pyridine/pyrimidine-1,2,3-triazoles(Royal Society of Chemistry, 2019) Reddyrajula, R.; Udayakumar, U.Ambien (zolpidem), an imidazo[1,2-a]pyridine derivative, is a commercial drug to treat insomnia which also possesses antitubercular activity against Mycobacterium tuberculosis H37Rv. In this paper, we describe the synthesis of three diverse lead series of imidazo[1,2-a]pyridine/pyrimidine-1,2,3-triazoles (IPTs) which are designed by specific structural modifications of zolpidem. Most of the IPTs exhibited remarkable in vitro antitubercular activity with an MIC of 1.56 ?g mL-1, which is two-fold higher than the MIC of zolpidem. Further, the synthesized IPTs displayed moderate inhibitory activity against several bacterial and fungal strains as well, and also showed an acceptable safety profile as verified through in vitro cytotoxicity assessment against Vero cells. In addition, the potent IPTs exhibited promising binding interactions within the active site of the InhA enzyme. An interesting correlation between the in vitro inhibitory activity and the binding mode was observed: most of the potent molecules (MIC = 1.56 ?g mL-1) interact through a H-bond with the Tyr 158 residue of the target enzyme. These efforts toward the structural modification of zolpidem could be helpful for further optimization of the IPT core to develop new anti-TB drugs. This journal is © 2019 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.Item Molecular hybridization approach for phenothiazine incorporated 1,2,3-triazole hybrids as promising antimicrobial agents: Design, synthesis, molecular docking and in silico ADME studies(Elsevier Masson SAS 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2019) Reddyrajula, R.; Udayakumar, U.; Madan Kumar, S.The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 ?g/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads. © 2019 Elsevier Masson SASItem Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2(Academic Press Inc. apjcs@harcourt.com, 2019) Manjula, R.; Gokhale, N.; Unni, S.; Deshmukh, P.; Reddyrajula, R.; Srinivas-Bharath, M.M.; Udayakumar, U.; Padmanabhan, B.Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases. © 2019 Elsevier Inc.