Identification and development of 2-methylimidazo[1,2-a]pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors

Samala, Ganesh; Nallangi, Radhika; Devi, Parthiban Brindha; Saxena, Shalini; Yadav, Reena; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.bmc.2014.05.038

Cited by 32 publications

(26 citation statements)

References 14 publications

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“…In the recent studies, several carbohydrazide of heterocyclic moieties containing N ′‐benzylidene at terminal part, are reported as potent inhibitor of pantothenate synthetase enzyme of M. tuberculosis . Moreover, our reported compounds also exhibit the similar pharmacophoric features, so probably they may share the similar mechanism of action, but further studies are required to know the exact mechanism of action.…”

Section: Resultsmentioning

confidence: 74%

Design, synthesis and biological evaluation of novel quinoline‐based carboxylic hydrazides as anti‐tubercular agents

et al. 2016

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In this study, seventeen novel quinoline-based carboxylic hydrazides were designed as potential anti-tubercular agents using molecular hybridization approach and evaluated in-silico for drug-likeness behavior. The compounds were synthesized, purified, and characterized using spectral techniques (like FTIR, (1) H NMR, and Mass). The in-vitro anti-tubercular activity (against Mycobacterium tuberculosisH37Ra) and cytotoxicity against human lung fibroblast cells were studied. Among the tested hydrazides, four compounds (6h, 6j, 6l, and 6m) exhibited significant anti-tubercular activity with MIC values below 20 μg/mL. The two most potent compounds of the series, 6j and 6m exhibited MIC values 7.70 and 7.13 μg/mL, respectively, against M. tuberculosis with selectivity index >26. Structure-activity relationship studies were performed for the tested compounds in order to explore the effect of substitution pattern on the anti-tubercular activity of the synthesized compounds.

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Section: Resultsmentioning

confidence: 74%

Design, synthesis and biological evaluation of novel quinoline‐based carboxylic hydrazides as anti‐tubercular agents

et al. 2016

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“…Samala et al. demonstrated that compound 198 is a promising inhibitor of mycobacterial pantothenate synthetase (IC 50 = 1.9 μM), and exhibit an MIC value of 4.53 μM against M. tuberculosis , and no cytotoxicity at 50 μM . Sardari and co‐workers showed that compound 199 possess anti‐TB activity (MIC = 4.59 μM) higher than isoniazid (MIC = 6.56 μM) .…”

Section: Pyridinesmentioning

confidence: 99%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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“…Compound (5e) with 4-fluorophenyl substitution was found to exhibit better activity when compared to the parent molecule with an IC 50 of 2.287 AE 0.03 mM. Post lead optimization, compound 5e emerged to be 3 times more potent than the parent molecule (10). The IC 50 s of all 16 compounds in Mtb PS inhibition assay is represented in Table 5.…”

Section: In Vitro Enzymatic Assaymentioning

confidence: 99%

“…[7][8] In continuation to our earlier reports and studies from our laboratory on Mtb PS inhibitors [9][10][11][12] , we attempted an energy-based pharmacophore (e-pharmacophore) based on a reported crystal structure of Mtb PS-inhibitor complex and utilized it for a high-throughput virtual screening strat- Abstract: Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Design of Novel Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors: Virtual Screening, Synthesis and In Vitro Biological Activities

Devi

Sridhar

Reddy

et al. 2015

Molecular Informatics

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Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis. Here we report new inhibitors active against MTB PS developed using energy based pharmacophore modelling of the available proteininhibitor complex (3IVX) and virtual screening of a large commercial library. The e-pharmacophore model consisted of a ring aromatic (R), negative ionizable (N) and acceptor (A) sites. Compounds 5 and 10 emerged as promising hits with IC50 s 2.18 µM and 6.63 µM respectively. Further structural optimization was attempted to optimize lead 10 using medicinal chemistry approach and six compounds were found to exhibit better enzyme inhibition compared to parent compound lead 10 (<6 µM).

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Identification and development of 2-methylimidazo[1,2-a]pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors

Cited by 32 publications

References 14 publications

Design, synthesis and biological evaluation of novel quinoline‐based carboxylic hydrazides as anti‐tubercular agents

Design, synthesis and biological evaluation of novel quinoline‐based carboxylic hydrazides as anti‐tubercular agents

New structural classes of antituberculosis agents

Design of Novel Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors: Virtual Screening, Synthesis and In Vitro Biological Activities

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