2021
DOI: 10.1080/14756366.2021.1919889
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Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

Abstract: A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 mg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MI… Show more

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Cited by 37 publications
(12 citation statements)
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“…are some recently discovered inhibitors of M. tuberculosis InhA. For all the compounds, good docking scores were observed as well as binding to the hydrophobic pocket of InhA as shown in Table . Literature revealed that a great majority of reported InhA inhibitors make a stable H-bonding to the backbone −OH group of the core chain Tyr158, responsible for blocking the InhA function. , The active compounds 3ia , 3if , 3mc , and 3md form H-bonding with the residue Tyr158 and the carbonyl moiety of the quinazolinone ring. Derivatives 3if , 3mc , and 3md were able to make additional H-bonding interactions with the residues in the active site.…”
Section: Resultsmentioning
confidence: 99%
“…are some recently discovered inhibitors of M. tuberculosis InhA. For all the compounds, good docking scores were observed as well as binding to the hydrophobic pocket of InhA as shown in Table . Literature revealed that a great majority of reported InhA inhibitors make a stable H-bonding to the backbone −OH group of the core chain Tyr158, responsible for blocking the InhA function. , The active compounds 3ia , 3if , 3mc , and 3md form H-bonding with the residue Tyr158 and the carbonyl moiety of the quinazolinone ring. Derivatives 3if , 3mc , and 3md were able to make additional H-bonding interactions with the residues in the active site.…”
Section: Resultsmentioning
confidence: 99%
“…The antitubercular property of the test compounds 3a – 3m was evaluated against two types of M. tuberculosis strains, namely, H37Rv and well-characterized MDR strains, using the colorimetric Resazurin Microplate Assay (REMA) method as described in our previous communication [ 79 ]. The MICs were defined as the minimum drug concentration required to inhibit the organism from growing while leaving no color changes in the well [ 51 ]. The MTB reference strain H37Rv (American Type Culture Collection (ATCC) 25177) and MDR-TB were cultured for a total of 3 weeks in Middlebrook 7H11 medium [ 80 ] and were then supplemented with Oleic Albumin Dextrose Catalase (OADC) (0.005% v / v oleic acid, 0.2% w / v glucose, 0.085% w / v NaCl, 0.02% v / v catalase, and 0.5% 171 w / v bovine serum albumin (BSA)).…”
Section: Methodsmentioning
confidence: 99%
“…Moreover, we attempted to identify the putative mycobacterial target of those compounds by applying a computational approach. We have been interested in identifying potential novel anti-TB compounds from nat ural sources [42,43], cyclic depsipeptides [44], and synthetic heterocyclic compounds hav ing pharmacophores, such as benzothiazoles, triazolyl 1,2,3,4-tetrahydropyrimidines, di hydropyrimidines, and substituted indolizines as potential antitubercular agents [45][46][47][48][49][50][51][52] In continuation of our efforts in identifying promising heterocyclic compounds for phar macological activity [53][54][55][56][57][58][59][60][61][62][63], this study aims to identify potential anti-TB compounds Herein, we screened a set of our recently reported substituted 2,3-dihydroquinazolin 4(1H)-one analogues (except the novel compound 3l) to assess their potency against dif ferent strains of MTB. These compounds were also further investigated to evaluate thei cytotoxicity against normal human dermal fibroblast cells.…”
Section: Introductionmentioning
confidence: 99%
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“…The thymidylate kinase of Mycobacterium tuberculosis and Pks13 are the other anti-tuberculosis targets we selected for this research due to their critical role in this disease. For anti-fungal activity, we analyzed our synthesized molecule’s activity against Saccharomyces cerevisiae CYP51 [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Absorption, distribution, metabolism, excretion, and toxicities (ADMET) prediction is one of the essential steps for drug discovery and development.…”
Section: Introductionmentioning
confidence: 99%