Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies
No Thumbnail Available
Date
2024
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier Ltd
Abstract
In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds’ selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC<inf>50</inf> > 300 μg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. © 2023 Elsevier Ltd
Description
Keywords
1 (4 benzoylpiperazin 1 yl) 2 (1h indol 3 yl)ethan 1 one, 1 (4 benzoylpiperazin 1 yl) 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one, 1 (4 benzoylpiperazin 1 yl) 3 (1 (4 fluorobenzyl) 1h indol 3 yl)propan 1 one, 1 (4 benzoylpiperazin 1 yl) 3 (1h indol 3 yl)propan 1 one, 1 (4 benzoylpiperazin 1 yl) 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 (2 chloroisonicotinoyl)piperazin 1 yl] 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 (2 chloronicotinoyl)piperazin 1 yl] 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one, 1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one, 1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one, 1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one, 1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one, 1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one, 1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one, 1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one, 1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one, 1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one, 1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one, 1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one, 1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one, 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one, 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one, 1,2,3 triazole derivative, 2 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)ethan 1 one, 2 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one, 2 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one, 2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)ethan 1 one, 2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one, 2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one, 2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]ethan 1 one, 3 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)propan 1 one, 3 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one, 3 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one, 3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one, 3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one, 3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one, 3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 nicotinoylpiperazin 1 yl)propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (3 fluoroisonicotinoyl)piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (4 methoxybenzoyl)piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (4 nitrobenzoyl)piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 [(4 methoxyphenyl)sulfonyl]piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 [(4 nitrophenyl)sulfonyl]piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 [2 (trifluoromethyl)benzoyl]piperazin 1 yl]propan 1 one, 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 [[2 (trifluoromethyl)phenyl]sulfonyl]piperazin 1 yl]propan 1 one, cytochrome P450, cytochrome P450 CYP121, enoyl acyl carrier protein reductase (NADH), indole, isoniazid, n 1,2,3 triazolyl indole piperazine derivative, n benzyl indole piperazine derivative, piperazine, piperazine derivative, pyrazinamide, tuberculostatic agent, unclassified drug, indole derivative, triazole derivative, antibacterial activity, Article, bacterial strain, computer model, controlled study, drug absorption, drug bioavailability, drug cytotoxicity, drug design, drug distribution, drug excretion, drug metabolism, drug potency, drug screening, drug selectivity, drug synthesis, Escherichia coli, first-line treatment, IC50, in vitro study, minimum inhibitory concentration, molecular docking, molecular hybridization, Mycobacterium tuberculosis, nonhuman, prediction, Pseudomonas aeruginosa, Staphylococcus aureus, structure activity relation, tuberculosis, validation process, Vero cell line, metabolism, microbial sensitivity test, Antitubercular Agents, Indoles, Isoniazid, Microbial Sensitivity Tests, Molecular Docking Simulation, Piperazine, Piperazines, Pyrazinamide, Structure-Activity Relationship, Triazoles
Citation
Bioorganic and Medicinal Chemistry, 2024, 98, , pp. -