Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies

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dc.contributor.authorReddyrajula, R.
dc.contributor.authorEtikyala, U.
dc.contributor.authorVijjulatha, V.
dc.contributor.authorUdayakumar, U.
dc.date.accessioned2026-02-04T12:25:17Z
dc.date.issued2024
dc.description.abstractIn 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
dc.identifier.citationBioorganic and Medicinal Chemistry, 2024, 98, , pp. -
dc.identifier.issn9680896
dc.identifier.urihttps://doi.org/10.1016/j.bmc.2023.117562
dc.identifier.urihttps://idr.nitk.ac.in/handle/123456789/21329
dc.publisherElsevier Ltd
dc.subject1 (4 benzoylpiperazin 1 yl) 2 (1h indol 3 yl)ethan 1 one
dc.subject1 (4 benzoylpiperazin 1 yl) 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one
dc.subject1 (4 benzoylpiperazin 1 yl) 3 (1 (4 fluorobenzyl) 1h indol 3 yl)propan 1 one
dc.subject1 (4 benzoylpiperazin 1 yl) 3 (1h indol 3 yl)propan 1 one
dc.subject1 (4 benzoylpiperazin 1 yl) 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one
dc.subject1 [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
dc.subject1 [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
dc.subject1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one
dc.subject1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one
dc.subject1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one
dc.subject1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one
dc.subject1 [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
dc.subject1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one
dc.subject1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one
dc.subject1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one
dc.subject1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one
dc.subject1 [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
dc.subject1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one
dc.subject1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one
dc.subject1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one
dc.subject1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one
dc.subject1 [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
dc.subject1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one
dc.subject1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one
dc.subject1,2,3 triazole derivative
dc.subject2 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)ethan 1 one
dc.subject2 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one
dc.subject2 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one
dc.subject2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)ethan 1 one
dc.subject2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one
dc.subject2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one
dc.subject2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]ethan 1 one
dc.subject3 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)propan 1 one
dc.subject3 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one
dc.subject3 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one
dc.subject3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one
dc.subject3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one
dc.subject3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one
dc.subject3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]propan 1 one
dc.subject3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 nicotinoylpiperazin 1 yl)propan 1 one
dc.subject3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subject3 [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
dc.subjectcytochrome P450
dc.subjectcytochrome P450 CYP121
dc.subjectenoyl acyl carrier protein reductase (NADH)
dc.subjectindole
dc.subjectisoniazid
dc.subjectn 1,2,3 triazolyl indole piperazine derivative
dc.subjectn benzyl indole piperazine derivative
dc.subjectpiperazine
dc.subjectpiperazine derivative
dc.subjectpyrazinamide
dc.subjecttuberculostatic agent
dc.subjectunclassified drug
dc.subjectindole derivative
dc.subjecttriazole derivative
dc.subjectantibacterial activity
dc.subjectArticle
dc.subjectbacterial strain
dc.subjectcomputer model
dc.subjectcontrolled study
dc.subjectdrug absorption
dc.subjectdrug bioavailability
dc.subjectdrug cytotoxicity
dc.subjectdrug design
dc.subjectdrug distribution
dc.subjectdrug excretion
dc.subjectdrug metabolism
dc.subjectdrug potency
dc.subjectdrug screening
dc.subjectdrug selectivity
dc.subjectdrug synthesis
dc.subjectEscherichia coli
dc.subjectfirst-line treatment
dc.subjectIC50
dc.subjectin vitro study
dc.subjectminimum inhibitory concentration
dc.subjectmolecular docking
dc.subjectmolecular hybridization
dc.subjectMycobacterium tuberculosis
dc.subjectnonhuman
dc.subjectprediction
dc.subjectPseudomonas aeruginosa
dc.subjectStaphylococcus aureus
dc.subjectstructure activity relation
dc.subjecttuberculosis
dc.subjectvalidation process
dc.subjectVero cell line
dc.subjectmetabolism
dc.subjectmicrobial sensitivity test
dc.subjectAntitubercular Agents
dc.subjectIndoles
dc.subjectIsoniazid
dc.subjectMicrobial Sensitivity Tests
dc.subjectMolecular Docking Simulation
dc.subjectPiperazine
dc.subjectPiperazines
dc.subjectPyrazinamide
dc.subjectStructure-Activity Relationship
dc.subjectTriazoles
dc.titleDiscovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies

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