Reddyrajula, R.Etikyala, U.Vijjulatha, V.Udayakumar, U.2026-02-042024Bioorganic and Medicinal Chemistry, 2024, 98, , pp. -9680896https://doi.org/10.1016/j.bmc.2023.117562https://idr.nitk.ac.in/handle/123456789/21329In 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 Ltd1 (4 benzoylpiperazin 1 yl) 2 (1h indol 3 yl)ethan 1 one1 (4 benzoylpiperazin 1 yl) 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one1 (4 benzoylpiperazin 1 yl) 3 (1 (4 fluorobenzyl) 1h indol 3 yl)propan 1 one1 (4 benzoylpiperazin 1 yl) 3 (1h indol 3 yl)propan 1 one1 (4 benzoylpiperazin 1 yl) 3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl]propan 1 one1 [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 one1 [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 one1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one1 [4 (4 chlorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one1 [4 (4 chlorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one1 [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 one1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one1 [4 (4 fluorobenzoyl)piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one1 [4 (4 fluorobenzoyl)piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one1 [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 one1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 2 [1 (4 fluorobenzyl) 1h indol 3 yl]ethan 1 one1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one1 [4 [(4 chlorophenyl)sulfonyl]piperazin 1 yl] 3 [1 (4 fluorobenzyl) 1h indol 3 yl]propan 1 one1 [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 one1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 2 (1h indol 3 yl)ethan 1 one1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl] 3 (1h indol 3 yl)propan 1 one1,2,3 triazole derivative2 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)ethan 1 one2 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one2 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)ethan 1 one2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]ethan 1 one2 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]ethan 1 one3 (1h indol 3 yl) 1 (4 tosylpiperazin 1 yl)propan 1 one3 (1h indol 3 yl) 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one3 (1h indol 3 yl) 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (4 methylbenzoyl)piperazin 1 yl]propan 1 one3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one3 [1 (4 fluorobenzyl) 1h indol 3 yl] 1 [4 [(4 fluorophenyl)sulfonyl]piperazin 1 yl]propan 1 one3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 nicotinoylpiperazin 1 yl)propan 1 one3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 (4 tosylpiperazin 1 yl)propan 1 one3 [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 one3 [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 one3 [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 one3 [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 one3 [1 [[1 (4 fluorobenzyl) 1h 1,2,3 triazol 4 yl]methyl] 1h indol 3 yl] 1 [4 (phenylsulfonyl)piperazin 1 yl]propan 1 one3 [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 one3 [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 one3 [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 one3 [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 one3 [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 onecytochrome P450cytochrome P450 CYP121enoyl acyl carrier protein reductase (NADH)indoleisoniazidn 1,2,3 triazolyl indole piperazine derivativen benzyl indole piperazine derivativepiperazinepiperazine derivativepyrazinamidetuberculostatic agentunclassified drugindole derivativetriazole derivativeantibacterial activityArticlebacterial straincomputer modelcontrolled studydrug absorptiondrug bioavailabilitydrug cytotoxicitydrug designdrug distributiondrug excretiondrug metabolismdrug potencydrug screeningdrug selectivitydrug synthesisEscherichia colifirst-line treatmentIC50in vitro studyminimum inhibitory concentrationmolecular dockingmolecular hybridizationMycobacterium tuberculosisnonhumanpredictionPseudomonas aeruginosaStaphylococcus aureusstructure activity relationtuberculosisvalidation processVero cell linemetabolismmicrobial sensitivity testAntitubercular AgentsIndolesIsoniazidMicrobial Sensitivity TestsMolecular Docking SimulationPiperazinePiperazinesPyrazinamideStructure-Activity RelationshipTriazoles