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

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 IC50 > 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.