Exploring Indole-Linked Triazole Sulfonamide Derivatives as Potent Mycobacterial Carbonic Anhydrase Inhibitors: Leveraging a Tail Approach for the Design, Synthesis, and In Silico Studies─An In-Depth Multidisciplinary Study

The alarming rise of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. To address this, a series of indole triazole sulfonamides were rationally designed, incorporating an indole pharmacophore hybridized with a triazole linker containing a sulfonamide group. Compound 5f had the highest anti-TB efficacy against Mtb with a MIC of 0.25 μg/mL. Additionally, compounds 5g and 5i elicited activity of 2 μg/mL. All potent compounds exhibited better safety profiles and selectivity. Compounds 5f and 5g are additive, while 5i is synergistic with rifampicin. Compound 5f had promising activity against drug-resistant strains of Mtb, highlighting its potential to address MDR-TB. The compounds were evaluated for MtCA inhibitory activity. The meta- and para-substituted derivatives demonstrated varying degrees of inhibition, with stronger inhibition observed for MtCA2. The potential of compound 5f as a promising antitubercular agent was further strengthened by in silico ligand–target interaction.