Exploring Indole-Linked Triazole Sulfonamide Derivatives as Potent Mycobacterial Carbonic Anhydrase Inhibitors: Leveraging a Tail Approach for the Design, Synthesis, and <i>In Silico</i> 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 <b>5f</b> had the highest anti-TB efficacy against <i>Mtb</i> with a MIC of 0.25 μg/mL. Additionally, compounds <b>5g</b> and <b>5i</b> elicited activity of 2 μg/mL. All potent compounds exhibited better safety profiles and selectivity. Compounds <b>5f</b> and <b>5g</b> are additive, while <b>5i</b> is synergistic with rifampicin. Compound <b>5f</b> had promising activity against drug-resistant strains of <i>Mtb</i>, highlighting its potential to address MDR-TB. The compounds were evaluated for MtCA inhibitory activity. The <i>meta</i>- and <i>para</i>-substituted derivatives demonstrated varying degrees of inhibition, with stronger inhibition observed for MtCA2. The potential of compound <b>5f</b> as a promising antitubercular agent was further strengthened by <i>in silico</i> ligand-target interaction.