The escalating prevalence of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. Carbonic anhydrase, a ubiquitous metalloenzyme, catalyses the reversible hydration of carbon dioxide in the CO2+ H2O ⇋ HCO3−+ H+reaction. Suppressing this enzymatic activity has recently been identified as a new pathway for the treatment of Mycobacterium tuberculosis. To address this, a series of isoxazole–sulphonamides was rationally designed, incorporating an isoxazole pharmacophore as the aromatic tail, amide as a linker, and sulphonamide as the zinc-binding group. These compounds were evaluated against Mycobacterium tuberculosis carbonic anhydrases (MtCA 1 and 3) and two human carbonic anhydrases (hCA I and II) to identify selective inhibitors of the bacterial enzymes. The findings indicated that molecules containing an isoxazole pharmacophore with amide-linked benzene-3-sulphonamide were significantly more selective for MtCA 3 than hCA I and II. Among these compounds, 12c, 12e, and 19b had the highest inhibition against the MtCA 3 with Kivalues between 0.08–0.09 μM compared to the standard acetazolamide with a Kivalue of 0.10 μM. Some of the best compounds exhibited potent and selective inhibition of MtCA 3 over hCA I and II, with the meta- and para-substituted derivatives demonstrating higher selectivity and stronger inhibition. Specifically, compound 19b proved to be 199 and 38 times more selective for MtCA 3 than hCA I and hCA II respectively, compared to the standard drug acetazolamide, which is a non-selective CA inhibitor. The potential of compound 19b as a promising antitubercular agent with a MIC value of 8 μg mL−1against mc26230 was further strengthened by in silico ligand–target interaction studies. Thus, compound 19b is emphasised as a promising lead in the pursuit of new, selective agents targeting MtCA 3.
Design and synthesis of isoxazole-functionalized benzene sulphonamides as novel inhibitors of Mycobacterium tuberculosis β-carbonic anhydrases / Bandela, R., Singampalli, A., Maddipatla, S., Kumar, P., Bellapukonda, S.M., Ramavath, R., Mahajan, L.S., Nanduri, S., Vemula, D., Dalal, A., kalia, N.P., Bhandari, V., Gratteri, P., Paoletti, N., Bonardi, A., Supuran, C.T., Yaddanapudi, V.M.. - In: RSC MEDICINAL CHEMISTRY. - ISSN 2632-8682. - STAMPA. - 16:(2025), pp. 6368-6379. [10.1039/d5md00744e]
Design and synthesis of isoxazole-functionalized benzene sulphonamides as novel inhibitors of Mycobacterium tuberculosis β-carbonic anhydrases
Gratteri, Paola;Paoletti, Niccolò;Bonardi, Alessandro;Supuran, Claudiu T.
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2025
Abstract
The escalating prevalence of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. Carbonic anhydrase, a ubiquitous metalloenzyme, catalyses the reversible hydration of carbon dioxide in the CO2+ H2O ⇋ HCO3−+ H+reaction. Suppressing this enzymatic activity has recently been identified as a new pathway for the treatment of Mycobacterium tuberculosis. To address this, a series of isoxazole–sulphonamides was rationally designed, incorporating an isoxazole pharmacophore as the aromatic tail, amide as a linker, and sulphonamide as the zinc-binding group. These compounds were evaluated against Mycobacterium tuberculosis carbonic anhydrases (MtCA 1 and 3) and two human carbonic anhydrases (hCA I and II) to identify selective inhibitors of the bacterial enzymes. The findings indicated that molecules containing an isoxazole pharmacophore with amide-linked benzene-3-sulphonamide were significantly more selective for MtCA 3 than hCA I and II. Among these compounds, 12c, 12e, and 19b had the highest inhibition against the MtCA 3 with Kivalues between 0.08–0.09 μM compared to the standard acetazolamide with a Kivalue of 0.10 μM. Some of the best compounds exhibited potent and selective inhibition of MtCA 3 over hCA I and II, with the meta- and para-substituted derivatives demonstrating higher selectivity and stronger inhibition. Specifically, compound 19b proved to be 199 and 38 times more selective for MtCA 3 than hCA I and hCA II respectively, compared to the standard drug acetazolamide, which is a non-selective CA inhibitor. The potential of compound 19b as a promising antitubercular agent with a MIC value of 8 μg mL−1against mc26230 was further strengthened by in silico ligand–target interaction studies. Thus, compound 19b is emphasised as a promising lead in the pursuit of new, selective agents targeting MtCA 3.
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