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

  • J Med Chem. 2025 Sep 11;68(17):18370-18388. doi: 10.1021/acs.jmedchem.5c01026.
Anuradha Singampalli  1 ,  Rani Bandela  1 ,  Bulti Bakchi  1 ,  Sarvan Maddipatla  1 ,  Pardeep Kumar  1 ,  Sri Mounika Bellapukonda  1 ,  Puja Kumari Agnivesh  2 ,  Kishan Kumar Parida  2 ,  Simone Giovannuzzi  3 ,  Karol Biernacki  3  4 ,  Alessandro Bonardi  3  5 ,  Paola Gratteri  5 ,  Harshada Anil Bhalerao  6 ,  Rajesh Sonti  6 ,  Srinivas Nanduri  1 ,  Claudiu T Supuran  3 ,  Nitin Pal Kalia  2 ,  Madhavi Venkata Yaddanapudi  1
Affiliations
  • 1. Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
  • 2. Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
  • 3. Department NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino (Florence) 50019, Italy.
  • 4. Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Gdańsk 80-233, Poland.
  • 5. Department NEUROFARBA - Pharmaceutical and nutraceutical section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino (Florence) 50019, Italy.
  • 6. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
PMID: 40833028 DOI: 10.1021/acs.jmedchem.5c01026
Abstract

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.

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