2. Academic Validation
  3. 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

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

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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