Structure-Activity Relationship Studies for 1,3,4-Thiadiazole-Based Bacterial Carbonic Anhydrase Inhibitors with In Vivo Efficacy against Drug-Resistant Neisseria gonorrhoeae

  • J Med Chem. 2026 May 28;69(10):12183-12204. doi: 10.1021/acs.jmedchem.6c00012.
Prabhakara R Tharra  1 ,  Molly S Youse  1 ,  Nader S Abutaleb  2  3 ,  Abdallah S Abdelsattar  2  3 ,  Katrina J Holly  1 ,  Alessio Nocentini  4 ,  Ahmed A Abouelkhair  2  3 ,  Carolyn K Metcalfe  1 ,  Chao-Jan Liao  5  6 ,  Venkatesh P Thriumalaikumar  5  6 ,  Farman Ali  1 ,  Anil Kumar Marapaka  1 ,  Faith L Drummond  1 ,  Olivia C Snell  1 ,  Claudiu T Supuran  4 ,  Mohamed N Seleem  2  3 ,  Daniel P Flaherty  1  7  8
Affiliations
  • 1. Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2. Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
  • 3. Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
  • 4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino 50019, Italy.
  • 5. Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, United States.
  • 6. Center for Plant Biology, Department of Botany and Plant Pathology, Purdue University, West Lafayette, Indiana 47907, United States.
  • 7. Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.
  • 8. Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, Indiana 47907, United States.
PMID: 42089225 DOI: 10.1021/acs.jmedchem.6c00012
Abstract

Drug-resistant Neisseria gonorrheae is becoming an increasingly concerning threat as cases continue to rise, highlighting the need for novel therapeutics. We, therefore, have further developed our previously established structure-activity relationship for derivatives of acetazolamide, an FDA-approved Carbonic Anhydrase Inhibitor. A large cohort of acetazolamide-based analogs was investigated for their activity against N. gonorrheae and their binding to NgCAs. Lead compounds were carried forward for in vitro ADME evaluation before prioritizing two molecules, 18 and 33, for in vivo PK analysis. These compounds were orally bioavailable and metabolically stable, and exhibited low cytotoxicity against mammalian cell lines. When investigated for in vivo efficacy in an infected mouse model, 18 was found to significantly decrease gonococcal bioburden compared with the vehicle control. Our studies culminated in the finding that acetazolamide-based compounds can be developed as effective drugs against N. gonorrheae and may be an answer in the search for new therapeutics.

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