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

: 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.