Optimization\nof Ethoxzolamide Analogs with Improved\nPharmacokinetic Properties for <i>In Vivo</i> Efficacy against Neisseria gonorrhoeae

Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae, for which there is no recommended\noral treatment. We have demonstrated that the FDA-approved human carbonic\nanhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus,\nwe sought to optimize the pharmacokinetic properties of the ethoxzolamide\nscaffold. These efforts resulted in analogs with improved activity\nagainst N. gonorrhoeae, increased metabolic\nstability in mouse liver microsomes, and improved Caco-2 permeability\ncompared to ethoxzolamide. Improvement in these properties resulted\nin increased plasma exposure <i>in vivo</i> after oral dosing.\nTop compounds were investigated for <i>in vivo</i> efficacy\nin a vaginal mouse model of gonococcal genital tract infection, and\nthey significantly decreased the gonococcal burden compared to vehicle\nand ethoxzolamide controls. Altogether, results from this study provide\nevidence that ethoxzolamide-based compounds have the potential to\nbe effective oral therapeutics against gonococcal infection.