Structure–Activity Relationship Studies of Acetazolamide-Based Carbonic Anhydrase Inhibitors with Activity against <i>Neisseria gonorrhoeae</i>

Abstract

<i>Neisseria gonorrhoeae</i> is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat <i>N. gonorrhoeae</i> infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities. Our team has repurposed the FDA-approved carbonic anhydrase inhibitor scaffold of acetazolamide to target <i>N. gonorrhoeae</i> and the bacteria's essential carbonic anhydrase, NgCA. This study established both structure-activity and structure-property relationships that contribute to both antimicrobial activity and NgCA activity. This ultimately led to molecules <b>20</b> and <b>23</b>, which displayed minimum inhibitory concentration values as low as 0.25 μg/mL equating to an 8- to 16-fold improvement in antigonococcal activity compared to acetazolamide. These analogues were determined to be bacteriostatic against the pathogen and likely on-target against NgCA. Additionally, they did not exhibit any detrimental effects in cellular toxicity assays against both a human endocervical (End1/E6E7) cell line or colorectal adenocarcinoma cell line (Caco-2) at concentrations up to 128 μg/mL. Taken together, this study presents a class of antigonococcal agents with the potential to be advanced for further evaluation in <i>N. gonorrhoeae</i> infection models.