N-(1,3,4-Oxadiazol-2-yl)Benzamides as Antibacterial Agents against Neisseria gonorrhoeae

Abstract

The Centers for Disease Control and Prevention (CDC) recognizes <i>Neisseria gonorrhoeae</i> as an urgent-threat Gram-negative bacterial pathogen. Additionally, resistance to frontline treatment (dual therapy with azithromycin and ceftriaxone) has led to the emergence of multidrug-resistant <i>N. gonorrhoeae</i>, which has caused a global health crisis. The drug pipeline for <i>N. gonorrhoeae</i> has been severely lacking as new antibacterial agents have not been approved by the FDA in the last twenty years. Thus, there is a need for new chemical entities active against drug-resistant <i>N. gonorrhoeae</i>. Trifluoromethylsulfonyl (SO₂CF₃), trifluoromethylthio (SCF₃), and pentafluorosulfanyl (SF₅) containing <i>N</i>-(1,3,4-oxadiazol-2-yl)benzamides are novel compounds with potent activities against Gram-positive bacterial pathogens. Here, we report the discovery of new <i>N</i>-(1,3,4-oxadiazol-2-yl)benzamides (<b>HSGN-237</b> and <b>-238</b>) with highly potent activity against <i>N. gonorrhoeae</i>. Additionally, these new compounds were shown to have activity against clinically important Gram-positive bacteria, such as methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), vancomycin-resistant enterococci (VRE), and <i>Listeria monocytogenes</i> (minimum inhibitory concentrations (MICs) as low as 0.25 µg/mL). Both compounds were highly tolerable to human cell lines. Moreover, <b>HSGN-238</b> showed an outstanding ability to permeate across the gastrointestinal tract, indicating it would have a high systemic absorption if used as an anti-gonococcal therapeutic.