Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N -methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N -methyl group when shifting the ortho-N -methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta -sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta -sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta -sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs. • LpxH in lipid A biosynthesis is a promising antibacterial target. • LpxH inhibitors showing activity on E. coli and K. pneumoniae were identified. • LpxH inhibitors show promising toxicological profile. • Two X-ray structures were solved in complex with LpxH inhibitors.