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

Benediktsdottir A, Sooriyaarachchi S, Cao S, Ottosson NE, Lindström S, Lundgren B, Kloditz K, Lola D, Bobileva O, Loza E, Hughes D, Jones TA, Mowbray SL, Zamaratski E, Sandström A, Karlén A

Eur J Med Chem 278 (-) 116790 [2024-11-15; online 2024-08-22]

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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

PubMed 39236497

DOI 10.1016/j.ejmech.2024.116790

Crossref 10.1016/j.ejmech.2024.116790

pii: S0223-5234(24)00671-8