{"entity": "publication", "iuid": "81e7a361674a4bb6a20708e035ded656", "timestamp": "2026-09-25T23:03:16.401Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/81e7a361674a4bb6a20708e035ded656.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/81e7a361674a4bb6a20708e035ded656"}}, "title": "Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors.", "authors": [{"family": "Benediktsdottir", "given": "Andrea", "initials": "A"}, {"family": "Sooriyaarachchi", "given": "Sanjeewani", "initials": "S"}, {"family": "Cao", "given": "Sha", "initials": "S"}, {"family": "Ottosson", "given": "Nina E", "initials": "NE"}, {"family": "Lindstr\u00f6m", "given": "Stefan", "initials": "S"}, {"family": "Lundgren", "given": "Bo", "initials": "B"}, {"family": "Kloditz", "given": "Katharina", "initials": "K"}, {"family": "Lola", "given": "Daina", "initials": "D"}, {"family": "Bobileva", "given": "Olga", "initials": "O"}, {"family": "Loza", "given": "Einars", "initials": "E"}, {"family": "Hughes", "given": "Diarmaid", "initials": "D"}, {"family": "Jones", "given": "T Alwyn", "initials": "TA"}, {"family": "Mowbray", "given": "Sherry L", "initials": "SL"}, {"family": "Zamaratski", "given": "Edouard", "initials": "E"}, {"family": "Sandstr\u00f6m", "given": "Anja", "initials": "A"}, {"family": "Karl\u00e9n", "given": "Anders", "initials": "A"}], "type": "journal article", "published": "2024-11-15", "journal": {"title": "Eur J Med Chem", "issn": "1768-3254", "volume": "278", "pages": "116790", "issn-l": "0223-5234"}, "abstract": "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.", "doi": "10.1016/j.ejmech.2024.116790", "pmid": "39236497", "labels": [], "xrefs": [{"db": "pii", "key": "S0223-5234(24)00671-8"}], "notes": [], "created": "2026-09-23T13:17:46.950Z", "modified": "2026-09-23T13:17:46.997Z"}