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

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

  • Eur J Med Chem. 2024 Nov 15:278:116790. doi: 10.1016/j.ejmech.2024.116790.
Andrea Benediktsdottir 1,  Sanjeewani Sooriyaarachchi 2,  Sha Cao 3,  Nina E Ottosson 4,  Stefan Lindström 5,  Bo Lundgren 6,  Katharina Kloditz 6,  Daina Lola 7,  Olga Bobileva 7,  Einars Loza 7,  Diarmaid Hughes 3,  T Alwyn Jones 2,  Sherry L Mowbray 8,  Edouard Zamaratski 5,  Anja Sandström 5,  Anders Karlén 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden. Electronic address: andrea.benediktsdottir@ilk.uu.se.
  • 2 Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-75123, Uppsala, Sweden.
  • 3 Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-75123, Uppsala, Sweden.
  • 4 Department of Biomedical and Clinical Sciences, BKV, Linköping University, SE-581 85, Linköping, Sweden; Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Tomtebodavägen 23a, 171 65, Solna, Sweden.
  • 5 Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden.
  • 6 Department of Biochemistry and Biophysics, Stockholm University, Biochemical and Cellular Assay Unit, Drug Discovery and Development Platform, Science for Life Laboratory, Tomtebodavägen 23A, SE-17165, Solna, Sweden.
  • 7 Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia.
  • 8 Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-75123, Uppsala, Sweden; Science for Life Laboratory, Uppsala University, Box 596, SE-751 24, Uppsala, Sweden.
  • 9 Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden. Electronic address: anders.karlen@ilk.uu.se.
PMID: 39236497 DOI: 10.1016/j.ejmech.2024.116790
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.

Keywords

Antimicrobial drug discovery; Gram-negative bacteria; Lipid A; Lipopolysaccharide synthesis; LpxH inhibitors; Meta-sulfonamidobenzamide; N-demethylation; hERG ion channel affinity.

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