Discovery of 1,3,4-Thiadiazole Sulfonamide-Based Potent Inhibitors against the Unsaturated Fatty Acid Synthase FabX of Helicobacter pylori

  • J Med Chem. 2025 Aug 28;68(16):17175-17188. doi: 10.1021/acs.jmedchem.5c00654.
Xiaoxue Ruan  1 ,  Lin Zhang  2 ,  Linlin Dong  3 ,  Yue Wang  1 ,  Liping Zeng  3 ,  Mingzhong Yang  1 ,  Hongkai Bi  3  4 ,  Meiqing Feng  1 ,  Liang Zhang  2  5 ,  Lu Zhou  1  6
Affiliations
  • 1. School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Department of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 3. Department of Pathogen Biology & Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 4. NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, China.
  • 5. Department of Chemical Biology, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 6. Quzhou Fudan Institute, Quzhou 324002, China.
PMID: 40811148 DOI: 10.1021/acs.jmedchem.5c00654
Abstract

Unsaturated fatty acids (UFAs) are essential for the membrane function in most bacteria. In Helicobacter pylori (H. pylori), a gastric pathogen, UFA biosynthesis depends on the bifunctional dehydrogenase/isomerase FabX, a promising target against H. pylori. Herein, we report the first FabX inhibitor, P61G11 (compound 1, IC50 = 3.7 ± 0.2 μM), identified via high-throughput screening and featuring a 1,3,4-thiadiazole sulfonamide scaffold. The costructure of FabX-1 reveals occupancy of the L-shaped substrate-binding tunnel via hydrophobic interactions and hydrogen bonds. Structure-based optimization led to more potent derivatives, among which compound 47 showed potent inhibition (IC50 = 0.128 ± 0.002 μM), representing a 29-fold improvement. Compound 47 also demonstrated strong in vitro Antibacterial activity (MIC = 0.5-1 μg/mL), when combined with membrane permeabilizers, efflux pump inhibitors, and clarithromycin, and exhibited narrow-spectrum efficacy against H. pylori, providing a novel strategy for anti-H. pylori therapy.

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