Discovery of sulfone containing metallo-β-lactamase inhibitors with reduced bacterial cell efflux and histamine release issues

  • Bioorg Med Chem Lett. 2024 Oct 11:114:129989. doi: 10.1016/j.bmcl.2024.129989.
Frank Bennett  1 ,  Yuhua Huang  2 ,  Shuzhi Dong  2 ,  Jinlong Jiang  2 ,  David Hunter  2 ,  Zhiqiang Zhao  2 ,  Xin Gu  2 ,  Jack D Scott  2 ,  Haiqun Tang  2 ,  Dexi Yang  2 ,  Li Xiao  3 ,  Giovanna Scapin  3 ,  Thierry Fischmann  3 ,  Asra Mirza  4 ,  Priya Dayananth  5 ,  Ronald E Painter  5 ,  Artjohn Villafania  5 ,  Charles G Garlisi  5 ,  Rumin Zhang  5 ,  Todd W Mayhood  5 ,  Qian Si  5 ,  Nianyu Li  6 ,  Rupesh P Amin  6 ,  Feifei Chen  6 ,  Bhavana Bhatt  6 ,  Christopher P Regan  6 ,  Hilary Regan  6 ,  Xinjie Lin  7 ,  Jin Wu  7 ,  Andrew Leithead  8 ,  Katherine Young  4 ,  Alexander Pasternak  2
Affiliations
  • 1. Merck & Co., Inc., Department of Medicinal Chemistry, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: [email protected].
  • 2. Merck & Co., Inc., Department of Medicinal Chemistry, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
  • 3. Merck & Co., Inc., Department of Computational and Structural Chemistry, 126 E. Lincoln Avenue., Rahway, NJ 07065, USA.
  • 4. Merck & Co., Inc., Department of Infectious Diseases, 770 Sumneytown Pike., West Point, PA 19486, USA.
  • 5. Merck & Co., Inc., Department of Pharmacology, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 6. Merck & Co., Inc., Department of Nonclinical Drug Safety, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 7. Merck & Co., Inc., Department of Pharmacokinetics and Pharmacodynamics, 770 Sumneytown Pike, West Point, PA 19486, USA.
  • 8. Merck & Co., Inc., Department of Pharmaceutical Sciences, 770 Sumneytown Pike, West Point, PA 19486, USA.
PMID: 39396683 DOI: 10.1016/j.bmcl.2024.129989
Abstract

The design, syntheses and Antibacterial evaluation of sulfone analogues of previously disclosed metallo-β-lactamase inhibitors (MBLis) are described. The novel derivatives were overall more effective in gram-negative Bacterial cell-based assays when combined with imipenem and relebactam. The major contributors to the improved anti-bacterial activity are enhanced enzyme-inhibitor interactions and reduced Bacterial cell efflux monitored via an efflux assay involving isogenic Pseudomonas aeruginosa efflux + and efflux - tool strains.

Keywords
Anti-bacterial; Metallo-β-lactamase; Sulfone; β-lactamase.
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