Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-β-Lactamase Inhibitors

• DOI: 10.1016/j.bmc.2022.116993
• Publication Date: 2022-09-05T22:18:03Z
• Authors: Rong Li; Huilin Su; Wei Chen; Yu-Hang Yan; Cong Zhou; Luohe Mou; Huan Yang; Shan Qian; Zhouyu Wang; Lingling Yang; Guo-Bo Li
• Keywords: 0301 basic medicine; Thiazoles; 03 medical and health sciences; Carboxylic Acids; Imidazoles; Meropenem; beta-Lactamase Inhibitors; beta-Lactams; beta-Lactamases; Anti-Bacterial Agents; Monobactams; 3. Good health

As one of important mechanisms to β-lactam antimicrobial resistance, metallo-β-lactamases (MBLs) have been receiving increasing worldwide attentions. Ambler subclass B1 MBLs are most clinically relevant, because they can hydrolyze almost all β-lactams with the exception of monobactams. However, it is still lacking of clinically useful drugs to combat MBL-medicated resistance. We previously identified 1H-imidazole-2-carboxylic acid as a core metal-binding pharmacophore (MBP) to target multiple B1 MBLs. Herein, we report structural optimization of 1H-imidazole-2-carboxylic acid and substituents. Structure-activity relationship (SAR) analyses revealed that replacement of 1H-imidazole-2-carboxylic acid with other structurally highly similar MBPs excepting thiazole-4-carboxylic acid resulted in decreased MBL inhibition. Further SAR studies identified more potent inhibitors to MBLs, of which 28 manifested IC50 values of 0.018 µM for both VIM-2 and VIM-5. The microbiological tests demonstrated that the most tested compounds showed improved synergistic effects; some compounds at 1 µg/ml were able to reduce meropenem MIC by at least 16-fold, which will be worth further development of new potent inhibitors particularly targeting VIM-type MBLs.