Synthesis and Kinetic Testing of Tetrahydropyrimidine-2-thione and Pyrrole Derivatives as Inhibitors of the Metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa

Metallo‐β‐lactamases (MBLs), produced by an increasing number of bacterial pathogens, facilitate the hydrolysis of many commonly used β‐lactam antibiotics. There are no clinically useful antagonists against MBLs. Two sets of tetrahydropyrimidine‐2‐thione and pyrrole derivatives were synthesized and assayed for their inhibitory effects on the catalytic activity of the IMP‐1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Nine compounds tested (1a, 3b, 5c, 6b, 7a, 8a, 11c, 13a, and 16a) showed micromolar inhibition constants (Ki values range from ∼20–80 μm). Compounds 1c, 2b, and 15a showed only weak inhibition. In silico docking was employed to investigate the binding mode of each enantiomer of the strongest inhibitor, 5c (Ki = 19 ± 9 μm), as well as 7a (Ki = 21 ± 10 μm), the strongest inhibitor of the pyrrole series, in the active site of IMP‐1. Several tetrahydropyrimidine‐2‐thione and pyrrole derivatives were synthesized. Twenty seven of them were assayed for their inhibitory effect against the metallo‐β‐lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa, twelve of the tested compounds showed good activity. In silico docking was employed to investigate the binding mode of the two most potent inhibitors.