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 (K(i) 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 (K(i) = 19 ± 9 μM), as well as 7a (K(i) =21 ± 10 μM), the strongest inhibitor of the pyrrole series, in the active site of IMP-1.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Ein Helwan, Helwan, Egypt.
Waleed M
WM
Hussein
Samar S
SS
Fatahala
Zainab M
ZM
Mohamed
Ross P
RP
McGeary
Gerhard
G
Schenk
David L
DL
Ollis
Mosaad S
MS
Mohamed
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000201:enzymology*; D062105:Molecular Docking Simulation; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
C512629:1,2,3,4-tetrahydropyrimidine-2-thione; D000900:Anti-Bacterial Agents; D011743:Pyrimidines; D011758:Pyrroles; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases