Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa

Hussein, Waleed M., Fatahala, Samar S., Mohamed, Zainab M., McGeary, Ross P., Schenk, Gerhard, Ollis, David L. and Mohamed, Mosaad S. (2012) Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chemical Biology and Drug Design, 80 4: 500-515.


Author Hussein, Waleed M.
Fatahala, Samar S.
Mohamed, Zainab M.
McGeary, Ross P.
Schenk, Gerhard
Ollis, David L.
Mohamed, Mosaad S.
Title Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa
Formatted title Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa
Journal name Chemical Biology and Drug Design  (ERA 2012 Listed)    (ERA 2010 Rank C)   Check publisher's open access policy
Publication date 2012-10
Sub-type Article
DOI 10.1111/j.1747-0285.2012.01440.x
Volume number 80
Issue number 4
ISSN 1747-0277; 1747-0285
Start page 500
End page 515
Total pages 16
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell
Collection year 2013
Language eng
Formatted abstract 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 ∼20-80μm). 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±9μm), as well as 7a (K i=21±10μm), 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.
Keyword Inhibition assays
Metallo-β-lactamases
Pyrrole
Tetrahydropyrimidine-2-thione
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 23 July 2012.

 
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Created: Thu, 04 Oct 2012, 14:34:55 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences