Rational design, synthesis, and evaluation of nanomolar type II dehydroquinase inhibitors.
The in silico design, synthesis, and biological evaluation of ten potent type II dehydroquinase inhibitors are described. These compounds contain an anhydroquinate core, incorporated as a mimic of the enolate reaction intermediate. This substructure is attached by a variety of linking units to a terminal phenyl group that binds in an adjacent pocket. Inhibitors were synthesised from (-)-quinic acid using palladium-catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants against type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis. These are among the most potent inhibitors of these enzymes reported to date.
Payne
Richard J
RJ
Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
Peyrot
Fabienne
F
Kerbarh
Olivier
O
Abell
Andrew D
AD
Abell
Chris
C
D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation
D004791:Enzyme Inhibitors; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase