Design, synthesis, and evaluation of aza inhibitors of chorismate mutase.
A series of aza inhibitors (4-9) of chorismate mutase (E.C. 5.4.99.5) was designed, prepared, and evaluated against the enzyme by monitoring the direct inhibition of the chorismate, 1, to prephenate, 2, conversion. None of these aza inhibitors displayed tighter binding to the enzyme than the native substrate chorismate or greater inhibitory action than the previously reported ether analogue, 3. Furthermore, no time-dependent loss of enzyme activity was observed in the presence of the two potentially reactive aza inhibitors (7 and 9). These results in conjunction with inhibition data from a broader series of chorismate mutase inhibitors allowed a novel proposal for the mechanistic role of chorismate mutase to be developed. This proposed mechanism was computationally verified and correlated with crystallographic studies of various chorismate mutases.
Hediger
Mark E
ME
College of Chemistry, Latimer Hall, The University of California, Berkeley, CA 94720-1460, USA. mhediger@comcast.net
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002826:Chorismate Mutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D001372:Aza Compounds; D004791:Enzyme Inhibitors; D002826:Chorismate Mutase