Origin of enantiomeric selectivity in the aryloxyphenoxypropionic acid class of herbicidal acetyl coenzyme A carboxylase (ACCase) inhibitors.
Molecular modeling was used to propose an "active conformation" for the R-2-phenoxypropionic acid portion of the aryloxyphenoxypropionic acid series of herbicidal acetyl CoA carboxylase (ACCase) inhibitors. This candidate active conformation is a low-energy conformer with the R-methyl distal to the phenoxy fragment, stabilized by the generalized anomeric effect around the propionate ether bond; the inactive S-enantiomer has difficulty accessing this conformation due to steric interaction of the S-methyl with the o-hydrogen of the phenyl. This candidate conformation was challenged by preparation of a series of novel rigid analogues. ACCase inhibition data suggest that the systems which contain a fused five-membered, but not a six-membered, ring present the necessary pharmacophore to the active site of ACCase, confirming the active conformation hypothesis and demonstrating that the precise placement of the carboxylate relative to the phenyl group is more critical than the placement of the methyl.
Turner
James A
JA
Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, Indiana 46268-1054, USA. jaturner@dow.com
Pernich
Daniel J
DJ
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006540:Herbicides / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010647:Phenyl Ethers; D011422:Propionates / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
C447201:2-phenoxypropionic acid; D004791:Enzyme Inhibitors; D006540:Herbicides; D010647:Phenyl Ethers; D011422:Propionates; D000103:Acetyl-CoA Carboxylase