Synthesis and quantitative structure-activity relationship of a new seriesof chiral 4-alkoxycarbonyl-2-(alkylamino)-1,3,2-oxa or thiazaphospholidine-2-ones

Twenty-one of the chiral 4-alkoxycarbonyl-2-(alpha-alkyl-alpha-ethoxycarbon yl methylamino)-1,3-2-thia or oxazaphospholidine-2-ones have been synthesiz ed by cyclization of L;-serine or L-cysteine ethyl or n-octyl ester with ph osphoryl chloride followed by reaction with a suitable L-amino acid ethyl e ster. proton NMR, IR, and mass spectra of these compounds have been discuss ed in detail. These compounds inhibited up to 68.52% of acetylcholinesteras e (AChE) at the 1 ppm concentration level. Regression analysis showed that AChE inhibition was determined by both the steric and electronic effects of the alkyl groups of the amino acid. The enzyme inhibition correlated direc tly with the steric bulk of the alkyl groups, indicating a steric requireme nt for maximizing inhibitor-enzyme interaction and an inverse relationship with the electron-donating ability of the alkyl groups. This supports the c oncept of a nucleophilic attack mechanism of a hydroxyl group of a serine a mino acid in the enzyme active center on the partially positive phosphorus atom of the oxazaphospholidines and thiazaphospholidines, with correlation coefficients of 0.999 and 0.838 rer spectively. Results also indicated that the steric requirement was more important than the electronic factor in af fecting the inhibition process, which explained the high activity of compou nds containing the isoleucine moiety. The high AChE inhibition activity of these compounds and the expected nontoxic products of their in vivo hydroly sis make them eligible for pesticidal application. (C) 1999 John Wiley & So ns, Inc.