Synthesis and quantitative structure–activity relationship of a new series of chiral 4‐alkoxycarbonyl‐2‐(alkylamino)‐1,3,2‐oxa or thiazaphospholidine‐2‐ones |
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Authors: | Hussein M. Ali Khaled A. Mohamed |
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Abstract: | Twenty‐one of the chiral 4‐alkoxycarbonyl‐2‐(α‐alkyl‐α‐ethoxycarbonyl methylamino)‐1,3‐2‐thia or oxazaphospholidine‐2‐ones have been synthesized by cyclization of L‐serine or L‐cysteine ethyl or n‐octyl ester with phosphoryl chloride followed by reaction with a suitable L‐amino acid ethyl ester. Proton NMR, IR, and mass spectra of these compounds have been discussed in detail. These compounds inhibited up to 68.52% of acetylcholinesterase (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 directly with the steric bulk of the alkyl groups, indicating a steric requirement for maximizing inhibitor–enzyme interaction and an inverse relationship with the electron‐donating ability of the alkyl groups. This supports the concept of a nucleophilic attack mechanism of a hydroxyl group of a serine amino 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, respectively. Results also indicated that the steric requirement was more important than the electronic factor in affecting the inhibition process, which explained the high activity of compounds containing the isoleucine moiety. The high AChE inhibition activity of these compounds and the expected nontoxic products of their in vivo hydrolysis make them eligible for pesticidal application. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 475–480, 1999 |
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