Synthesis and in Vitro Anticholinesterase Activity of a Series of Oxime N-Methylcarbamates. Structure-Activity Relationships?

Abstract

A series of 33 oxime N-methylcarbamates RlRzC=NOCONHCH3 [RI and RZ = H, alkyl, cycloalkyl, haloalkyl, substituted aryl, or groups like (CH~)ZC=CHC, F3COCHzI was synthesized and tested for potential anticholinesterase activity. Some of those compounds such as the a,a,a-trifluoroacetophenoxime derivatives were studied for their in vitro and in vivo activity; other structures are novel ones. The configuration of those compounds was assigned by spectroscopic methods (NMR, IR, UV). The measure of the residual activity of the acetylcholinesterase (bovine erythrocyte) after the inhibition by those molecules allowed the determination of the dissociation constant Kd and the bimolecular carbamoylation rate constant ki. To take isomerism into account, the group Rz is always cis to the carbamic moiety. The structure-activity relationship studies were performed with the usual structural parameters and included commercial compounds such as aldicarb, methomyl, and oxamyl. The correlation equation obtained is log ki = 0.4652u* + 0.474u*~z+ 0 . 4 0 7 8~+ 2.247 (n = 35, r = 0.862, s = 0.74), where the electronic effect of the groups R1 and RZ is depicted by the Taft inductive constant u* and the lipophilic contribution by the Hansch parameter T. Specific correlations exhibit the prevailing participation of the group Rz in the formation of the enzyme-inhibitor complex and in the interactions of the inhibitor with the trimethyl site.