Correlation of toxicity and acetylcholinesterase (AChE) inhibition in 2-alkyl substituted 1,3-benzodioxolyl-4 N-methylcarbamates and related compounds

Abstract

2-Alkyl substituted-1,3-benzodioxolyl-4 and 1,3-benzodioxolyl-5 N-methylcarbamates; 2-methyl substituted indanyl-4 and indanyl-5 N-methylcarbamates; and 2-methyl substituted quinolinyl-8 N-methylcarbamates were examined in this study. Oral toxicity (LD 50) to female mice and topical LD 50 values to the housefly were determined. Main's kinetic constants (affinity, carbamylation, and overall inhibition rate) on acetylcholinesterase (AChE, EC3.1.1.7) were also determined. Good correlations were found between the in vivo toxicity to mice (without synergist) or houseflies (with synergist) and in vitro overall enzyme inhibition rate. Increasing the number or the size of the alkyl substitution (i.e., unsubstituted vs monomethyl, monomethyl vs dimethyl, or dimethyl vs diethyl) increased the toxicity and the overall enzyme inhibition. The increase in the enzyme inhibition by substitution was mainly due to the increase in the affinity of the enzyme-inhibitor complex. It is interpreted that the substituted alkyl groups interact with the anionic or hydrophobic site of the AChE through van der Waal's forces or hydrophobic bonding. The enzyme inhibition and toxicity were maximal when the second ring of these bicyclic compounds was attached in the 2,3-position in relation to the hydroxyl group of the phenyl ring.