4-(2-chloroacetamido) Benzoic Acid Derivatives as Local Anesthetic Agents: Design, Synthesis, and Characterization

Abstract

Local anesthetic activity was investigated with an assumed hypothesis that the essential alkyl substituted nitrogen having strong ionization characteristics (pKa in basic side) generally found in local anesthetics can be replaced by amide nitrogen, having chloro methyl group attached to the carbonyl carbon of amide. In this type of arrangement, the inductive effect exerted by chlorine provided enough ionization character to amide nitrogen. Eight esters, ten amides and one imidazole derivatives of 4-(2-chloroacetamido) benzoic acid were synthesized by Fischer’s esterification, Schotten-Baumann and substitution reactions. The synthesized derivatives (A1–A18 and A.im) were characterized by various instrumental techniques.ACD Lab Suite® was used to determine various physiochemical properties of synthesized molecules. Initially, infiltration local anesthetic activity was determined by Bianchi’s method. Five compounds (A1, A2, A4, A10, and A.im) showed promising local anesthetic activity, where the comparison was made with lignocaine HCl, thus conforming assumed hypothesis. However, the studied compounds have potency lower than that of lignocaine HCl. Compounds showing promising activity with low toxicity were studied further by in-vivo rat sciatic nerve block method using increasing doses. A.im was studied for topological similarity with lignocaine HCl where it showed good local anesthetic activity and was relatively very less toxicity. The reduced toxicity of these molecules may be attributed due to the carbonyl chloro methyl side chain. Further structural advancement may be done by researchers to increase the potency of these compounds since they are relatively less toxic than lignocaine.