Synthesis of potential aldose reductase inhibitors based on minimal pharmacophore requirements

A series of 17 compounds were synthesized based on the premise that the minimal pharmacophore for aldose reductase inhibition requires the presence of both an aryl group and polar group connected by a linking structure. Three groups of compounds were synthesized, the first possessing an aniline-4-(2′-6′-methylbenzothiazole) or 2-aminobenzothiazole group as the aryl group, the second possessing a 2-naphthyl as the aryl group and the third possessing either a 4-(2-phenylthiazole) or 2-(5-2′-nitrophenylfuran) as the aryl group. In all three of these groups the carboxylate or its methyl ester are linked to the aryl group through various lengths of methylene carbons and amide or cinnamide groups. Optimal activity was observed when the carboxylic group was separated from the aryl group by a linking structure of five atoms in length. Both a double bond and an amide moiety are well tolerated in the linking structure.