Using Bioisosteric Replacements to Enhance the Analgesic Properties of 4-Hydroxy-6,7-Dimethoxy-2-oxo-1,2-Dihydroquinoline-3-Carboxamides

Abstract

Guided by bioisosteric replacement principles, a series of new N-(hetarylmethyl)-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxamides were synthesized. Pharmacological tests showed that replacement of the benzyl phenyl ring in N-benzyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxamides by an isosteric heterocycle led to a noticeable increase in the analgesic activity only for the 3-Py derivative. The corresponding isomeric 2- and 4-Py derivatives were close to the benzylamide baseline level of analgesic properties whereas the furan, tetrahydrofuran, and thiophene analogs were characterized by a significant decrease in the analgesic activity.