Synthesis and in vitro aldose reductase inhibitory activity of compounds containing an N-acylglycine moiety

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Abstract
A number of N-benzoylglycines (6), N-acetyl-N-phenylglycines (7), N-benzoyl-N-phenylglycines (8), and tricyclic N-acetic acids (9-12) were synthesized as analogues of the N-acylglycine-containing aldose reductase inhibitors alrestatin and 2-oxoquinoline-1-acetic acid. Derivatives of 6, which represent ring-simplified analogues of alrestatin, are very weak inhibitors of aldose reductase obtained from rat lens, producing 50% inhibition only at concentrations exceeding 100 .mu.M. Compounds of series 7 were designed as ring-opened analogues of the 2-oxoquinolines. While these derivatives are more potent than compounds of series 6 (IC50s of 6-80 .mu.M), they are less active than the corresponding 2-oxoquinolines. Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxo-quinoline-1-acetic acids. These compounds are substantially more potent than compounds of series 6 and 7 and display inhibitory activities comparable to or greater than alrestatin or the 2-oxoquinolines (IC50s of 0.1-10 .mu.M). Of the rigid analogues of 8, the most potent derivative is benzoxindole (12) with an IC50 of 0.67 .mu.M, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.