Synthesis and in vitro aldose reductase inhibitory activity of compounds containing an N-acylglycine moiety.
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 microM. 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 microM), they are less active than the corresponding 2-oxoquinolines. Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxoquinoline-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 microM). Of the rigid analogues of 8, the most potent derivative is benzoxindole (12) with an IC50 of 0.67 microM, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.
DeRuiter
J
J
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Alabama 36849.
Swearingen
B E
BE
Wandrekar
V
V
Mayfield
C A
CA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008968:Molecular Conformation; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase