Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-ß-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1.

ABSTRACT

New substituted (1-thioxo-1,2,3,4-tetrahydro-ß-carbolin-9-yl)acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6-methoxy-1-thioxo-1,2,3,4-tetrahydro-ß-carbolin-9-yl)acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC(50)=0.15µM) with clinically used epalrestat (IC(50)=0.1µM). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-ß-carbolin-9-yl)acetic acid (7t), which showed strong inhibitory effect (IC(50)=0.17µM) and very high selectivity for AKR1B1 against AKR1A1 (3111) and AKR1B10 (2531) compared with epalrestat.