Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors

Abstract

A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(−)-enantiomer exhibited the strongest aldose reductase activity with an IC₅₀ value of 0.120 μM, which was 35 times more active than the S-(+)-enantiomer. Thus, the stereocenter at the C4 position of this scaffold was shown to have a major impact on the activity and selectivity.

• Absolute configuration determination
• aldose reductase inhibitors
• 1,2-benzothiazine 1,1-dioxide
• chiral resolution

Declaration of interest

The authors report no conflicts of interest. This work was supported by the National Natural Science Foundation of China (grant no. 21272025), the Research Fund for the Doctoral Program of Higher Education of China (grant no. 20111101110042), the Science and Technology Commission of Beijing, China (grant no. Z131100004013003) and the Beijing Natural Science Foundation (grant no. 3100021501401).

Supplementary material available online