Spirohydantoin Derivatives of Thiopyrano[2,3-b]pyridin-4(4H)-one as Potent in Vitro and in Vivo Aldose Reductase Inhibitors

Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one have been synthesized and examined for their inhibitory activity against aldose reductase. The 2,3-dihydrospiro[4H-thiopyrano[2,3-b]pyridin-4,4′-imidazolidine]- 2′,5′-dione 3 and its 7-methyl analogue 4 were synthesized and tested for their ability to inhibit aldose reductase (ALR2). To expand the structure-activity relationships, the sulfone 5 and the acetic acid derivative 7 were also prepared and tested. Compounds 3 and 4 proved to be potent ALR2 inhibitors, with IC 50 values in the submicromolar range (0.96 and 0.94 μM, respectively) similar to that of sorbinil (0.65 μM). Moreover, compound 3 was found to be highly potent in preventing cataract development in severely galactosemic rats, like tolrestat, when administered as an eyedrop solution. Docking simulations of both R- and S-isomers of 3 into the ALR2 crystal structure were carried out to guide, prospectively, the design of new analogues.