Synthesis and Aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

Abstract—Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). Themost active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic sidechain on N-3of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery ofa very potent ARI (4c), whose activity level (IC50=0.13 mM) was in the same range of Tolrestat. Moreover, the correspondingmethyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstitutedcompounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of Nunsubstituted2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than thepara-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.