Synthesis and Biological Evaluation of New Benzylidenethiazolidine-2,4-dione Derivatives as 15-hydroxyprostaglandin Dehydrogenase Inhibitors to Control the Intracellular Levels of Prostaglandin E2 for Wound Healing

Abstract

A novel series of benzylidenethiazolidine-2,4-dione derivatives was synthesized and investigated for 15-hydroxyprostaglandin dehydrogenase (15-PGDH)-scavenging activity, PGE2 release, and wound-healing activity. Among the tested derivatives, seven compounds (3, 9, 11, 12, 13, 14, and 25) resulted in a 50% inhibition of 15-PGDH at concentrations between 0.07 and 0.2 µM and increased PGE2 levels from 300 to over 600% in A549 cells treated with 5.0 and 10.0 µM of the compounds for 12 h. A scratch wound-healing assay using HaCaT cell line was conducted to verify the effects of 10 µM of these compounds on cell regeneration. The closure rate of the scratch wound healing showed that all compounds (3, 9, 11, 12, 13, 14, and 25) had greater wound regeneration effects than the cell growth factor, TGF-β1, which was used as the positive control. In particular, (Z)-N-benzyl-4-((2,4-dioxothiazolidin-5-ylidene)methyl)benzamide (compound 14) showed that the highest wound closure rate, which was 360%; this is about 3.6-fold higher than that of TGF-β1. Overall, these results show that compound 14 may be considered a promising candidate for the development of novel wound-healing agents.