Inhibitory effects of multi-substituted benzylidenethiazolidine-2,4-diones on LDL oxidation

Multi-substituted benzylidenethiazolidine-2,4-diones 3a-h were synthesized by Knoevenagel condensation of di- or tri-substituted 4-hydroxybenzaldehydes [or 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone] 1 with thiazolidine-2,4-dione (2) and evaluated for antioxidant activities of Cu2+-induced oxidation of human low-density lipoproteins (LDL). Among compounds 3a-h, 3a was superior to probucol in LDL-antioxidant activities and found to be ninefold more active than probucol. Due to its potency, compound 3a was tested for complementary in vitro investigations, such as TBARS assay (IC50 = 0.1 muM), lag time (240 min at 1.5 muM), relative electrophoretic mobility (REM) of ox-LDL (inhibition of 83% at 10 muM), fragmentation of apoB-100 (inhibition of 61% at 5 muM), and radical DPPH scavenging activity on copper-mediated LDL oxidation. In macro phage-mediated LDL oxidation, the TBARS formation was also inhibited by compound 3a. (C) 2004 Elsevier Ltd. All rights reserved.