Synthesis, structure–activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase

Abstract

A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (<i>h</i>DHODH) inhibitors. Compounds <b>26</b> and <b>31</b> displayed IC₅₀ values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound <b>31</b> could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the <i>para</i>- or <i>meta</i>-position of the phenyl group at R will lead to the identification of more potent <i>h</i>DHODH inhibitors.