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 (DHODH) inhibitors. Compounds and displayed IC values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound 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- or -position of the phenyl group at R will lead to the identification of more potentDHODH inhibitors.

Structural Optimization and Structure–Activity Relationship of 4-Thiazolidinone Derivatives as Novel Inhibitors of Human Dihydroorotate Dehydrogenase

“…In order to probe the inner subsite of the ubiquinone-binding site of h DHODH, biphenyl derivatives were firstly designed and synthesized. The binding mode of 9 was simulated using the same molecular docking method reported previously [31,32]. It was shown that the introduction of 4-phenyl moiety could enhance the hydrophobic interaction between the biphenyl compounds and the binding pocket (Figure 3 and Figure 4).…”

“…Recently we had described 4-thiazolidinone derivatives 7 and 8 as novel h DHODH inhibitors [31]. It was found that the binding mode of 4-thiazolidinone with h DHODH was different from the classic inhibitors, that is, the thiazolidinone fragment locates at the outside of the bind pocket, cyano group contacts ALA-59 by a water-mediated hydrogen bond, carbonyl and TYR-38 forms hydrogen bond interaction, while the aromatic fragment contacts MET-43 by hydrophobic interaction (Figure 2A).…”

“…It was found that the binding mode of 4-thiazolidinone with h DHODH was different from the classic inhibitors, that is, the thiazolidinone fragment locates at the outside of the bind pocket, cyano group contacts ALA-59 by a water-mediated hydrogen bond, carbonyl and TYR-38 forms hydrogen bond interaction, while the aromatic fragment contacts MET-43 by hydrophobic interaction (Figure 2A). But, it was found that compound 8 only occupies the hydrophobic subsite of the ubiquinone-binding site with its naphthalenyl group (Figure 2B,C) [31]. The binding mode of compound 8 suggested us that the replacement of its naphthalenyl group with a suitable longer aryl group could orient the new ligand towards the inner side of the binding site.…”

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

“…Compound 9 , discovered in our previously designed DHODH inhibitor 58 , consists of a hydrophilic head and a hydrophobic tail ( Fig. 2 ) and may be a potential DHODH inhibitor in view of the classic binding mode of reported DHODH inhibitors.…”

“…Toward this end, we wish to report new and potent DHODH inhibitors. The new structures are developed based on our previously discovered DHODH inhibitor intermediate 2-acetamidobenzoic acid 58 . Its derivative 2-acrylamidobenzoic acid analog 11 was identified as the new starting point for structural optimization.…”