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

Fanxun Zeng,Letian Zhang,Tiantian Qi,Guantian Yang,Shiliang Li,Xiaoyong Xu,Honglin Li,Lina Quan,Lili Zhu

doi:10.3390/molecules24152780

Abstract

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure–activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 μM and 1.45 μM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

Highlights

Pyrimidine, as a key precursor of RNA, DNA, glycoproteins, and phospholipids, plays a critical role in cellular metabolism and cell growth [1,2]
InInorder to probe the inner subsite of the ubiquinone-binding site of Human dihydroorotate dehydrogenase (hDHODH), biphenyl derivatives order to probe the inner subsite of the ubiquinone-binding site of hDHODH, biphenyl were firstly designed and synthesized
It was shown that the introduction of could enhance the could hydrophobic between the biphenyl compounds and the binding pocket

Summary

Introduction

Pyrimidine, as a key precursor of RNA, DNA, glycoproteins, and phospholipids, plays a critical role in cellular metabolism and cell growth [1,2]. Leflunomide (1, Figure 1) was approved by FDA for the treatment of rheumatoid arthritis in 1998 [16,17]. This compound was found to be a prodrug, forming its active metabolite teriflunomide via a base caused ring-opening reaction in vivo [18,19]. Brequinar (2), one of the strongest inhibitors of hDHODH, only showed modest anticancer effects on a number of solid tumors in a phase II clinical trial [21,22].

Methods

Discussion

Conclusion