人二氢乳清酸脱氢酶（hDHODH）是催化嘧啶从头合成的关键酶。近年来，各种研究表明，抑制这种酶可以治疗类风湿性关节炎（RA）和癌症等自身免疫性疾病。本研究设计并合成了一系列新型噻唑烷酮hDHODH抑制剂。通过生物活性评价，发现化合物14具有较高的抑制活性，IC50值达到纳摩尔水平。初步构效关系研究发现，R1中的羧基和R2中的萘是提高活性的关键因素。通过分子对接，阐明了抑制剂与蛋白质之间的结合模式。该研究为进一步优化 hDHODH 抑制剂提供了重要参考。© 2023 John Wiley

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme that catalyzes the de novo synthesis of pyrimidine. In recent years, various studies have shown that inhibiting this enzyme can treat autoimmune diseases such as rheumatoid arthritis (RA) and cancer. This study designed and synthesized a series of novel thiazolidone hDHODH inhibitors. Through biological activity evaluation, Compound 14 was found to have high inhibitory activity, with an IC50 value reaching nanomolar level. Preliminary structure-activity relationship studies found that the carboxyl group in R1 and the naphthalene in R2 are key factors in improving activity. Through molecular docking, the binding mode between inhibitors and proteins was elucidated. This study provides an important reference for further optimizing hDHODH inhibitors.© 2023 John Wiley & Sons A/S.