One of the deadliest infectious diseases, malaria, still has a significant impact on global morbidity and mortality. dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine nucleotide biosynthesis and has been clinically validated as an innovative and promising target for the development of novel targeted antimalarial drugs. DHODH inhibitors have the potential to significantly slow down parasite growth at the blood and liver stages. Several DHODH inhibitors based on various scaffolds have been explored over the past two decades. Among them, triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based derivatives known as DSM compounds showed tremendous potential as novel antimalarial agents, and one of the triazolopyrimidine-based compounds () was able to reach phase IIa clinical trials. DSM compounds were synthesized as DHODH inhibitors with various substitutions based on structure-guided medicinal chemistry approaches and further optimised as well. For the first time, this review provides an overview of all the synthetic approaches used for the synthesis, alternative synthetic routes, and novel strategies involving various catalysts and chemical reagents that have been used to synthesize DSM compounds. We have also summarized SAR study of all these DHODH inhibitors. In an attempt to assist readers, scientists, and researchers involved in the development of new DHODH inhibitors as antimalarials, this review provides accessibility of all synthetic techniques and SAR studies of the most promising triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based DHODH inhibitors.

中文翻译：

---

对发现 PfDHODH 抑制剂作为抗疟药物的合成策略和 SAR 研究的全面综述。第 1 部分：三唑并嘧啶、异恶唑并嘧啶和吡咯基 (DSM) 化合物

疟疾是最致命的传染病之一，仍然对全球发病率和死亡率产生重大影响。二氢乳清酸脱氢酶 (DHODH) 催化嘧啶核苷酸生物合成的第四步，并已被临床验证为开发新型靶向抗疟药物的创新且有前景的靶标。 DHODH 抑制剂有可能显着减缓血液和肝脏阶段寄生虫的生长。在过去的二十年里，人们已经探索了几种基于各种支架的 DHODH 抑制剂。其中，被称为DSM化合物的三唑并嘧啶、异恶唑并嘧啶和基于吡咯的衍生物显示出作为新型抗疟药的巨大潜力，其中一种基于三唑并嘧啶的化合物能够进入IIa期临床试验。基于结构引导的药物化学方法，合成了具有各种取代基的 DSM 化合物作为 DHODH 抑制剂，并进一步优化。本综述首次概述了用于合成的所有合成方法、替代合成路线以及涉及用于合成 DSM 化合物的各种催化剂和化学试剂的新策略。我们还总结了所有这些 DHODH 抑制剂的 SAR 研究。为了帮助读者、科学家和研究人员参与开发新型抗疟药 DHODH 抑制剂，本综述提供了最有前途的三唑并嘧啶、异恶唑并嘧啶和基于吡咯的 DHODH 抑制剂的所有合成技术和 SAR 研究。