Malaria remains a severe global health concern, with 249 million cases reported in 2022, according to the World Health Organization (WHO) . DHODH is an essential enzyme in malaria parasites that helps to synthesize certain building blocks for their growth and development. It has been confirmed that targeting dihydroorotate dehydrogenase (DHODH) enzyme could lead to new and effective antimalarial drugs. Inhibitors of DHODH have shown potential for slowing down parasite growth during both the blood and liver stages. Over the last two decades, many species selective DHODH inhibitors have been designed, including DSM compounds and other non-DSM compounds. In the first chapter of this review, we have reviewed all synthetic schemes and structure–activity relationship (SAR) studies of DSM compounds. In this second chapter, we have compiled all the other non-DSM DHODH inhibitors based on dihydrothiophenones, thiazoles, hydroxyazoles, and -alkyl-thiophene-2-carboxamides. The review not only offers an insightful overview of the synthetic methods employed but also explores into alternative routes and innovative strategies involving different catalysts and chemical reagents. A critical aspect covered in the review is the SAR studies, which provide a comprehensive understanding of how structural modifications impact the efficacy of DHODH inhibitors and challenges related to the discovery of DHODH inhibitors. This information is invaluable for scientists engaged in the development of new antimalarial drugs, offering insights into the most promising scaffolds and their synthetic techniques.

中文翻译：

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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 2 部分：非 DSM 化合物


据世界卫生组织 (WHO) 称，疟疾仍然是一个严重的全球健康问题，2022 年报告病例数为 2.49 亿例。 DHODH 是疟疾寄生虫中的一种必需酶，有助于合成其生长和发育的某些组成部分。已经证实，靶向二氢乳清酸脱氢酶（DHODH）可以产生新的有效的抗疟药物。 DHODH 抑制剂已显示出在血液和肝脏阶段减缓寄生虫生长的潜力。在过去的二十年中，已经设计了许多种类的选择性DHODH抑制剂，包括DSM化合物和其他非DSM化合物。在本综述的第一章中，我们回顾了 DSM 化合物的所有合成方案和构效关系（SAR）研究。在第二章中，我们编译了基于二氢噻吩酮、噻唑、羟唑和-烷基-噻吩-2-甲酰胺的所有其他非 DSM DHODH 抑制剂。该综述不仅对所采用的合成方法进行了深入的概述，而且还探讨了涉及不同催化剂和化学试剂的替代路线和创新策略。该综述涵盖的一个关键方面是 SAR 研究，它提供了对结构修饰如何影响 DHODH 抑制剂的功效以及与 DHODH 抑制剂发现相关的挑战的全面了解。这些信息对于从事新型抗疟药物开发的科学家来说非常宝贵，为最有前途的支架及其合成技术提供了见解。