Novel Selective and Potent Inhibitors of Malaria Parasite Dihydroorotate Dehydrogenase: Discovery and Optimization of Dihydrothiophenone Derivatives

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• 作者：Minghao Xu ; Junsheng Zhu ; Yanyan Diao ; Hongchang Zhou ; Xiaoli Ren ; Deheng Sun ; Jin Huang ; Dongmei Han ; Zhenjiang Zhao ; Lili Zhu ; Yufang Xu ; Honglin Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：7911-7924
• 全文大小：660K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure鈥揳ctivity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC₅₀ = 6 nM, with >14鈥?00-fold species-selectivity over hDHODH) and parasite growth in vitro (IC₅₀ = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.