Journal of Medicinal Chemistry p. 7911 - 7924 (2013)
Update date:2022-08-15
Topics:
Xu, Minghao
Zhu, Junsheng
Diao, Yanyan
Zhou, Hongchang
Ren, Xiaoli
Sun, Deheng
Huang, Jin
Han, Dongmei
Zhao, Zhenjiang
Zhu, Lili
Xu, Yufang
Li, Honglin
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-activity 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 >14 000-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.
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