Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, and ‡Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
J Med Chem. 2013 Oct 24;56(20):7911-24. doi: 10.1021/jm400938g. Epub 2013 Oct 11.
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.
考虑到耐药性的出现和缺乏有效的抗疟疫苗，开发新型抗疟药物治疗疟疾具有重要意义。在此，我们阐明了一系列二氢噻吩酮衍生物作为新型疟原虫二氢乳清酸脱氢酶（PfDHODH）特异性抑制剂的发现和构效关系。最有前途的化合物 50 选择性抑制 PfDHODH（IC50 = 6 nM，对 hDHODH 的物种选择性超过 14,000 倍）和体外寄生虫生长（对 3D7 和 Dd2 细胞的 IC50 分别为 15 和 18 nM）。此外，通过体内药代动力学研究确定化合物 50 的口服生物利用度为 40%。这些结果进一步表明 PfDHODH 是抗疟化疗的有效靶点，本工作中报道的新型支架可能会发现新的抗疟药物。
