Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives.
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.
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.
Minghao
M
Xu
Junsheng
J
Zhu
Yanyan
Y
Diao
Hongchang
H
Zhou
Xiaoli
X
Ren
Deheng
D
Sun
Jin
J
Huang
Dongmei
D
Han
Zhenjiang
Z
Zhao
Lili
L
Zhu
Yufang
Y
Xu
Honglin
H
Li
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D000090722:Dihydroorotate Dehydrogenase; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D005663:Furans; D015800:Protozoan Proteins; C586837:ethyl 2-(naphthalen-2-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate; D015081:2-Naphthylamine; D044925:Oxidoreductases Acting on CH-CH Group Donors