Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives

Minghao Xu; Junsheng Zhu; Yanyan Diao; Hongchang Zhou; Xiaoli Ren; Deheng Sun; Jin Huang; Dongmei Han; Zhenjiang Zhao; Lili Zhu; Yufang Xu; Honglin Li

doi:10.1021/jm400938g

Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives

J Med Chem. 2013 Oct 24;56(20):7911-24. doi: 10.1021/jm400938g. Epub 2013 Oct 11.

Authors

Minghao Xu¹, Junsheng Zhu, Yanyan Diao, Hongchang Zhou, Xiaoli Ren, Deheng Sun, Jin Huang, Dongmei Han, Zhenjiang Zhao, Lili Zhu, Yufang Xu, Honglin Li

Affiliation

¹ 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.

PMID: 24073986
DOI: 10.1021/jm400938g

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

2-Naphthylamine / analogs & derivatives
2-Naphthylamine / chemistry
2-Naphthylamine / pharmacokinetics
2-Naphthylamine / pharmacology
Animals
Antimalarials / chemistry
Antimalarials / pharmacokinetics
Antimalarials / pharmacology
Area Under Curve
Dihydroorotate Dehydrogenase
Drug Discovery
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Furans / chemistry
Furans / pharmacokinetics
Furans / pharmacology
Host-Parasite Interactions / drug effects
Humans
Malaria, Falciparum / parasitology
Malaria, Falciparum / prevention & control*
Male
Models, Chemical
Molecular Structure
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Plasmodium falciparum / physiology
Protozoan Proteins / antagonists & inhibitors*
Protozoan Proteins / metabolism
Rats
Rats, Sprague-Dawley

Substances

Antimalarials
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Furans
Protozoan Proteins
ethyl 2-(naphthalen-2-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate
2-Naphthylamine
Oxidoreductases Acting on CH-CH Group Donors