Citation: Chen Wenhua, Yao Xue, Huang Zhenghui, Mao Fei, Guan Longfei, Tang Yun, Jiang Hualiang, Li Jian, Huang Jin, Jiang Lubin, Zhu Jin. Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation[J]. Chinese Chemical Letters, ;2019, 30(1): 250-254. doi: 10.1016/j.cclet.2017.11.041 shu

Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation

Chen Wenhua ^a ,
Yao Xue ^a ,
Huang Zhenghui ^b ,
Mao Fei ^a ,
Guan Longfei ^a ,
Tang Yun ^a ,
Jiang Hualiang ^a ,
Li Jian ^a ,
Huang Jin ^a,, ,
Jiang Lubin ^b,, ,
Zhu Jin ^a,,

a.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b.
Key Laboratory of Molecular Virology & Immunology, Unit of Human Parasite Molecular and Cell Biology, Institute Pasteur of Shanghai, University of Chinese Academy of Science, Shanghai 200031, China

Corresponding author: Huang Jin, huangjin@ecust.edu.cn Jiang Lubin, lbjiang@ips.ac.cn Zhu Jin, jinz@ecust.edu.cn
Received Date: 27 September 2017
Revised Date: 25 November 2017
Accepted Date: 30 November 2017
Available Online: 5 January 2017

Figures(3)

Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme (IC₅₀=6.8±1.8 mmol/L and IC₅₀=8.8±0.3 mmol/L) and P. falciparum 3D7 strain (IC₅₀=2.9 mmol/L). Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P. falciparum Dd2 strain (IC₅₀=1.1 mmol/L) than pyrimethamine (IC₅₀ >10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC₅₀=2.6 mmol/L) and GB4 (IC₅₀=1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.
- Antimalarial drug,
- Plasmodium falciparum,
- FP-2,
- PfDHFR,
- Dual inhibitor
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