Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely.

Abstract

Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments 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 discovery of 24, which showed high potency against FP-2 (IC50 = 10.0 µM), PfDHFR (IC50 = 84.1 nM), P. falciparum 3D7 (IC50 = 53.1 nM), clinical isolated strains Fab9 (IC50 = 14.2 nM) and GB4 (IC50 = 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.

• Authors: Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 24 Pg. 6467-6478 (12 15 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 29111368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antimalarials
• Cysteine Proteinase Inhibitors
• Folic Acid Antagonists
• Tetrahydrofolate Dehydrogenase
• Cysteine Endopeptidases
• falcipain 2

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cysteine Endopeptidases (metabolism)
• Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Discovery
• Folic Acid Antagonists (chemical synthesis, chemistry, pharmacology)
• Malaria (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Molecular Structure
• Parasitic Sensitivity Tests
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects, enzymology, growth & development)
• Structure-Activity Relationship
• Tetrahydrofolate Dehydrogenase (metabolism)