Document Detail

Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents.
MedLine Citation:
PMID:  23341167     Owner:  NLM     Status:  MEDLINE    
Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC(50) values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine.
Florian C Schrader; Serghei Glinca; Julia M Sattler; Hans-Martin Dahse; Gustavo A Afanador; Sean T Prigge; Michael Lanzer; Ann-Kristin Mueller; Gerhard Klebe; Martin Schlitzer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-22
Journal Detail:
Title:  ChemMedChem     Volume:  8     ISSN:  1860-7187     ISO Abbreviation:  ChemMedChem     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-25     Completed Date:  2013-08-30     Revised Date:  2014-03-03    
Medline Journal Info:
Nlm Unique ID:  101259013     Medline TA:  ChemMedChem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  442-61     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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MeSH Terms
Antimalarials / chemical synthesis,  chemistry*,  toxicity
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*,  metabolism
Enzyme Inhibitors / chemical synthesis,  chemistry*,  toxicity
Fatty Acids / biosynthesis*
HeLa Cells
Molecular Docking Simulation
Plasmodium berghei / drug effects,  enzymology
Protein Structure, Tertiary
Structure-Activity Relationship
Grant Support
U01 AI082180/AI/NIAID NIH HHS; U01 AI082180-0101/AI/NIAID NIH HHS
Reg. No./Substance:
0/Antimalarials; 0/Enzyme Inhibitors; 0/Fatty Acids; EC Reductase (NADH)

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