학술논문
Synthesis, Structure−Activity Relationship, and Mode-of-Action Studies of Antimalarial Reversed Chloroquine Compounds.
Document Type
Article
Author
Source
Subject
*ANTIMALARIALS
*STRUCTURE-activity relationship in pharmacology
*ORGANIC synthesis
*CHLOROQUINE
*BIOCHEMICAL mechanism of action
*DRUG resistance
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Language
ISSN
0022-2623
Abstract
We have previously shown that a “reversed chloroquine (RCQ)” molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum(Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H.J. Med. Chem.2006, 49, 5623. Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly, J. X.; Peyton, D. H.J. Med. Chem.2010, 53, 916). Here, we present an investigation into the structure−activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite’s digestive vacuole in a manner similar to that of chloroquine. [ABSTRACT FROM AUTHOR]