Abstract
Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC(50) = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Artemisinins / pharmacology
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Chlorocebus aethiops
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Drug Design
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Parasitic Sensitivity Tests
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Peroxides / chemical synthesis*
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Peroxides / chemistry
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Peroxides / pharmacology
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Plasmodium falciparum / drug effects*
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / chemistry
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Sesquiterpenes, Guaiane / chemical synthesis*
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Sesquiterpenes, Guaiane / chemistry
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Sesquiterpenes, Guaiane / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thapsigargin / chemical synthesis
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Thapsigargin / chemistry
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Thapsigargin / pharmacology
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Vero Cells
Substances
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Antimalarials
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Artemisinins
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Peroxides
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Sesquiterpenes, Guaiane
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Thapsigargin
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artemisinin
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Sarcoplasmic Reticulum Calcium-Transporting ATPases