Abstract
We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.
MeSH terms
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Animals
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Antifungal Agents / chemical synthesis
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Antifungal Agents / pharmacology
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Antifungal Agents / toxicity
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Antimalarials / chemical synthesis*
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Antimalarials / pharmacology
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Antimalarials / toxicity
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Cell Line
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Clotrimazole / analogs & derivatives*
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Clotrimazole / chemical synthesis*
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Clotrimazole / pharmacology
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Clotrimazole / toxicity
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Cytochrome P-450 Enzyme Inhibitors
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Drug Design
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Female
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Ferric Compounds / chemistry
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Heme / chemistry
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Humans
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In Vitro Techniques
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Mice
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Models, Molecular
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Oxidoreductases / antagonists & inhibitors
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Parasitic Sensitivity Tests
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Plasmodium berghei / drug effects
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Plasmodium chabaudi / drug effects
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Plasmodium falciparum / drug effects
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Protoporphyrins / chemistry
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Stereoisomerism
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Sterol 14-Demethylase
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Structure-Activity Relationship
Substances
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1-((4-chlorophenyl)bis(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)-1H-imidazole
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1-((4-fluorophenyl)(4-(pyrrolidin-1-ylmethyl)phenyl)(7-chloroquinolin-4-yl)methyl)-1H-imidazole
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Antifungal Agents
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Antimalarials
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CYP51A1 protein, human
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Cytochrome P-450 Enzyme Inhibitors
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Ferric Compounds
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Protoporphyrins
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iron protoporphyrin IX
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Heme
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Oxidoreductases
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Cyp51 protein, mouse
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Sterol 14-Demethylase
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Clotrimazole