Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: design, synthesis, and biological and structure-activity relationship studies.
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.
Gemma
Sandra
S
Universita di Siena, Sienna, Italy.
Campiani
Giuseppe
G
Butini
Stefania
S
Kukreja
Gagan
G
Coccone
Salvatore Sanna
SS
Joshi
Bhupendra P
BP
Persico
Marco
M
Nacci
Vito
V
Fiorini
Isabella
I
Novellino
Ettore
E
Fattorusso
Ernesto
E
Taglialatela-Scafati
Orazio
O
Savini
Luisa
L
Taramelli
Donatella
D
Basilico
Nicoletta
N
Parapini
Silvia
S
Morace
Giulia
G
Yardley
Vanessa
V
Croft
Simon
S
Coletta
Massimiliano
M
Marini
Stefano
S
Fattorusso
Caterina
C
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D003022:Clotrimazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D016788:Plasmodium chabaudi / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011524:Protoporphyrins / Q000737:chemistry; D013237:Stereoisomerism; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship
C529290:1-((4-chlorophenyl)bis(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)-1H-imidazole; C529291:1-((4-fluorophenyl)(4-(pyrrolidin-1-ylmethyl)phenyl)(7-chloroquinolin-4-yl)methyl)-1H-imidazole; D000935:Antifungal Agents; D000962:Antimalarials; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D005290:Ferric Compounds; D011524:Protoporphyrins; C448299:iron protoporphyrin IX; D006418:Heme; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D003022:Clotrimazole