title: Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: design, synthesis, and biological and structure-activity relationship studies.
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.
authors.affiliation: Universita di Siena, Sienna, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Gagan
authors.initials: G
authors.lastname: Kukreja
authors.forename: Salvatore Sanna
authors.initials: SS
authors.lastname: Coccone
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Joshi
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Giulia
authors.initials: G
authors.lastname: Morace
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Simon
authors.initials: S
authors.lastname: Croft
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Coletta
authors.forename: Stefano
authors.initials: S
authors.lastname: Marini
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: 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
chemical_list: 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