title: Design and synthesis of potent antimalarial agents based on clotrimazole scaffold: exploring an innovative pharmacophore.
abstract: Identification of new molecular scaffolds structurally unrelated to known antimalarials may represent a valid strategy to overcome resistance of P. falciparum (Pf) to currently available drugs. We describe herein the investigation of a new polycyclic pharmacophore, related to clotrimazole, to develop innovative antimalarial agents. This study allowed us to discover compounds characterized by a high in vitro potency, particularly against Pf CQ-resistant strains selectively targeting free heme, which are easy to synthesize by low-cost synthetic strategies.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Universita' di Siena, via Aldo Moro, 53100 Siena, 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: Bhupendra P
authors.initials: BP
authors.lastname: Joshi
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
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: Giulia
authors.initials: G
authors.lastname: Morace
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003022:Clotrimazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004351:Drug Resistance; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D006576:Heterocyclic Compounds, 4 or More Rings; D003022:Clotrimazole