Design and synthesis of potent antimalarial agents based on clotrimazole scaffold: exploring an innovative pharmacophore.
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.
Gemma
Sandra
S
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Universita' di Siena, via Aldo Moro, 53100 Siena, Italy.
Campiani
Giuseppe
G
Butini
Stefania
S
Kukreja
Gagan
G
Joshi
Bhupendra P
BP
Persico
Marco
M
Catalanotti
Bruno
B
Novellino
Ettore
E
Fattorusso
Ernesto
E
Nacci
Vito
V
Savini
Luisa
L
Taramelli
Donatella
D
Basilico
Nicoletta
N
Morace
Giulia
G
Yardley
Vanessa
V
Fattorusso
Caterina
C
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
D000935:Antifungal Agents; D000962:Antimalarials; D006576:Heterocyclic Compounds, 4 or More Rings; D003022:Clotrimazole