title: A new class of antimalarial dioxanes obtained through a simple two-step synthetic approach: rational design and structure-activity relationship studies.
abstract: A new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold, was designed on the basis of a previously developed pharmacophore. Through a simplified and versatile scheme of synthesis, which utilizes cheap and commercially available starting materials, it was possible to obtain several structurally and stereochemically different compounds that were tested against P. falciparum. Most of compounds showed antimalarial activity in the low micromolar range and no cellular toxicity, all being significantly more active on chloroquine resistant (CQ-R) than on chloroquine sensitive (CQ-S) strains. Resulting structure-activity relationships were analyzed by means of experimental and computational techniques, validating our design rationale and tailoring it for the new scaffold. Our study demonstrated that according to the hypothesized mechanism of action, the antimalarial activity can be improved through rational structural modifications, paving the way for the development of new simplified antimalarial endoperoxides.
authors: Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Via D. Montesano, 49 I-80131 Napoli, Italy.
authors: Marco
authors: M
authors: Persico
authors: Arianna
authors: A
authors: Quintavalla
authors: Francesca
authors: F
authors: Rondinelli
authors: Claudio
authors: C
authors: Trombini
authors: Marco
authors: M
authors: Lombardo
authors: Caterina
authors: C
authors: Fattorusso
authors: Valeria
authors: V
authors: Azzarito
authors: Donatella
authors: D
authors: Taramelli
authors: Silvia
authors: S
authors: Parapini
authors: Yolanda
authors: Y
authors: Corbett
authors: Giuseppina
authors: G
authors: Chianese
authors: Ernesto
authors: E
authors: Fattorusso
authors: Orazio
authors: O
authors: Taglialatela-Scafati
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance; D042783:Endothelial Cells / Q000187:drug effects; D005296:Ferrous Compounds / Q000737:chemistry; D055806:Microvessels / Q000166:cytology; D008958:Models, Molecular; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004146:Dioxanes; D005296:Ferrous Compounds; D002738:Chloroquine; C029451:ferrous chloride