title: Further optimization of plakortin pharmacophore: structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity.
abstract: For the optimization of the plakortin pharmacophore, we recently proposed a straightforward synthesis of 4-carbomethoxy-3-methoxy-1,2-dioxanes as potential antimalarial drug candidates. Herein we report the chemoselective reduction of the 4-carbomethoxy group which has allowed us to prepare in good yields twenty-four new endoperoxides carrying either the hydroxymethyl or the methoxymethyl group on C4 in various stereochemical arrangements with respect to the alkyl groups on C3 and C6 (the endoperoxide carbons). Some of these compounds showed promising in vitro antimalarial activities, both against chloroquine-resistant (CQ-R) and susceptible (CQ-S) strains of Plasmodium falciparum, with IC₅₀ values in the range of 0.5-1.0 μM. Compound 8g showed activity against the CQ-R strain comparable to that of the structurally more demanding plakortin.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy; Italian Malaria Network - Centro Interuniversitario di Ricerche sulla Malaria (CIRM), Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Via del Giochetto, 06126 Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Marco
authors.initials: M
authors.lastname: Lombardo
authors.forename: Luca
authors.initials: L
authors.lastname: Petrizza
authors.forename: Arianna
authors.initials: A
authors.lastname: Quintavalla
authors.forename: Francesca
authors.initials: F
authors.lastname: Rondinelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Trombini
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C000591578:4-oxymethyl-1,2-dioxane; D000962:Antimalarials; D004146:Dioxanes
keywords: 1,2-Dioxanes; Antimalarial drugs; DFT; Malaria; SAR