title: The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism.
abstract: In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.affiliation: Second University of Naples, Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Via Vivaldi 43, Caserta, 81100, Italy.|Institute of Biostructures and Bioimages (IBB) CNR, Via Mezzocannone 16, Naples, 80134, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fattorusso
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.affiliation: Institute of Biostructures and Bioimages (IBB) CNR, Via Mezzocannone 16, Naples, 80134, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: de Paola
authors.affiliation: Institute of Biostructures and Bioimages (IBB) CNR, Via Mezzocannone 16, Naples, 80134, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zaccaro
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rondinelli
authors.affiliation: Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.|Alma Mater Studiorum University of Bologna, Department of Chemistry "G. Ciamician", Via Selmi 2, Bologna, 40126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.|Alma Mater Studiorum University of Bologna, Department of Chemistry "G. Ciamician", Via Selmi 2, Bologna, 40126, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Quintavalla
authors.affiliation: Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.|Alma Mater Studiorum University of Bologna, Department of Chemistry "G. Ciamician", Via Selmi 2, Bologna, 40126, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trombini
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.affiliation: University of Naples "Federico II", Department of Pharmacy, Via D. Montesano 49, Napoli, 80131, Italy.|Italian Malaria Network - Centro Interuniversitario di Ricerca Sulla Malaria (CIRM) Department of Experimental Medicine and Biochemical Science, Via Del Giochetto, Perugia, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.affiliation: Institute of Biostructures and Bioimages (IBB) CNR, Via Mezzocannone 16, Naples, 80134, Italy.|Advanced Accelerator Applications, Via Vivaldi 43, Caserta, 81100, Italy.
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Farina
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004146:Dioxanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008968:Molecular Conformation; D062105:Molecular Docking Simulation
chemical_list: D000962:Antimalarials; D004146:Dioxanes; D005296:Ferrous Compounds; D006418:Heme; C029451:ferrous chloride