title: Endoperoxide polyketides from a Chinese Plakortis simplex: further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes.
abstract: Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4-7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure-activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.affiliation: Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.affiliation: Key Laboratory for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Key Laboratory for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: franklin67@126.com.
authors.forename: Hou-Wen
authors.initials: HW
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China.
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Guo
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Via Pascal 36, I-20133 Milano, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via Pascal 36, I-20133 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via Pascal 36, I-20133 Milano, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy. Electronic address: scatagli@unina.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004146:Dioxanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D047229:Plakortis / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*; D061065:Polyketides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004146:Dioxanes; D010545:Peroxides; D061065:Polyketides
keywords: 1,2-Dioxanes; Computational analysis; In vitro antimalarial activity; Marine sponges; Stereochemistry