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      Endoperoxide polyketides from a Chinese Plakortis simplex: further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes.

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          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.

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          Author and article information

          Journal
          Bioorg. Med. Chem.
          Bioorganic & medicinal chemistry
          Elsevier BV
          1464-3391
          0968-0896
          Sep 01 2014
          : 22
          : 17
          Affiliations
          [1 ] Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
          [2 ] Key Laboratory for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
          [3 ] 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.
          [4 ] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China.
          [5 ] Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Via Pascal 36, I-20133 Milano, Italy.
          [6 ] Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via Pascal 36, I-20133 Milano, Italy.
          [7 ] Dipartimento di Farmacia, Università di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy. Electronic address: scatagli@unina.it.
          Article
          S0968-0896(14)00550-1
          10.1016/j.bmc.2014.07.034
          25115700
          71b51ea1-526c-4180-a03e-cf9f4a5f6d64
          History

          1,2-Dioxanes,Computational analysis,In vitro antimalarial activity,Marine sponges,Stereochemistry

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