Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 17, Pages 4572-4580Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.034
Keywords
Marine sponges; 1,2-Dioxanes; In vitro antimalarial activity; Stereochemistry; Computational analysis
Funding
- European Union: Project Bluegenics [311848]
- European Union: Project IRSES [246987]
- Italian MIUR: FIRB Project [RBFR12WB3W_003]
- China National Funds for Distinguished Young Scientists [81225023]
- National Natural Science Foundation of China [81172978, 41106127]
- National High Technology Research and Development Program of China [2011AA09070107, 2013AA092902]
- [12XD1400200]
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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. (C) 2014 Elsevier Ltd. All rights reserved.
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