The activities of wortmannilactones against helminth electron transport chain enzymes, structure-activity relationships, and the effect on Trichinella spiralis infected mice


Biotransformation of wortmannilactone F (3) using the marine-derived fungus DL1103 generated wortmannilactone M (1), a novel analog of wortmannilactone, which was a reduction product of 3 at the C-3 carbonyl group. The in vitro inhibitory activities of 10 wortmannilactones, including 1, against electron transport enzymes indicated that all the wortmannilactones were selective inhibitors of NADH-fumarate reductase and NADH–rhodoquinone reductase. The structure–activity relationship analysis showed that the relative configuration of C1” and C5”, the positions of double bonds, the oxygen atoms in the dihydropyran moiety, and the keto-carbonyl group in the oxabicyclo-[2.2.1]-heptane moiety were important to the inhibitory activity of wortmannilactones. In vivo studies indicated that 3 significantly decreased the number and size of adult worms in Trichinella spiralis-infected mice in a dose-dependent manner. Notable changes in the cuticle and microvilli of T. spiralis were also observed. Our data provided useful information in the research and development of polyketides with dihydropyran and oxabicyclo [2.2.1] heptane moieties as antihelminthics.

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This work was supported by the National Natural Science Foundation of China (81172966). We are grateful to Dr. Jun Kun, Dalian University of Technology, for help in obtaining NMR and MS data and are grateful to Dr Yuanhua Qin, Department of Parasitology, College of Basic Medical Sciences, Dalian Medical University, for suggestions concerning the animal experiments.

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Correspondence to Yu Cui or Yue-Sheng Dong.

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Liu, W., Ren, Y., Hao, A. et al. The activities of wortmannilactones against helminth electron transport chain enzymes, structure-activity relationships, and the effect on Trichinella spiralis infected mice. J Antibiot 71, 731–740 (2018) doi:10.1038/s41429-018-0061-z

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