Design and synthesis of potent inhibitors of bc1 complex based on natural product neopeltolide

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Abstract

Neopeltolide, a natural product isolated from deep-water sponge specimen of the family neopeltidae, has been proven to be a novel inhibitor of cytochrome bc1. In this study, a series of neopeltolide derivatives was designed by replacing the 14-membered macrolactone with indole ring and confirmed by 1H NMR, 13C NMR, and HRMS. Based on the binding mode of 12h with bc1 complex, the IC50 values of compounds 16a-f (ranging from 0.70 to 1.46 μM) were improved significantly than the ester derivatives 12a-u by replacing the ester with amide linker. Subsequently, the molecular docking results indicated that compound 16e could form a π-π interaction with Phe274 and two H-bonds with Glu271 and His161 and the latter H-bond was found to account for its high activity. The present work accelerates the discovery of novel bc1 complex inhibitors to deal with the resistance that the existing bc1 complex inhibitors are facing and provides a valuable idea for the design of new fungicides.

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Acknowledgements

The research was supported in part by the National Key Research and Development Program of China (2017YFD0200506), the National Natural Science Foundation of China (No.21977035, 21772057), and State Key Laboratory of the Discovery and Development of Novel Pesticide (Shenyang Sinochem Agrochemicals R&D Co. Ltd (2018NYRD01).

Mao-Qian Xiong and Tao Chen are co-first authors due to their equal contribution to this work.

References (38)

  • X.G. Guo et al.

    Structural basis for the quinone reduction in the bc1 complex: A comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site

    Biochemistry

    (2003)
  • L. Xiong et al.

    Succinate dehydrogenase: An ideal target for fungicide discovery

    ACS Symp Ser

    (2015)
  • M.Y. Wang et al.

    FungiPAD: A free web tool for compound property evaluation and fungicide-likeness analysis

    J Agric Food Chem.

    (2019)
  • G.F. Hao et al.

    Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex

    J Am Chem Soc.

    (2012)
  • G.F. Hao et al.

    ACFIS: A web server for fragment-based drug discovery

    Nucl Acids Res.

    (2016)
  • J.F. Yang et al.

    PADFrag: A database built for the exploration of bioactive fragment space for drug discovery

    J Chem Inf Model.

    (2018)
  • F.X. Wu et al.

    AIMMS suite: A web server dedicated for prediction of drug sensitivity and resistance on protein mutation

    Briefings Bioinf

    (2020)
  • F. Wang et al.

    Graph attention convolutional neural network accurately predicts chemical poisoning of honey bees

    Sci Bull.

    (2020)
  • A.E. Wright et al.

    Neopeltolide, a macrolide from a lithistid sponge of the family neopeltidae

    J Nat Prod.

    (2007)
  • Cited by (0)

    c

    Co-first authors due to their equal contribution.

    View full text