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Asymmetric synthesis and study of biological activity of (epi-)benzoanalogues of bioactive phenanthroquinolizidine alkaloids

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Abstract

The increasing microbial resistance to primary active structures remains alarming and the effort to look for new antibacterial active structures is still of scientific interest. One of the attractive ways to find new active structures is derivatization of well-known natural compounds. Alkaloids are a structurally diverse group of natural products with a wide range of biological effects. Historically, an attempt to increase the antimicrobial activity of alkaloids through chemical modifications has been successful. In this work, 12 new quinolizidine derivatives were synthesized and tested for their antimicrobial activity. The asymmetric synthesis of the benzoanalogue of the phenanthroquinolizidine bioactive alkaloid (−)-cryptopleurine and the epi-benzoanalogues of (−)-(15R)-hydroxycryptopleurine were achieved in six or seven steps starting from available enantiopure (S)-2-aminoadipic acid used as source of chirality as well as nitrogen. The highest antimicrobial activity was observed in the presence of the final saturated structure, the benzoanalogue of naturally occurring plant alkaloid cryptopleurine. It features selective toxicity, and significantly inhibits the growth of G+ bacteria, especially Staphylococcus sp. Tested derivatives have shown only a weak antifungal activity, but partial inhibition has been observed in the case of model yeasts.

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Acknowledgements

This work was supported by the Grant Agency of the Slovak Republic (Grant no. 1/0371/16). This contribution is also the result of the project: Research Center for Industrial Synthesis of Drugs, ITMS 26240220061, supported by the Research & Development Operational Programme funded by the ERDF.

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Authors and Affiliations

  1. Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, 81237, Bratislava, Slovak Republic

    Tomáš Pagáč, Zuzana Ježíková, Jana Kubíčková & Petra Olejníková

  2. Department of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, 81237, Bratislava, Slovak Republic

    Peter Šafář, Štefan Marchalín & Barbora Balónová

  3. Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University, 84215, Bratislava, Slovak Republic

    Miroslava Šupolíková & Eva Nováková

  4. Central Laboratories, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, 81237, Bratislava, Slovak Republic

    Michal Šoral

  5. Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology in Bratislava, Námestie slobody 17, 812 31, Bratislava, Slovak Republic

    Július Sivý

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  1. Tomáš Pagáč
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  2. Peter Šafář
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  4. Zuzana Ježíková
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  8. Jana Kubíčková
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  9. Michal Šoral
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  10. Július Sivý
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  11. Petra Olejníková
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Correspondence to Petra Olejníková.

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Pagáč, T., Šafář, P., Marchalín, Š. et al. Asymmetric synthesis and study of biological activity of (epi-)benzoanalogues of bioactive phenanthroquinolizidine alkaloids. Monatsh Chem 149, 1865–1876 (2018). https://doi.org/10.1007/s00706-018-2244-5

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  • DOI: https://doi.org/10.1007/s00706-018-2244-5

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