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Antimicrobial activity of triphenylphosphonium (TPP) conjugates of alkynyl−substituted nucleic bases and their analogues

The Journal of Antibiotics volume 78, pages 731–756 (2025)Cite this article

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Abstract

Twenty triphenylphosphonium (TPP) conjugates in which 1-alkynyl-substituted nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) were connected to the TPP cation via an octyl or decyl linker were synthesized. In vitro evaluation of their antibacterial activity against five Gram-positive bacteria, two Gram-negative bacteria and fungus C. albicans revealed six lead compounds which exhibited high bacteriostatic activity (MIC 0.2–0.9 μM) against Gram-positive bacteria S. aureus, B. cereus, E. faecalis, as well as MRSA strains. These lead compounds are TPP-conjugates in which 1-alkynylquinazoline-2,4-dione moiety is bound to the TPP cation via the decyl (4 d, 4 f) or octyl (4e) linker and biscationic TPP-conjugates in which two TPP cations are attached to the N-1 and N-3 atoms of 5-alkynylquinazoline-2,4-dione moiety via the decyl (5 d, 5 f) or octyl (5e) linkers. Biscations 5 d and 5e showed high in vitro bacteriostatic and bactericidal activity (MIC/MBC 0.2–7.8 μM) against Gram-negative bacteria E. coli and P. aeruginosa. In addition, biscations 5 d and 5 f exhibited noticeable in vitro fungistatic and fungicidal activity against fungus C. albicans. Using colorimetric and fluorimetric methods, it was found that all lead compounds at concentrations corresponding to the MIC and MBC values caused cytoplasmic membrane damage and depolarization, without violating the integrity of the S. aureus cell wall. In addition, all lead compounds inhibited the formation of S. aureus biofilm by 80-100% at concentrations close to the MBC value (about 0.8 μM), and destroyed already formed S. aureus biofilm at concentrations in the range of 6.3–12.5 μM.

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Acknowledgements

We are grateful to the Assigned Spectral-Analytical Center of FRC Kazan Scientific Center of RAS for technical assistance in research.

Funding

This research was funded by the Russian Science Foundation (grant no. 24-13-00006).

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Authors and Affiliations

  1. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

    Olga V. Andreeva, Alexandra D. Voloshina, Anna P. Lyubina, Bulat F. Garifullin, Irina Yu. Strobykina, Mayya G. Belenok, Olga B. Babaeva, Vasily M. Babaev, Ravil F. Aznagulov, Liliya F. Saifina, Vyacheslav E. Semenov & Vladimir E. Kataev

  2. Kazan National Research Technological University, Kazan, Russian Federation

    Bulat F. Garifullin & Ravil F. Aznagulov

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  1. Olga V. Andreeva
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Correspondence to Alexandra D. Voloshina.

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Andreeva, O.V., Voloshina, A.D., Lyubina, A.P. et al. Antimicrobial activity of triphenylphosphonium (TPP) conjugates of alkynyl−substituted nucleic bases and their analogues. J Antibiot 78, 731–756 (2025). https://doi.org/10.1038/s41429-025-00864-1

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