Synthesis, biological evaluation and structure-activity relationship of 2-(2-hydroxyaryl)alkenylphosphonium salts with potency as anti-MRSA agents

Natalia V Terekhova; Anna P Lyubina; Alexandra D Voloshina; Anastasiya S Sapunova; Khasan R Khayarov; Daut R Islamov; Konstantin S Usachev; Vladimir G Evtugyn; Dmitry A Tatarinov; Vladimir F Mironov

doi:10.1016/j.bioorg.2022.106030

Synthesis, biological evaluation and structure-activity relationship of 2-(2-hydroxyaryl)alkenylphosphonium salts with potency as anti-MRSA agents

Bioorg Chem. 2022 Oct:127:106030. doi: 10.1016/j.bioorg.2022.106030. Epub 2022 Jul 16.

Affiliations

¹ Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov Str. 8, Kazan 420088, Russian Federation.
² Institute of Chemistry, Kazan Federal University, Kremlevskaya Str. 18, Kazan 420008, Russian Federation.
³ Laboratory for Structural Studies of Biomacromolecules, FRC Kazan Scientific Center of RAS, Lobachevskogo Str., 2/31, Kazan 420111, Russian Federation.
⁴ Interdisciplinary center for Analytical microscopy, Kazan Federal University, Kremlevskaya str. 18, Kazan 420008, Russian Federation.
⁵ Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov Str. 8, Kazan 420088, Russian Federation; Institute of Chemistry, Kazan Federal University, Kremlevskaya Str. 18, Kazan 420008, Russian Federation. Electronic address: datint@iopc.ru.

PMID: 35870414
DOI: 10.1016/j.bioorg.2022.106030

Abstract

Here we report the synthesis, in vitro antimicrobial activity, preliminary toxicity and mechanism study of a new series of 2-(2-hydroxyaryl)alkenylphosphonium salts with the variation of phosphonium moiety obtained by a two-step synthetic method from phosphine oxides. The salts showed pronounced activity against Gram-positive bacteria, including MRSA strains, and some fungi. Mechanism of action against S. aureus was studied by CV test, TEM and proteomic assay. No cell wall integrity loss was observed while proteomic assay results suggested interference in different metabolic processes of S. aureus. For this series, lipophilicity was determined as a key factor for the inhibition of Gram-positive bacteria growth and S. aureus killing. Biological properties of methylated derivatives were notably different with manifested action against Gram-negative bacteria.

Keywords: Antimicrobial activity; Cytotoxicity; Lipophilicity; MRSA; Phosphine oxides; Phosphonium salts; Proteomic analysis; S. aureus; TEM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology
Gram-Positive Bacteria
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests
Proteomics
Salts*
Staphylococcus aureus
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Salts