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Phosphonamidates Integrating Sterically Hindered Phenols with Membrane-Active Cations: A Redox-Activated Approach to Antimicrobial Agents
Автор(ы)
Elmira Gibadullina
Adel Shakirov
Margarita Neganova
Yulia Aleksandrova
Alexandra Voloshina
Anna Lyubina
Anastasiya Sapunova
Anna Strelnik
Kamil Ivshin
Assel Shuragaziyeva
Altynkul Toibazarova
Anipa Tapalova
Nurbol Appazov
Alexander Burilov
Дата публикации
18 мая 2026 г.
Тип
journal article
Издатель
Multidisciplinary Digital Publishing Institute
Том
27
Выпуск
10
Первая страница
4524
Последняя страница
4524
ISSN
1422-0067
Аннотация
A strategy to create highly effective antimicrobial agents was proposed based on the conjugation of three functional components: a cationic quaternary ammonium salt (QAS) that exerts a membrane-disrupting effect and promotes selective accumulation on bacterial surfaces; a phosphonamidate linker for controlled activation; and a sterically hindered phenol (SHP) fragment as a potential redox component. This approach enabled the preparation of 40 target phosphonamidate–SHP/QAS hybrids in high yields (88–98%). Evaluation of their antimicrobial activity against major pathogens and methicillin-resistant Staphylococcus aureus (MRSA) revealed high potency against Gram-positive bacteria. The lead compounds achieved minimum inhibitory concentration (MIC) values of 0.7–2.8 μM, which is up to 10 times lower than that of the reference drug, norfloxacin. Mechanistic studies confirmed that these hybrids disrupt the bacterial membrane. In addition, an increase in intracellular ROS levels was observed for the most active compound. The SHP/QAS hybrids retained high activity against S. aureus ATCC 209P after 17 passages and showed low cytotoxicity (SI = 62–92) and negligible hemolysis. These properties indicate that this approach may offer a useful strategy for developing antibacterial agents with a potentially lower risk of inducing conventional resistance mechanisms.
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