Introducing 2-Thioxocoumarins as a New Class of Photosensitizers for Antimicrobial Photodynamic Therapy

Abstract

Antimicrobial photodynamic therapy (aPDT) has gained increasing attention as an alternative approach to combat bacterial resistance, although the development of efficient visible-light photosensitizers (PSs) remains a major challenge. Despite the extensive investigation of coumarin derivatives for photodynamic applications, 2-thioxocoumarins have not previously been explored for aPDT. Herein, we introduce 2-thioxocoumarins as a new class of photosensitizers for aPDT through the rational design and synthesis of four derivatives (TCM-1–TCM-4). Thionation, combined with strategic bromination, modulated the photophysical and photochemical properties of the coumarin scaffold, promoting visible-light absorption and efficient generation of reactive oxygen species (ROS) via both Type I and Type II photochemical pathways. Biological evaluation identified the monobrominated derivative TCM-2 as the lead photosensitizer, exhibiting potent light-induced antibacterial activity against methicillin-sensitive and methicillin-resistant Staphylococcus aureus with minimum inhibitory concentrations of 4–8 μM and no detectable dark toxicity. Although the tribrominated derivatives (TCM-3–TCM-4) exhibited enhanced Type I ROS generation, this was not accompanied by a proportional increase in photodynamic antibacterial activity, highlighting that efficient photodynamic inactivation depends not only on ROS generation but also on molecular properties governing bacterial interactions. These findings establish 2-thioxocoumarins as promising antimicrobial PSs for surface disinfection in healthcare settings and as a valuable molecular scaffold for the development of next-generation antimicrobial photosensitizers.