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

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.