Effects of Mono- and Dicapsaicinoid Functionalization on the Physicochemical Properties and Antimicrobial Photodynamic Activity of Protoporphyrin IX

Abstract

Antimicrobial photodynamic therapy (aPDT) is a promising alternative for combating multidrug-resistant bacteria and overcoming limitations of conventional antimicrobial treatments. To improve aPDT performance, two Protoporphyrin IX (PpIX) derivatives functionalized with one or two capsaicin fragments were synthesized and biologically evaluated. Their physicochemical, photophysical, and antimicrobial properties were assessed against susceptible and resistant Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains. Mono- and disubstituted capsaicinoid-functionalized derivatives were isolated in 17% and 40% yields, respectively. Structural modification induced minor photophysical changes compared to PpIX, including slightly reduced singlet oxygen generation and photostability. Aggregation studies revealed that PpIX-capsaicin 1 exhibited a lower tendency to aggregate, whereas PpIX-capsaicin 2 showed persistent aggregation with coexistence of H- and J-type species. A significant increase in lipophilicity (Log P) was observed only for PpIX-capsaicin 2. Photoinactivation assays demonstrated superior efficacy of PpIX-capsaicin 1 against S. aureus, achieving ~3-log reduction, while limited activity was observed against E. coli, likely due to its complex cell envelope. In contrast, PpIX-capsaicin 2 showed no significant photoactivity. Overall, these findings demonstrate that increased functionalization does not necessarily improve photodynamic performance, highlighting the importance of balanced lipophilicity and aggregation control in photosensitizer design.