Modulating the amphiphilic character of porphyrins with pH-activatable cationic centers and fluorocarbon chains to enhance antimicrobial photodynamic activity against Candida albicans.

The rise of antifungal-resistant yeast and the increasing prevalence of invasive mycoses, particularly those caused by Candida albicans, pose a significant global public health challenge. This is primarily due to the limited availability of new antifungal drugs and the continuous emergence of multidrug-resistant strains. Photodynamic inactivation (PDI) has emerged as a promising strategy to combat drug-resistant yeast and complex fungal infections. A key factor in improving this therapy is the development of novel and well-designed photosensitizers (PS) capable of selectively targeting and effectively inactivating fungal cells. In this context, we designed and synthesized four novel porphyrin derivatives bearing different numbers of fluorocarbon chains and tertiary alkylamino groups. At physiological pH, the tertiary amines are protonated, forming cationic centers and resulting in compounds with distinct degrees of amphiphilicity. Absorption and fluorescence studies in solution and in cell suspensions showed that the spectroscopic properties of the porphyrin chromophore were preserved across all substitution patterns. All tetrapyrrolic compounds were able to generate reactive oxygen species through both type I and type II photodynamic mechanisms, with similar yields. However, in vitro PDI treatments against C. albicans revealed a significant influence of the substitution patterns on photokilling efficiency. The compound with the highest dipolar moment achieved complete eradication of the treated fungal cell suspension at a concentration of 5.0 µM after 30 min of irradiation. Furthermore, the PDI treatments were extended to biofilm studies, in which this compound also retained superior photoinactivation efficiency against yeast cells embedded in biofilms. These findings indicate that modulating the dipolar character influences photokilling efficacy, providing useful insights for the design of amphiphilic porphyrins with antifungal photodynamic activity.