Ru-terpyridine complexes containing clotrimazole as potent photoactivatable selective antifungal agents

• Published in: Journal of inorganic biochemistry 2024-11, Vol.260, p.112692, Article 112692
• Main Authors: Gonzalo-Navarro, Carlos, Troyano, Antonio J., Bermejo, Beatriz García-Béjar, Organero, Juan Ángel, Massaguer, Anna, Santos, Lucía, Rodríguez, Ana M., Manzano, Blanca R., Durá, Gema
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal ruthenium complexes; Antimicrobial; Candida albicans - drug effects; Clotrimazole; Clotrimazole - chemistry; Clotrimazole - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - radiation effects; Humans; Light; Microbial Sensitivity Tests; PhotoActivated therapy PACT; Photodissociation; Pyridines - chemistry; Pyridines - pharmacology; Ruthenium - chemistry; Substituted terpyridine ligands
• ISSN: 0162-0134; 1873-3344; 1873-3344
• DOI: 10.1016/j.jinorgbio.2024.112692

The overuse of antimicrobial agents in medical and veterinary applications has led to the development of antimicrobial resistance in some microorganisms and this is now one of the major concerns in modern society. In this context, the use of transition metal complexes with photoactivatable properties, which can act as drug delivery systems triggered by light, could become a potent strategy to overcome the problem of resistance. In this work several Ru complexes with terpyridine ligands and the clotrimazole fragment, which is a potent antimycotic drug, were synthesized. The main goal was to explore the potential photoactivated activity of the complexes as antifungal agents and evaluate the effect of introducing different substituents on the terpyridine ligand. The complexes were capable of delivering the clotrimazole unit upon irradiation with visible light in a short period of time. The influence of the substituents on the photodissociation rate was explained by means of TD-DFT calculations. The complexes were tested against three different yeasts, which were selected based on their prevalence in fungal infections. The complex in which a carboxybenzene unit was attached to the terpyridine ligand showed the best activity against the three species under light, with minimal inhibitory concentration values of 0.88 μM and a phototoxicity index of 50 achieved. The activity of this complex was markedly higher than that of free clotrimazole, especially upon irradiation with visible light (141 times higher). The complexes were more active on yeast species than on cancer cell lines. Ruthenium complexes with clotrimazole, antifungal agent, and different terpyridine ligands were obtained. They dissociated clotrimazole after irradiation, a fact rationalized after theoretical calculations. They behaved as antifungal, especially after photoactivated. One complex was 141 times more active than clotrimazole. They were more active on yeast species than on cancer cells. [Display omitted] •Antifungal ruthenium complexes with terpyridine and clotrimazole ligands.•The photoactivation liberates clotrimazole and increases the antifungal activity.•Substituents on the terpyridine ligands affect dissociation rates.•Theoretical calculations and photophysical properties explain the dissociation rates.•One complex is 141 times more antifungal than clotrimazole after irradiation.