Discovery of novel purinylthiazolylethanone derivatives as anti-Candida albicans agents through possible multifaceted mechanisms

An unprecedented amount of fungal and fungal-like infections has recently brought about some of the most severe die-offs and extinctions due to fungal drug resistance. Aimed to alleviate the situation, new effort was made to develop novel purinylthiazolylethanone derivatives, which were expected to combat the fungal drug resistance. Some prepared purinylthiazolylethanone derivatives possessed satisfactory inhibitory action towards the tested fungi, among which compound 8c gave a MIC value of 1 μg/mL against C. albicans. The active molecule 8c was able to kill C. albicans with undetectable resistance as well as low hematotoxicity and cytotoxicity. Furthermore, it could hinder the growth of C. albicans biofilm, thus avoiding the occurrence of drug resistance. Mechanism research manifested that purinylthiazolylethanone derivative 8c led to damage of cell wall and membrane disruption, so protein leakage and the cytoplasmic membrane depolarization were observed. On this account, the activity of fungal lactate dehydrogenase was reduced and metabolism was impeded. Meanwhile, the increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) disordered redox equilibrium, giving rise to oxidative damage to fungal cells and fungicidal effect. Novel purinylthiazolylethanone derivatives as anti-C. albicans potentiators were developed, and their antifungal activities as well as probable antifungal mechanisms were explored. [Display omitted] •Novel purine derivatives as antifungal agents were developed for the first time.•Compound 8c endowed superior efficacy towards C. albicans to fluconazole.•Molecule 8c killed C. albicans with undetectable resistance and low toxicity.•Hybrid 8c could damage cell wall and disturb membrane integrity.•Compound 8c could impede metabolism and trigger oxidative stress.