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

8An 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 mg/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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel purinylthiazolylethanone derivative 8c shows significant inhibitory action against C. albicans, with no detectable resistance and low toxicity. The compound kills fungi by damaging cell wall and membrane disruption, hinder the growth of fungal biofilm. Imbalance of redox equilibrium leads to oxidative damage to fungal cells and fungicidal effect.