Anticandidal Effect of New Imidazole Derivatives Over Aspartic Protease Inhibition

Abstract Candidiasis is one of the most serious microbial infections in the world. One of the main virulence factors for Candida albicans is the crucial secretion of aspartic proteases (Saps). Saps are hydrolytic enzymes that play a major role in many fungal pathophysiological processes as well as in many levels of the associations between the fungus and its host. In this work, we report on the synthesis, characterization, and anti‐candida agent evaluation of a family of 13 imidazolidine‐based aspartate protease inhibitors. In vitro and in silico enzyme inhibition studies have confirmed these compounds′ ability to inhibit fungal aspartate protease. Based on the molecular mechanistic value scores from molecular docking and MD simulations, we selected the top compounds 5b (binding energy −13.90 kcal/mol) and 5m (binding energy −12.94 kcal/mol) from among 5a – l based on the molecular mechanistic value scores from molecular docking and MD simulations for use in in vitro validations. In the results, imidazolidine derivatives showed strong aspartic protease inhibition activity. In conclusion, compounds 5b and 5m were found as potent anti‐candida agents and screened for further pre‐clinical and clinical validations.