Design, Synthesis and Antifungal Activity Evaluation of New Thiazolin-4-ones as Potential Lanosterol 14α-Demethylase Inhibitors

Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with alpha-monochloroacetic acid or ethyl alpha-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), H-1 NMR (proton nuclear magnetic resonance), C-13 NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds' lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14 alpha-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14 alpha-demethylase and can be further optimized and developed as lead compounds.