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

Abstract

Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), 1H NMR (proton nuclear magnetic resonance), 13C 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 14α-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 14α-demethylase and can be further optimized and developed as lead compounds.

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

“…CYP51 is one of the key enzymes of sterol biosynthesis in different biological kingdoms and serves the metabolic function such as membrane permeability, membrane fluidity, enzyme activity, cell morphology, and cell cycle progression [7][8][9]. This enzyme is found in all eukaryotes (including humans) and because the azoles interact also with other cytochrome P450-dependent enzymes (CYP3A4), a selective inhibition of the enzyme is essential for an increased therapeutic index [10][11][12].…”

Novel 2,4-Disubstituted-1,3-Thiazole Derivatives: Synthesis, Anti-Candida Activity Evaluation and Interaction with Bovine Serum Albumine

“…The determination of MFC confirmed the previously obtained MIC values. The MFC/MIC ratio values for all of the tested compounds were equal to 2, which suggested that these molecules may exert a fungicidal effect [23].…”

Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

“…Arylidene rings are reported to confer stability to the molecule and its biological activity [22]. Many studies have assessed various other arylidene derivatives exhibiting antibacterial [23], antifungal [24], or anticancer [25, 26] activities. Other members of our study group have also reported anti-cancer properties [17, 21] for a few derivatives of this family.…”