Exploring SAR and Antifungal Activity of Pyrazole-Thiazole-Hydrazone Compounds Through Synthesis and Docking Studies

Given the growing resistance to existing antifungal agents, a new series of pyrazole-thiazole derivatives (2a-2j) was synthesized and characterized by HRMS and NMR analyses to ensure molecular accuracy. In vitro testing against various Candida species revealed notable antifungal activity, with compounds 2c and 2e showing strong inhibition (MIC₅₀ = 0.98 µg/mL against Candida albicans), comparable to ketoconazole and fluconazole. To further explore their mechanism of action, in silico studies including molecular docking and molecular dynamics simulations were performed. These analyses confirmed the strong binding affinity and stability of these compounds within the active site of 14-α-sterol demethylase enzyme, a key enzyme in ergosterol biosynthesis. The electron-withdrawing effects of chlorine and fluorine substituents at the C-4 position of the phenyl ring in compounds 2c and 2e, respectively, likely enhance their antifungal activity. ADME predictions were also performed to assess pharmacokinetic properties, drug-likeness, and potential safety profile of the synthesized derivatives. Among the tested compounds, 2c stood out with superior activity across multiple Candida species, with MIC₅₀ values of 0.98 µg/mL against C. albicans, and 1.96 µg/mL against both C. parapsilosis and C. krusei. These results suggest that compounds likely exert their antifungal effects by inhibiting ergosterol biosynthesis through interaction with 14-α-sterol demethylase.