Structure-Based Discovery of Novel 1,2,4-Triazole- Hydrazone Hybrids as Lanosterol 14α-Demethylase Inhibitors with Antifungal Potential

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Objectives: The global rise in opportunistic and systemic fungal infections, coupled with increasing resistance to conventional azole antifungal agents, has created an urgent demand for novel antifungal chemotypes with improved efficacy and safety profiles. In this study, a new series of 1,2,4-Triazole-Hydrazone Hybrid Derivatives (TH-1-TH-8) was rationally designed, synthesized, and evaluated for antifungal activity using combined in vitro and in silico approaches. Eight target compounds were synthesized through a multi-step synthetic route and structurally characterized by melting point analysis, Fourier-TransformInfrared Spectroscopy (FT-IR), ¹H and ¹³C Nuclear Magnetic Resonance (NMR) spectroscopy, and mass spectrometry, confirming their identity and purity. Materials and Methods: The antifungal potential of the synthesized derivatives was assessed in vitro against Candida albicans, Candida glabrata, and Aspergillus niger using the broth microdilution method, with fluconazole serving as the reference drug. Several compounds displayed moderate to potent antifungal activity, particularly those containing electron-withdrawing substituents on the aromatic ring, indicating their favorable influence on biological activity. To elucidate the possible mechanism of action, molecular docking studies were carried out against lanosterol 14α-Demethylase (CYP51). Results and Conclusion: The active derivatives exhibited strong binding affinities and key interactions within the enzyme active site, comparable to fluconazole. Furthermore, in-silico ADMET predictions revealed acceptable drug-likeness, pharmacokinetic properties, and safety profiles. A clear Structure-Activity Relationship (SAR) was established, highlighting the role of aromatic substitution in enhancing antifungal potency. These findings suggest that 1,2,4-triazole-hydrazone hybrids represent promising lead molecules for further antifungal drug development.

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