Exploring new antifungal leads: synthesis, characterization, and computational study of a series of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid derivatives with promising CYP51-binding affinity

Alsalhy, Saja; Al-humadi, Hussam W.

doi:10.22075/chem.2026.41619.2460

Exploring new antifungal leads: synthesis, characterization, and computational study of a series of 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid derivatives with promising CYP51-binding affinity

Articles in Press

Document Type : Original Article

Authors

Saja Alsalhy ¹

Hussam w. Al-humadi ²

¹ College of Pharmacy, University of Babylon

² College of Pharmacy, University of Babylon, Hillah, Iraq

10.22075/chem.2026.41619.2460

Abstract

ABSTRACT: Starting from 4-(4-chlorophenyl) cyclohexane-1-carboxylic acid, a multi-steps processes were used to create a novel series of 1,2,4-triazole derivatives with a 4-(4-chlorophenyl) cyclohexane moiety. These processes included Fischer esterification, hydrazide formation, thiosemicarbazides preparation, cyclization to form the triazole core (Compound 5), and subsequent S-alkylation with butyl iodide, iodoethane, and ethyl bromo acetate to produce derivatives 5a, 5b, and 5c. FT-IR and 1H NMR spectroscopy were used to describe each constituent. All derivatives successfully bonded inside the active site of the fungal CYP51 enzyme (PDB: 4WMZ), according to molecular docking, with significant pi-alkyl and pi-sulphur interactions with important residues like Lys151, Tyr140, His468, and Cys470. Compound 5 had the highest binding affinity (-10.1 kcal/mol), which was comparable to the reference medication fluconazole (-11.9 kcal/mol). All compounds met Lipinski's rule of five, had favourable physicochemical characteristics with a high bioavailability score of 0.55, and were not anticipated to cross the blood-brain barrier, according to ADMET profiling using Swiss ADME. Notably, Compound 5 was uniquely predicted to have high gastrointestinal absorption despite the majority of derivatives being P-glycoprotein substrates with low absorption. These results suggest that Compound 5 is a viable lead candidate for additional in vitro and in vivo testing as a possible antifungal drug.

Keywords

Heterocyclic compounds

4-Triazole

ADMET profiling

Molecular docking

Fungal infections

Subjects