Engineering Novel Terbinafine-Piperazine Hybrids: A Strategy for Design, Synthesis, and Assessment as Potent Antifungal Agents with Improved Oral Bioavailability

Abstract

Fungal infections, particularly those caused by opportunistic pathogens, such as Candida albicans, pose
a growing global health challenge due to rising resistance and limited therapeutic options. In response to
the urgent need for more effective antifungal therapies, the present study explores the design, synthesis,
and evaluation of novel terbinafine-piperazine hybrid (TPH) compounds. Terbinafine, a potent allylamine
antifungal agent, was structurally modified through hybridization with bioactive piperazine-based Schiff
bases to enhance antifungal efficacy and oral bioavailability. The synthesis was accomplished through a
two-step reaction: Initial formation of a Schiff base between substituted benzaldehydes and piperazine,
followed by nucleophilic substitution with terbinafine hydrochloride. The synthesized hybrids were
characterized using Fourier-transform infrared spectroscopy, thin-layer chromatography, and melting
point analysis. Their antifungal activities were assessed against clinically significant fungal strains using
agar well diffusion and broth microdilution methods. Lipophilicity studies were conducted to estimate
Log P and Log D values through the shake-flask method, simulating gastrointestinal and physiological
environments. Results indicated that the hybrids maintained structural integrity, demonstrated notable
antifungal activity comparable to fluconazole, and possessed moderate lipophilicity an essential feature
for oral bioavailability. Statistical analysis using analysis of variance confirmed the reliability and
reproducibility of the biological and physicochemical data. This research highlights the potential of hybrid
drug design as a viable strategy to overcome present antifungal limitations. The TPH s exhibit promising
characteristics that warrant further pharmacological investigation and in vivo validation as next-generation
antifungal agents.