Clotrimazole-based hybrid structures of pyrazole and benzimidazole: synthesis, antifungal evaluation and computational studies.

Some new N-substituted hetero aromatic compounds, derived from clotrimazole, were synthesized. In this regard, imidazole ring of clotrimazole was replaced by pyrazole (Series A; P₁-P₄) and benzimidazole moieties (Series B; P₅-P₈). All new compounds were evaluated against different species of fungi using broth microdilution method as recommended by clinical and laboratory standard institute (CLSI). Their cytotoxicity was assessed against MRC-5 as normal human fibroblasts cell line using MTT method. To augury the binding mode of the synthesized compounds against cytochrome P₄₅₀ lanosterol 14α-demethylase, molecular docking studies were also performed. Our results indicated that some compounds showed desirable antifungal activities at concentrations ranging from 0.5 to 1 µg/mL. Among them, compounds 4-nitro-1-trityl-1H-pyrazole (P₂) and 5-cyclopropyl-2-trityl-2H-pyrazol-3-ylamine (P₄) which bearing pyrazole ring, had the most antifungal activities (MIC₅₀ = 0.25–16 µg/mL), against all tested fungi species. Moreover, compound P₄ showed bactericidal activity at higher concentration of MIC. In vitro cytotoxic evaluation revealed that the potent compounds (P₂ and P₄) were non-toxic at therapeutic dosages toward human cells. In addition, the results showed good correlation between docking energies and biological activities of the compounds. According to both antifungal and computational studies, P₄, which containing special chemical structure, had desire potential to be consider as antifungal agent. Also, Density functional theory (DFT) was employed to study the reactivity descriptors of P₄ such as HOMO-LUMO energy gap, electronegativity, electron affinity, ionization potential, molecular hardness, and molecular softness. Based on the DFT study, the heterocyclic residue of P₄ has the favourable potent in accepting electrophilic reactions which is in agreement with the experimental data. [ABSTRACT FROM AUTHOR]