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.