Pyrazole derivatives as antileishmanial agents: Biological evaluation, molecular docking study, DFT analysis and ADME prediction

Leishmaniasis is a parasitic disease that is commonly found in tropical and sub-tropical regions. Currently, there is no protective antileishmanial vaccine, and the available clinical drugs have serious side effects. On the other hand, due to the emergence of multidrug-resistant strains of the causative pathogens, the study and design of novel antileishmanial agents is urgently needed. Accordingly, fourteen previously synthesized pyrazole and pyrano [2,3-c] pyrazole derivatives (P ₁ -P ₁₄ ) were evaluated for antileishmanial efficacy against the protozoan parasite, Leishmania major. Among the tested compounds, seven derivatives including P ₁ , P ₃ , P ₅ , P ₈ , P ₁₂ , P ₁₃ , and P ₁₄ exhibited promising antileishmanial activity with IC₅₀ values in the range of 34.79-43.55 μg/mL, compared to the standard drug (Glucantime) with an IC₅₀ value of 97.31 μg/mL. In the case of pyrazole derivatives, P ₁ , P ₅ , and P ₈ exhibited significant antileishmanial activity with IC₅₀ values of 35.53, 36.79, and 37.40 μg/mL, respectively. The most potent antileishmanial activity is belong to P ₁₂ and P ₁₄ , with IC₅₀ values of 34.79 and 38.51 μg/mL, respectively. Molecular docking outputs presented that P ₁₂ and P ₁₄ formed favorable interactions with key residues in the active site of the 14-alpha demethylase enzyme, which is an important target for antileishmanial agents. Various DFT parameters were also calculated for compounds P ₁ and P ₁₂ , which were the most and least active compounds, respectively. The outputs indicated that compound P ₁ was more thermodynamically stable than P ₁₂ . Additionally, P ₁ had higher hardness and a higher energy gap, resulting in greater stability. In addition, these compounds showed satisfactory theoretical ADME properties. The present results indicate that the investigated pyrazole and pyrano [2,3-c] pyrazole derivatives can be considered as promising agents for the development of antileishmaniasis treatments.