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 were evaluated for antileishmanial efficacy against the protozoan parasite, . Among the tested compounds, seven derivatives including , , , , , , and exhibited promising antileishmanial activity with IC values in the range of 34.79-43.55 μg/mL, compared to the standard drug (Glucantime) with an IC value of 97.31 μg/mL. In the case of pyrazole derivatives, , , and exhibited significant antileishmanial activity with IC values of 35.53, 36.79, and 37.40 μg/mL, respectively. The most potent antileishmanial activity is belong to and , with IC values of 34.79 and 38.51 μg/mL, respectively. Molecular docking outputs presented that and 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 and , which were the most and least active compounds, respectively. The outputs indicated that compound was more thermodynamically stable than . Additionally, 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.