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 (P1-P14) were evaluated for antileishmanial efficacy against the protozoan parasite, Leishmania major. Among the tested compounds, seven derivatives including P1, P3, P5, P8, P12, P13, and P14 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, P1, P5, and P8 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 P12 and P14, with IC50 values of 34.79 and 38.51 μg/mL, respectively. Molecular docking outputs presented that P12 and P14 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 P1 and P12, which were the most and least active compounds, respectively. The outputs indicated that compound P1 was more thermodynamically stable than P12. Additionally, P1 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.
Read full abstract