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

Year: 2024

Type: article

Abstract: 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 IC 50 values in the range of 34.79–43.55 μg/mL, compared to the standard drug (Glucantime) with an IC 50 value of 97.31 μg/mL. In the case of pyrazole derivatives, P 1 , P 5 , and P 8 exhibited significant antileishmanial activity with IC 50 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 IC 50 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.

Source: Heliyon

DOI: 10.1016/j.heliyon.2024.e40444