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 <b>(P</b> <sub><b>1</b></sub> <b>-P</b> <sub><b>14</b></sub> <b>)</b> were evaluated for antileishmanial efficacy against the protozoan parasite, <i>Leishmania major</i>. Among the tested compounds, seven derivatives including <b>P</b> <sub><b>1</b></sub> , <b>P</b> <sub><b>3</b></sub> , <b>P</b> <sub><b>5</b></sub> , <b>P</b> <sub><b>8</b></sub> , <b>P</b> <sub><b>12</b></sub> , <b>P</b> <sub><b>13</b></sub> , and <b>P</b> <sub><b>14</b></sub> exhibited promising antileishmanial activity with IC<sub>50</sub> values in the range of 34.79-43.55 μg/mL, compared to the standard drug (Glucantime) with an IC<sub>50</sub> value of 97.31 μg/mL. In the case of pyrazole derivatives, <b>P</b> <sub><b>1</b></sub> , <b>P</b> <sub><b>5</b></sub> , and <b>P</b> <sub><b>8</b></sub> exhibited significant antileishmanial activity with IC<sub>50</sub> values of 35.53, 36.79, and 37.40 μg/mL, respectively. The most potent antileishmanial activity is belong to <b>P</b> <sub><b>12</b></sub> and <b>P</b> <sub><b>14</b></sub> , with IC<sub>50</sub> values of 34.79 and 38.51 μg/mL, respectively. Molecular docking outputs presented that <b>P</b> <sub><b>12</b></sub> and <b>P</b> <sub><b>14</b></sub> 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 <b>P</b> <sub><b>1</b></sub> and <b>P</b> <sub><b>12</b></sub> , which were the most and least active compounds, respectively. The outputs indicated that compound <b>P</b> <sub><b>1</b></sub> was more thermodynamically stable than <b>P</b> <sub><b>12</b></sub> . Additionally, <b>P</b> <sub><b>1</b></sub> 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.
Authors
- Elaheh Ataollahi
- Soghra Khabnadideh (ORCID: https://orcid.org/0000-0003-1176-6143)
- Leila Zamani
- Fatemeh Zare (ORCID: https://orcid.org/0000-0003-0788-6732)
- Leila Emami (ORCID: https://orcid.org/0000-0001-6453-9492)
- Gholamreza Hatam (ORCID: https://orcid.org/0000-0002-7807-4793)
- Sara Sadeghian (ORCID: https://orcid.org/0000-0001-6598-2074)
- Razieh Sabet (ORCID: https://orcid.org/0000-0002-8636-9508)
- Bahram Kazemi (ORCID: https://orcid.org/0000-0002-3072-8831)
- M M Naghizadeh Jahromi (ORCID: https://orcid.org/0000-0002-9930-2249)
Institutions
- Shiraz University of Medical Sciences (IR)
Publication Details
- Journal
- Heliyon
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1016/j.heliyon.2024.e40444
- Citations
- 2
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Shiraz University of Medical Sciences
- Shiraz University