Pyrazole Derivatives As Antileishmanial Agents: Biological Evaluation, Molecular Docking Study, DFT Analysis and ADME Prediction

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Dec 11

PMID 39660189

Authors

Razieh Sabet

Gholamreza Hatam

Leila Emami

Elaheh Ataollahi

Fateme Zare

Leila Zamani

Behnaz Kazemi

Masood Mohabati Jahromi

Sara Sadeghian

Soghra Khabnadideh

Affiliations

Soon will be listed here.

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 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.

References

De S, Aamna B, Sahu R, Parida S, Behera S, Dan A . Seeking heterocyclic scaffolds as antivirals against dengue virus. Eur J Med Chem. 2022; 240:114576. PMC: 9250831. DOI: 10.1016/j.ejmech.2022.114576. View

Motazedian M, Fakhar M, Motazedian M, Hatam G, Mikaeili F . A urine-based polymerase chain reaction method for the diagnosis of visceral leishmaniasis in immunocompetent patients. Diagn Microbiol Infect Dis. 2007; 60(2):151-4. DOI: 10.1016/j.diagmicrobio.2007.09.001. View

Gomha S, Abdallah M, Abbas I, Kazem M . Synthesis, Cytotoxicity Evaluation, Molecular Docking and Utility of Novel Chalcones as Precursors for Heterocycles Incorporating Pyrazole Moiety. Med Chem. 2017; 14(4):344-355. DOI: 10.2174/1573406413666171020114105. View

Berhe H, Birhan Y, Beshay B, Habib H, Hymete A, Bekhit A . Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives. BMC Chem. 2024; 18(1):9. PMC: 10775556. DOI: 10.1186/s13065-023-01111-0. View

Mohammadpour I, Hatam G, Handjani F, Bozorg-Ghalati F, Pourkamal D, Motazedian M . Leishmania cytochrome b gene sequence polymorphisms in southern Iran: relationships with different cutaneous clinical manifestations. BMC Infect Dis. 2019; 19(1):98. PMC: 6352432. DOI: 10.1186/s12879-018-3667-7. View

Abu-Melha S, Edrees M, Riyadh S, Abdelaziz M, Elfiky A, Gomha S . Clean Grinding Technique: A Facile Synthesis and In Silico Antiviral Activity of Hydrazones, Pyrazoles, and Pyrazines Bearing Thiazole Moiety against SARS-CoV-2 Main Protease (M). Molecules. 2020; 25(19). PMC: 7582706. DOI: 10.3390/molecules25194565. View

Foroughi-Parvar F, Hatam G . Vaccines for canine leishmaniasis. Adv Prev Med. 2015; 2014:569193. PMC: 4297634. DOI: 10.1155/2014/569193. View

Hassani B, Zare F, Emami L, Khoshneviszadeh M, Fazel R, Kave N . Synthesis of 3-hydroxypyridin-4-one derivatives bearing benzyl hydrazide substitutions towards anti-tyrosinase and free radical scavenging activities. RSC Adv. 2023; 13(46):32433-32443. PMC: 10629491. DOI: 10.1039/d3ra06490e. View

Esteves M, Fragiadaki I, Lopes R, Scoulica E, Cruz M . Synthesis and biological evaluation of trifluralin analogues as antileishmanial agents. Bioorg Med Chem. 2009; 18(1):274-81. DOI: 10.1016/j.bmc.2009.10.059. View

10.

Almandil N, Taha M, Rahim F, Wadood A, Imran S, Alqahtani M . Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies. Bioorg Chem. 2019; 85:109-116. DOI: 10.1016/j.bioorg.2018.12.025. View

11.

Ebenezer O, Shapi M, Tuszynski J . A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives. Biomedicines. 2022; 10(5). PMC: 9139179. DOI: 10.3390/biomedicines10051124. View

12.

Ferreira Espuri P, Reis L, Peloso E, Silva Gontijo V, Colombo F, Nunes J . Synthesis and evaluation of the antileishmanial activity of silver compounds containing imidazolidine-2-thione. J Biol Inorg Chem. 2019; 24(3):419-432. DOI: 10.1007/s00775-019-01657-2. View

13.

Mekarnia N, Benallal K, Sadlova J, Vojtkova B, Mauras A, Imbert N . Effect of Phlebotomus papatasi on the fitness, infectivity and antimony-resistance phenotype of antimony-resistant Leishmania major Mon-25. Int J Parasitol Drugs Drug Resist. 2024; 25:100554. PMC: 11261056. DOI: 10.1016/j.ijpddr.2024.100554. View

14.

Marrapu V, Mittal M, Shivahare R, Gupta S, Bhandari K . Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents. Eur J Med Chem. 2011; 46(5):1694-700. DOI: 10.1016/j.ejmech.2011.02.021. View

15.

Maciel-Rezende C, de Almeida L, Costa E, Pires F, Alves K, Viegas Jr C . Synthesis and biological evaluation against Leishmania amazonensis of a series of alkyl-substituted benzophenones. Bioorg Med Chem. 2013; 21(11):3114-9. DOI: 10.1016/j.bmc.2013.03.045. View

16.

Khan T, Al Nasr I, Koko W, Ma J, Eckert S, Brehm L . Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents. ChemMedChem. 2023; 18(12):e202300132. DOI: 10.1002/cmdc.202300132. View

17.

Khan I, Kanugala S, Shareef M, Ganapathi T, Shaik A, Chandra Shekar K . Synthesis of new bis-pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti-biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans. Chem Biol Drug Des. 2019; 94(1):1339-1351. DOI: 10.1111/cbdd.13509. View

18.

Imberty A, HARDMAN K, CARVER J, Perez S . Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A. Glycobiology. 1991; 1(6):631-42. DOI: 10.1093/glycob/1.6.631. View

19.

Viana G, Soares D, Vinicius Santana M, do Amaral L, Meireles P, Nunes R . Antileishmanial Thioureas: Synthesis, Biological Activity and in Silico Evaluations of New Promising Derivatives. Chem Pharm Bull (Tokyo). 2017; 65(10):911-919. DOI: 10.1248/cpb.c17-00293. View

20.

Yousuf M, Mukherjee D, Dey S, Pal C, Adhikari S . Antileishmanial ferrocenylquinoline derivatives: Synthesis and biological evaluation against Leishmania donovani. Eur J Med Chem. 2016; 124:468-479. DOI: 10.1016/j.ejmech.2016.08.049. View