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Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

ABSTRACT: Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and ¹H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC₅₀ = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC₅₀ = 3.130) and amphotericin B deoxycholate (IC₅₀ = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.

SUBMITTER: Berhe HG

PROVIDER: S-EPMC10775556 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

Berhe Halefom Gebreselasse HG Birhan Yihenew Simegniew YS Beshay Botros Youssef BY Habib Huda Jawad HJ Hymete Ariaya A Bekhit Adnan Ahmed AA

BMC chemistry 20240108 1

Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and <sup>1</sup>H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate a ...[more]

PMID: 38191485

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Project description:Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane-pyrazole (OZ1, OZ2) and tetraoxane-pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane-pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.

Dataset Information

Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

Publications

Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

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