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Anhydroparthenin as a dual-target inhibitor against Sterol C-24 methyltransferase and Sterol 14-α demethylase of Leishmania donovani: A comprehensive in vitro and in silico study.
- Source :
-
International journal of biological macromolecules [Int J Biol Macromol] 2024 Jun; Vol. 269 (Pt 1), pp. 132034. Date of Electronic Publication: 2024 May 01. - Publication Year :
- 2024
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Abstract
- Parthenium hysterophorus plant has a diverse chemical profile and immense bioactive potential. It exhibits excellent pharmacological properties such as anti-cancer, anti-inflammatory, anti-malarial, microbicidal, and anti-trypanosomal. The present study aims to evaluate the anti-leishmanial potential and toxicological safety of anhydroparthenin isolated from P. hysterophorus. Anydroparthenin was extracted from the leaves of P. hysterophorus and characterized through detailed analysis of <superscript>1</superscript> H, <superscript>13</superscript> C NMR, and HRMS. Dye-based in vitro and ex vivo assays confirmed that anhydroparthenin significantly inhibited both promastigote and amastigote forms of the Leishmania donovani parasites. Both the cytotoxicity experiment and hemolytic assay revealed its non-toxic nature and safety index in the range of 10 to 15. Further, various mechanistic assays suggested that anhydroparthenin led to the generation of oxidative stress, intracellular ATP depletion, alterations in morphology and mitochondrial membrane potential, formation of intracellular lipid bodies, and acidic vesicles, ultimately leading to parasite death. As a dual targeting approach, computational studies and sterol quantification assays confirmed that anhydroparthenin inhibits the Sterol C-24 methyl transferase and Sterol 14-α demethylase proteins involved in the ergosterol biosynthesis in Leishmania parasites. These results suggest that anhydroparthenin could be a promising anti-leishmanial molecule and can be developed as a novel therapeutic stratagem against leishmaniasis.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Antiprotozoal Agents pharmacology
Antiprotozoal Agents chemistry
Molecular Docking Simulation
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemistry
Membrane Potential, Mitochondrial drug effects
Computer Simulation
Animals
Humans
Leishmania donovani drug effects
Leishmania donovani enzymology
Sterol 14-Demethylase metabolism
Sterol 14-Demethylase chemistry
Methyltransferases metabolism
Methyltransferases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0003
- Volume :
- 269
- Issue :
- Pt 1
- Database :
- MEDLINE
- Journal :
- International journal of biological macromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 38702006
- Full Text :
- https://doi.org/10.1016/j.ijbiomac.2024.132034