The Uses of Dimedone for the Synthesis of Thiophene, Thiazole and Annulated Derivatives with Antitumor, Pim-1 Kinase Inhibitions, PAINS Evaluations and Molecular Docking

Author(s):

Wagnat W. Wardakhan*, Amira M. Elmetwally, Abeer A. Mohamed and Rafat M. Mohareb   Pages 2258 - 2277 ( 20 )

Abstract:

<p>Background: Dimedone is considered as one of the most important classes of compounds belonging to cyclohexan-1,3-dione. Such groups of compounds were considered as precursors for many pharmaceutically active heterocyclic compounds. </P><P> Objective: The target molecules in this work were synthesized from arylhydrazones of dimedone with different substituents enhancing the study of their structure-activity relationship. </P><P> Methods: Arylhydrazones of dimedones were subjected to a series of heterocyclization reactions affording annulated compounds. The anti-proliferative activities of the synthesized molecules were evaluated against six cancer cell lines. In addition, inhibitions toward tyrosine kinases, Pim-1 kinases and PAINS of the most active compounds were also studied. c-Met enzymatic inhibitions and molecular docking studies were carried out for three compounds. </P><P> Results: Anti-cancer evaluations together with tyrosine and Pim-1 kinases of most of the synthesized compounds were carried out through this work. The study revealed that changing of substituents had a strong impact on the activity of the molecule. </P><P> Conclusion: Many of the synthesized compounds exhibited high inhibitions towards the six cancer cell lines. This will encourage further work through the synthesis of target molecules with the same ring systems. The three compounds 7b, 8c and 12b that revealed excellent inhibitions were tested against c-Met kinase and their molecular modelling was expressed.</p>

Keywords:

Dimedone, arylhydrazone, thiophene, pyran, anti-proliferative activity, molecular docking.

Affiliation:

National Organization for Drug Control and Research (NODCAR) P.O. 29, Cairo, National Organization for Drug Control and Research (NODCAR) P.O. 29, Cairo, National Organization for Research and Control of Biologicals.51 Wezaret El-Zeraa St, Dokki, Giza, Department of Chemistry, Faculty of Science, Cairo University, Giza

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