Design, Synthesis, Molecular Docking, and Biological Studies of New Heterocyclic
Compounds Derived from β-Diketones as Novel EGFR and Pim-1 Inhibitors
Endowed with Antitumor Activity

Rafat   Milad   Mohareb; Noha   M. Asaad   Bagato; Ibrahim   Taha   Radwan

doi:10.2174/1871520622666220112104320

Abstract

Background: Cancer is a disease illustrated by a shift in the controlled mechanisms that control both cell proliferation and differentiation. It is regarded as a prime health problem worldwide and a leading cause of human death rate exceeded only by cardiovascular diseases. Many reported works are concerned with discovering new antitumor compounds, encouraging us to synthesize new anticancer agents.

Objective: In this work, we aimed to synthesize target molecules from 1,3-dicarbonyl compounds through heterocyclization reactions.

Methods: The reaction of either 4-methylaniline (1a) or 1-naphthylamine (1b) with diethyl malonate (2) gave the anilide derivatives 3a and 3b, respectively. The latter underwent a series of heterocyclization reactions to give the pyridine, pyran, and thiazole derivatives confirmed by the required spectral data.

Results: The in-vitro antitumor evaluation of the newly synthesized products against three cancer cell lines, MCF-7, NCI-H460, SF-268, and WI 38, which were used as the normal cell lines, was conducted, and the data revealed that compounds 11a, 18b, 18c, and 20d showed high antitumor activity and 20d individualized with potential antitumor activity towards cell lines with lowest cytotoxicity effect. Both EGFR and PIM-1 enzymes inhibition were investigated for the compound 20d, and it was found that the inhibition effect of compound 20d was promising for each enzyme, showing IC₅₀ = 45.67 ng and 553.3 ng for EGFR and PIM-1, respectively.

Conclusion: Molecular docking results of compound 20d showed strong binding interactions with both the enzymes, where good binding modes were obtained in the case of EGFR, which was closely similar to the binding mode of standard Erlotinib.While 20d showed complete superimposition binding interactions with VRV-cocrystallized ligand of PIM-1 that may expound the in-vitro antitumor activity.

Keywords: Pyridine, pyran, quinoline, anti-tumor, molecular docking, cell cycle apoptosis.

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DOI https://dx.doi.org/10.2174/1871520622666220112104320	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992

Anti-Cancer Agents in Medicinal Chemistry

Design, Synthesis, Molecular Docking, and Biological Studies of New Heterocyclic Compounds Derived from β-Diketones as Novel EGFR and Pim-1 Inhibitors Endowed with Antitumor Activity

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