Microwave-assisted N-alkylation of amines with alcohols catalyzed by MnCl2 : Anticancer, docking, and DFT studies.

K Yogesh Kumar, C B Pradeep Kumar, K N N Prasad, Byong-Hun Jeon, Ali Alsalme, M K Prashanth

Archiv der Pharmazie 2022 May

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A new protocol for the N-alkylation of amines with alcohols for the synthesis of tertiary amines in the presence of MnCl2 as a catalyst, under microwave conditions, is described. The advantages of this protocol include stable reaction profiles, a wide substrate variety, excellent yields, low cost, high yields, and easy workup conditions. The anticancer efficacy of all the synthesized compounds was tested in vitro against various cancer cell lines, such as MCF-7, MDA-MB-231 (human breast), HT-29, HCT 116 (colon cancer), A549 (human lung carcinoma), and Vero cells. Among the screened compounds, 3e, 3h, and 3i demonstrated potent anticancer activity, with compound 3h surpassing the reference drug cisplatin against A549, MCF7, MDA-MB-231, and HCT116 cancer cells. The introduction of an electron-withdrawing group on the phenyl ring resulted in increased anticancer activity. The most potent compounds, 3e, 3h, and 3i, were tested against VEGFR-2, HER2, and EGFR in multikinase inhibition assays, with compounds 3h and 3i showing improved potency against the HER2 kinase. The compounds formed two H-bonds with amino acids, indicating that they had a high affinity for the target HER2 kinase (PDB ID: 3RCD), according to the docking analysis. The absorption, distribution, metabolism, excretion, and toxicity properties of the optimized analogs were also assessed in vitro, enabling the discovery of promising anticancer agents. Finally, the B3LYP level was used to measure density functional theory geometry optimization and the related quantum parameters for the active compounds. © 2022 Deutsche Pharmazeutische Gesellschaft.

Citation

K Yogesh Kumar, C B Pradeep Kumar, K N N Prasad, Byong-Hun Jeon, Ali Alsalme, M K Prashanth. Microwave-assisted N-alkylation of amines with alcohols catalyzed by MnCl2 : Anticancer, docking, and DFT studies. Archiv der Pharmazie. 2022 May;355(5):e2100443