Synthesis of new Michael acceptors with cinnamamide scaffold as potential anti-breast cancer agents: cytotoxicity and ADME in silico studies

In pursuit of potent inhibitors with antiproliferative effects against breast cancer, fifteen new compounds containing a Michael Acceptor Moiety (MAM) were synthesized. The cinnamamide scaffold, a natural source of MAM, was chosen for its versatile structural framework, which offers rich potential for chemical modifications and optimization of biological activity. The first step consisted of obtaining five unprotected amines (5a-e), yielding between 40% and 90% yield. Subsequently, these amines were coupled with various cinnamic acid derivatives, resulting in target products in yields ranging from 30% to 94%. This study aimed to assess the impact of these compounds on cell viability, focusing on two human breast cancer cell lines, MCF-7 and MDA-MB-231. Among the compounds examined, eight (7a, 7b, 7d, 7f-i, 7l) showed activity against MDA cells (IC₅₀ range: 2.5–53.0 µM), and five (7b, 7 g-i, 7l) showed activity against MCF-7 cells (IC₅₀ range: 11.2–50.6 µM). 7f was the most active molecule, with an IC₅₀ of 2.5 µM toward MDA cells and a good selective index (SI = 7.9) toward a normal cell line (MCF-10A). In silico ADME studies were carried out with prospective compounds using the SwissADME tool.