Novel Acrylate-Based Derivatives: Design, Synthesis, Antiproliferative Screening, and Docking Study as Potential Combretastatin Analogues

[Image: see text] A variety of 3-(4-chlorophenyl) acrylic acids 4a,b and 3-(4-chlorophenyl)acrylate esters 5a–i were synthesized and structurally proven by spectroscopic studies such as IR, (1)H NMR, and (13)C NMR as well as mass spectrometry. All substances were investigated for their antiproliferative efficacy against the MDA-MB-231 cell line. Among these, acrylic acid compound 4b demonstrated the most potent cytotoxic effect with an IC(50) value of 3.24 ± 0.13 μM, as compared to CA-4 (IC(50) = 1.27 ± 09 μM). Additionally, acrylic acid molecule 4b displayed an inhibitory effect against β-tubulin polymerization with a percentage inhibition of 80.07%. Furthermore, compound 4b was found to produce considerable cell cycle arrest at the G2/M stage and cellular death, as demonstrated by FACS analysis. In addition, the in vivo antitumor screening of the sodium salt of acrylic acid 4b was carried out, and the results have shown that the tested molecule showed a significant decrease in viable EAC count and EAC volume, accompanied by a considerable increase in the life span prolongation, if compared to the positive control group. Furthermore, molecular modeling studies were performed to understand how the highly efficient chemicals 4b and 5e interact with the colchicine-binding region on tubulin. This work aims to shed light on the reasons behind their exceptional cytotoxicity and their better capacity to inhibit tubulin in comparison to CA-4.