In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, ) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2 = 82.578, Q2 = 80.436, and Q2 = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2 = 80.534, Q2 = 78.186, and Q2 = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC ( ) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone ( ), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds and were synthesized by two- and three-step reactions. The structures were confirmed by H and C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone . Finally, we employed as a molecular scaffold for the generation of cinnamate candidates ( - ), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds and , as well as the proposed chalcones and , are the best candidates with adequate drug-likeness properties. From all these results, we propose (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.