A series of novel-substituted chalcone analogs were synthesized and evaluated for antiproliferative activity against estrogen receptor-positive MCF-7 breast cancer cell lines. Among the synthesized derivatives 4a, 5a, 5b, 5c, 5e, 5′a, and 5′d show good antiproliferative activity as compared to standard tamoxifen. The study highlighted the advantage of introducing the amine side chain pharmacophore in substituted chalcone enhances the anticancer potential. The study also suggests that these analogs can serve as better therapeutic agents against breast cancer and can provide starting point for building more potent analogs in future. The binding mechanism and ADME properties of target compounds were analysed using Schrödinger software.