The analogs of coumarin-chalcones have been reported to exhibit antineoplastic, anti-allergic, antihepatoprotective, and estrogenic activity. Herein, we have reported 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2H-chromen-2-one derivatives as a new class of compounds that exhibit selectivity for ER-α binding along with antiproliferative and cytotoxic activity on human breast cancer cell line. The active compounds which show prominent activity against estrogen receptor-alpha-positive (ER+) human breast cancer cell lines MCF-7 and Zr-75-1 are subjected to in vivo screening. The Glide XP docking was performed for designed scaffold to optimize its structural requirement for ER-α inhibition.