In this study, novel linear 3-(arylamino)naphtho[2,3-b]furan-2,4,9(3H)-trione derivatives has been synthesized via annulation reaction of 2-hydroxy-1,4-naphthoquinone with aromatic amines and glyoxylic acid monohydrate using p-TSOH as catalyst at ambient temperature for the first time. The mechanism proceeds via an initial intermolecular aldol condensation, subsequent Michael addition, and final intramolecular nucleophilic annulation. The linear or angular configurations of the products was confirmed through - C heteronuclear multiple-bond correlation (HMBC) analysis. To evaluate the inhibitory activity of the synthesized compounds, computational methods such as molecular docking and ADME analysis were employed. Compounds 4h and 4i displayed potent activity against tested estrogen receptor alpha (ERα) as compared to Doxorubicin.