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They demonstrated effectiveness against both multiple myeloma and solid tumors. Herein, the synthesis and biological evaluation of 20 novel RID analogs that exhibit inhibitory effects on the three catalytic subunits of the 20S proteasome are reported. All the compounds were tested on the National Cancer Institute (NCI) 60 cancerous cell lines. The compounds bear symmetric aminoalkoxy groups on rings <jats:bold>B<\/jats:bold> and <jats:bold>C<\/jats:bold>, different substituents on ring <jats:bold>A<\/jats:bold>, and the terminal side chain on the ethylene backbone was modified to methyl and cyclopentyl groups.Compound <jats:bold>43<\/jats:bold> was the most potent inhibitor for both CT\u2010L and PGPH (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.22, 0.05\u2009\u03bcM), which is threefold more potent for CT\u2010L and tenfold more potent on PGPH than RID\u2010F. Most of the analogs showed pan activity toward different cancer cell lines, and compound <jats:bold>20<\/jats:bold> was more potent than tamoxifen. Compound <jats:bold>20<\/jats:bold> showed submicromolar IC<jats:sub>50<\/jats:sub> values for CT\u2010L and PGPH activities, indicating that it mediates its cytotoxic activity via proteasomal inhibition. Selected compounds were tested against Ebolavirus, and compound <jats:bold>36<\/jats:bold> showed the highest antiviral activity, surpassing the EC<jats:sub>50<\/jats:sub> of the reference compound favipiravir.<\/jats:p>","DOI":"10.1002\/cmdc.202500451","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T21:05:07Z","timestamp":1755810307000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Synthesis of Potent Ridaifen Analogues: Evaluation as Anticancer, 20S Proteasomal Inhibitors, and Antiebola Virus Agents through In vitro and In Silico Studies"],"prefix":"10.1002","volume":"20","author":[{"given":"Merna A.","family":"Vector","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy and Biotechnology German University in Cairo  Cairo 11835 Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sae","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Faculty of Bioscience Nagahama Institute of Bio\u2010Science and Technology  1266 Tamura\u2010cho Nagahama Shiga 526\u20130829 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunhao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Faculty of Bioscience Nagahama Institute of Bio\u2010Science and Technology  1266 Tamura\u2010cho Nagahama Shiga 526\u20130829 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Faculty of Bioscience Nagahama Institute of Bio\u2010Science and Technology  1266 Tamura\u2010cho Nagahama Shiga 526\u20130829 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takatsugu","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry Faculty of Science Tokyo University of Science  Tokyo 162\u20108601 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaho","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry Faculty of Science Tokyo University of Science  Tokyo 162\u20108601 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isamu","family":"Shiina","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry Faculty of Science Tokyo University of Science  Tokyo 162\u20108601 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashraf H.","family":"Abadi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy and Biotechnology German University in Cairo  Cairo 11835 Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-3387","authenticated-orcid":false,"given":"Nermin 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