{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:25:48Z","timestamp":1778779548333,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a\u2013e and 7a\u2013e\u00a0via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a\u2013e with 1,5-\/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal\u2013Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a\u2013e and 7a\u2013e were evaluated. Compounds 4a\u2013e and 7a\u2013e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.<\/jats:p>","DOI":"10.3390\/molecules27248765","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T04:34:20Z","timestamp":1670819660000},"page":"8765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3804-9729","authenticated-orcid":false,"given":"Essmat M.","family":"El-Sheref","sequence":"first","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed A.","family":"Ameen","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal M.","family":"El-Shaieb","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fathy F.","family":"Abdel-Latif","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmaa I.","family":"Abdel-naser","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan B.","family":"Brown","sequence":"additional","affiliation":[{"name":"Chemistry Department, Florida Institute of Technology, 150 W University Blvd, Melbourne, FL 32901, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hazem M.","family":"Fathy","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7697-9572","authenticated-orcid":false,"given":"Iqrar","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India"},{"name":"Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule 424002, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0920-1266","authenticated-orcid":false,"given":"Harun","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7510-8428","authenticated-orcid":false,"given":"Hesham A. M.","family":"Gomaa","sequence":"additional","affiliation":[{"name":"Pharmacology Department, College of Pharmacy, Jouf University, Sakaka 72314, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-6548","authenticated-orcid":false,"given":"Bahaa G. M.","family":"Youssif","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmaa H.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/jac\/dkg208","article-title":"The quinolones: Decades of development and use","volume":"51","author":"Emmerson","year":"2003","journal-title":"J. Antimicrob. 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