{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T15:50:52Z","timestamp":1774885852960,"version":"3.50.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>Novel series of amidines were synthesized <jats:italic>via<\/jats:italic> the interaction between alicyclic amines, cyclic ketones, and a highly electrophilic 4-azidoquinolin-2(1<jats:italic>H<\/jats:italic>)-ones without any catalyst or additive. All the obtained products were elucidated based on NMR spectroscopy, mass spectrometry, and elemental analysis. The reaction conditions were optimized using cyclohexanone (2), piperidine (3a), and 4-azido-quinolin-2(1<jats:italic>H<\/jats:italic>)-one (1a) under an air atmosphere. The new compounds 4a-l and 5a-c were tested for antiproliferative activity against four cancer cell lines using doxorubicin as a reference drug. The most potent derivatives were compounds 4b, 4d, 4e, 4i, and 5c, with GI<jats:sub>50<\/jats:sub> ranging from 1.00\u00a0\u00b5M to 1.50\u00a0\u00b5M. Compound 5c was the most effective derivative against the four cancer cell lines, outperforming doxorubicin. The compounds 4b, 4d, 4e, 4i, and 5c were studied further as topoisomerase I and II\u03b1 inhibitors. The compounds tested showed selective inhibition of topo I over topo II\u03b1. Finally, docking studies explain why these compounds prefer topo I over topo II\u03b1.<\/jats:p>","DOI":"10.3389\/fchem.2022.1039176","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T07:32:12Z","timestamp":1668756732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties"],"prefix":"10.3389","volume":"10","author":[{"given":"Essmat M.","family":"El-Sheref","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendawy N.","family":"Tawfeek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa A.","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Br\u00e4se","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed A. I.","family":"Elbastawesy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hesham A. M.","family":"Gomaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaser A.","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bahaa G. M.","family":"Youssif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1800270","DOI":"10.1002\/ardp.201800270","article-title":"Novel quinoline derivatives carrying nitrones\/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase\u20103 activation activities","volume":"352","author":"Abdelbaset","year":"2019","journal-title":"Arch. Pharm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"18594","DOI":"10.1039\/d2ra02896d","article-title":"Recent advances in chemistry and therapeutic potential of functionalized quinoline motifs\u2013a review","volume":"12","author":"Ajani","year":"2022","journal-title":"RSC Adv."},{"key":"B3","doi-asserted-by":"publisher","first-page":"104260","DOI":"10.1016\/j.bioorg.2020.104260","article-title":"Design and synthesis of novel 2, 3-dihydropyrazino [1, 2-a] indole-1, 4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors","volume":"104","author":"Al-Wahaibi","year":"2020","journal-title":"Bioorg. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.bioorg.2018.10.044","article-title":"Design, synthesis and biological evaluation of fused naphthofuro [3, 2-c] quinoline-6, 7, 12-triones and pyrano [3, 2-c] quinoline-6, 7, 8, 13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma","volume":"82","author":"Aly","year":"2019","journal-title":"Bioorg. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/bs.aihch.2020.08.001","article-title":"Quinolones as prospective drugs: Their syntheses and biological applications","volume":"137","author":"Aly","year":"2021","journal-title":"Adv. Heterocycl. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1007\/s00280-004-0994-8","article-title":"Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer","volume":"56","author":"Briasoulis","year":"2005","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"52","DOI":"10.18433\/j3302n","article-title":"Nonclassical biological activities of quinolone derivatives","volume":"15","author":"Daneshtalab","year":"2012","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"104551","DOI":"10.1016\/j.phrs.2019.104551","article-title":"Topoisomerase inhibitors: Pharmacology and emerging nanoscale delivery systems","volume":"151","author":"Dehshahri","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1042\/bcj20160583","article-title":"Topoisomerases as anticancer targets","volume":"475","author":"Delgado","year":"2018","journal-title":"Biochem. J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.lungcan.2007.08.005","article-title":"Serum levels of apoptosis biomarkers, survivin and TNF-alpha in nonsmall cell lung cancer","volume":"59","author":"Derin","year":"2008","journal-title":"Lung cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"103291","DOI":"10.1016\/j.bioorg.2019.103291","article-title":"Recent advances in the synthetic and medicinal perspective of quinolones: A review","volume":"92","author":"Dhiman","year":"2019","journal-title":"Bioorg. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1016\/j.tetlet.2016.03.058","article-title":"A catalyst and additive-free three-component reaction of highly electrophilic azides with cyclic ketones and cycloaliphatic amines. Synthesis of novel N-heteroaryl amidines","volume":"57","author":"Efimov","year":"2016","journal-title":"Tetrahedron Lett."},{"key":"B13","doi-asserted-by":"publisher","first-page":"6798","DOI":"10.3390\/molecules26226798","article-title":"Design and synthesis of (2-oxo-1, 2-Dihydroquinolin-4-yl)-1, 2, 3-triazole derivatives via click reaction: Potential apoptotic antiproliferative agents","volume":"26","author":"El-Sheref","year":"2021","journal-title":"Molecules"},{"key":"B14","doi-asserted-by":"publisher","first-page":"103045","DOI":"10.1016\/j.bioorg.2019.103045","article-title":"Novel Pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors","volume":"90","author":"Elbastawesy","year":"2019","journal-title":"Bioorg. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s11030-019-10021-0","article-title":"Identification and molecular modeling of new quinolin-2-one thiosemicarbazide scaffold with antimicrobial urease inhibitory activity","volume":"25","author":"Elbastawesy","year":"2021","journal-title":"Mol. Divers."},{"key":"B16","doi-asserted-by":"publisher","first-page":"103628","DOI":"10.1016\/j.bioorg.2020.103628","article-title":"Arylidenes of Quinolin-2-one scaffold as Erlotinib analogues with activities against leukemia through inhibition of EGFR TK\/STAT-3 pathways","volume":"96","author":"Elbastawesy","year":"2020","journal-title":"Bioorg. Chem."},{"key":"B17","first-page":"2431","article-title":"Topoisomerase inhibitors and types of them","volume":"2","author":"Goftar","year":"2014","journal-title":"Int. J. Adv. Biol. Biomed. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3109\/14756366.2011.654113","article-title":"Synthesis, antimicrobial activity and molecular modeling study of substituted 5-aryl-pyrimido [5, 4-c] quinoline-2, 4-diones","volume":"28","author":"Ismail","year":"2013","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.3390\/molecules25081909","article-title":"A review on recent advances in nitrogen-containing molecules and their biological applications","volume":"25","author":"Kerru","year":"2020","journal-title":"Molecules"},{"key":"B20","doi-asserted-by":"publisher","first-page":"113555","DOI":"10.1016\/j.ejmech.2021.113555","article-title":"Quinoline anticancer agents active on DNA and DNA-interacting proteins: From classical to emerging therapeutic targets","volume":"220","author":"Lauria","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"24095","DOI":"10.1039\/d0ra09250a","article-title":"Discovery of quinolone derivatives as antimycobacterial agents","volume":"11","author":"Liu","year":"2021","journal-title":"RSC Adv."},{"key":"B22","doi-asserted-by":"publisher","first-page":"104090","DOI":"10.1016\/j.bioorg.2020.104090","article-title":"Design and synthesis of new 1, 6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation","volume":"102","author":"Marzouk","year":"2020","journal-title":"Bioorg. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"115973","DOI":"10.1016\/j.bmc.2020.115973","article-title":"A comprehensive review on the biological interest of quinoline and its derivatives","volume":"32","author":"Matada","year":"2021","journal-title":"Bioorg. Med. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"105693","DOI":"10.1016\/j.bioorg.2022.105693","article-title":"Discovery of new pyrimido [5, 4-c] quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies","volume":"121","author":"Mekheimer","year":"2022","journal-title":"Bioorg. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"104510","DOI":"10.1016\/j.bioorg.2020.104510","article-title":"Design and synthesis of novel quinoline\/chalcone\/1, 2, 4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases","volume":"106","author":"Mohassab","year":"2021","journal-title":"Bioorg. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3892\/ijmm.2012.961","article-title":"Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido [4, 5-c] isoquinoline-7, 10-quinones","volume":"30","author":"Monsalve","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"177ra37","DOI":"10.1126\/scitranslmed.3005029","article-title":"Quinolone-3-diarylethers: A new class of antimalarial drug","volume":"5","author":"Nilsen","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"10187","DOI":"10.1002\/slct.202002790","article-title":"Navigating the synthesis of quinoline hybrid molecules as promising anticancer agents","volume":"5","author":"Panda","year":"2020","journal-title":"ChemistrySelect"},{"key":"B29","doi-asserted-by":"publisher","first-page":"12857","DOI":"10.1039\/c9cc05524j","article-title":"A chromenone analog as an ATP-competitive, DNA non-intercalative topoisomerase II catalytic inhibitor with preferences toward the alpha isoform","volume":"55","author":"Park","year":"2019","journal-title":"Chem. Commun."},{"key":"B30","doi-asserted-by":"publisher","first-page":"128450","DOI":"10.1016\/j.bmcl.2021.128450","article-title":"Lipophilic quinolone derivatives: Synthesis and in vitro antibacterial evaluation","volume":"55","author":"Sadowski","year":"2022","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4236\/ojmc.2020.101001","article-title":"Anti-cancer activity and molecular docking of some pyrano[3, 2&amp;amp;#8209;c]quinoline analogues","volume":"10","author":"Saeed","year":"2020","journal-title":"Open J. Med. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/cxo.13102","article-title":"Fluoroquinolones are a potent form of chemotherapy","volume":"104","author":"Schmid","year":"2021","journal-title":"Clin. Exp. Optom."},{"key":"B33","doi-asserted-by":"publisher","first-page":"439","DOI":"10.2174\/1568011033482279","article-title":"The quinolone family: From antibacterial to anticancer agents","volume":"3","author":"Sissi","year":"2003","journal-title":"Curr. Med. Chem. Anticancer Agents"},{"key":"B34","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1007\/bf00815924","article-title":"Potential non-steroidal estrogens and antiestrogens, IV Organic azides in heterocyclic synthesis, part 13: Synthesis of aza-and diazacoumestrols via azido derivatives","volume":"122","author":"Stadlbauer","year":"1991","journal-title":"Monatsh. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1021\/jm049146p","article-title":"Structures of three classes of anticancer agents bound to the human topoisomerase I\u2212 DNA covalent complex","volume":"48","author":"Staker","year":"2005","journal-title":"J. Med. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1002\/jhet.5570310662","article-title":"Synthesis of oxazolo [4, 5\u2010c] quinolones by thermolytic degradation of 4\u2010azido\u20102 (1H)\u2010quinolones","volume":"31","author":"Steinschifter","year":"1994","journal-title":"J. Heterocycl. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nrm3228","article-title":"All tangled up: How cells direct, manage and exploit topoisomerase function","volume":"12","author":"Vos","year":"2011","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1900045","DOI":"10.1002\/ardp.201900045","article-title":"Quinolone derivatives: Potential anti\u2010HIV agent\u2014Development and application","volume":"352","author":"Wang","year":"2019","journal-title":"Arch. Pharm. Weinh."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2022.1039176\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T07:32:15Z","timestamp":1668756735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2022.1039176\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":38,"alternative-id":["10.3389\/fchem.2022.1039176"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2022.1039176","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]},"article-number":"1039176"}}