{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:51:16Z","timestamp":1775667076949,"version":"3.50.1"},"reference-count":17,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T00:00:00Z","timestamp":1574208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and national funds by FCT \u2013 Foundation for Science and Technology","award":["UID\/QUI\/00081\/2019 and FEDER\/COMPETE POCI-01-0145-FEDER-028397"],"award-info":[{"award-number":["UID\/QUI\/00081\/2019 and FEDER\/COMPETE POCI-01-0145-FEDER-028397"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base\/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B\u201310B) were obtained with good yields (54\u201393%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.<\/jats:p>","DOI":"10.3390\/molecules24234214","type":"journal-article","created":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T11:06:03Z","timestamp":1574247963000},"page":"4214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Optimizing the Synthetic Route of Chromone-2-carboxylic Acids: A Step forward to Speed-up the Discovery of Chromone-based Multitarget-directed Ligands"],"prefix":"10.3390","volume":"24","author":[{"given":"Fernando","family":"Cagide","sequence":"first","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"given":"Catarina","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"given":"Joana","family":"Reis","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4960","DOI":"10.1021\/cr400265z","article-title":"Chromone: A Valid Scaffold in Medicinal Chemistry","volume":"114","author":"Gaspar","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7941","DOI":"10.1021\/acs.jmedchem.6b01720","article-title":"Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances","volume":"60","author":"Reis","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.1016\/j.tetlet.2011.09.095","article-title":"Accelerating lead optimization of chromone carboxamide scaffold throughout microwave-assisted organic synthesis","volume":"52","author":"Cagide","year":"2011","journal-title":"Tetrahedron Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fchem.2018.00126","article-title":"Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors","volume":"6","author":"Oliveira","year":"2018","journal-title":"Front. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ejmech.2018.07.056","article-title":"Multi-target-directed ligands for Alzheimer\u2019s disease: Discovery of chromone-based monoamine oxidase\/cholinesterase inhibitors","volume":"158","author":"Reis","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Loupy, A. (2006). Microwaves in Organic and Medicinal Chemistry. Microwaves in Organic Synthesis, Wiley-VCH. [2nd ed.].","DOI":"10.1002\/9783527619559"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1359-6446(02)02178-5","article-title":"The impact of microwave-assisted organic chemistry on drug discovery","volume":"7","author":"Wathey","year":"2002","journal-title":"Drug Discov. Today"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ddtec.2005.05.002","article-title":"Accelerating lead development by microwave-enhanced medicinal chemistry","volume":"2","author":"Shipe","year":"2005","journal-title":"Drug Discov. Today Technol."},{"key":"ref_9","unstructured":"Spencer, J., and Bagley, M.C. (2014). Microwave-assisted processing techniques in medicinal chemistry. Microwaves in Drug Discovery and Development: Recent Advances, Future Medicine Ltd.. [1st ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ellis John, G.P. (1977). Chromenes, Chromanones, and Chromones. the Chemistry of Heterocyclic Compounds, Wiley & Sons. [1st ed.].","DOI":"10.1002\/9780470187012"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1021\/jo802783z","article-title":"Synthesis of 2-Alkyl-Substituted Chromone Derivatives Using Microwave Irradiation","volume":"74","author":"Pemberton","year":"2009","journal-title":"J. Org. Chem."},{"key":"ref_12","first-page":"1278","article-title":"Microwave assisted synthesis of 1-(2-hydroxyphenyl)-5-phenylpent-4-ene-1,3-diones and their conversion to 2-styrylchromones","volume":"45","author":"Goel","year":"2006","journal-title":"Indian J. Chem. Sect. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1055\/s-0036-1591898","article-title":"An Efficient Microwave-Assisted Propylphosphonic Anhydride (T3P)-Mediated One Chromone Synthesis via Enaminones","volume":"29","author":"Balakrishna","year":"2018","journal-title":"Synlett"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/BF00481575","article-title":"Researches on pyranes, their analogs, and related compounds","volume":"3","author":"Zagorevskii","year":"1967","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1021\/cr950066q","article-title":"Bioisosterism: A rational approach in drug design","volume":"96","author":"Patani","year":"1996","journal-title":"Chem. Rev."},{"key":"ref_16","unstructured":"Lemke, T.L., Williams, D.A., Roche, V.F., and Zito, S.W. (2013). Foye\u2019s Principles of Medicinal Chemistry, Lippincott Williams & Wilkins. [7th ed.]."},{"key":"ref_17","first-page":"173","article-title":"Excellentes voies de synthese des derives des 4-oxo-4H-1-benzopyranes avec le concours de micro-ondes","volume":"49","author":"Bratulescu","year":"2002","journal-title":"Acta Chim. 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