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The discovery and subsequent development of CFTR modulators\u2014small molecules acting on the basic molecular defect in CF\u2014have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA\u2019s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.<\/jats:p>","DOI":"10.3390\/molecules29040821","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T06:19:59Z","timestamp":1707718799000},"page":"821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-6997","authenticated-orcid":false,"given":"Filipa","family":"Ferreira","sequence":"first","affiliation":[{"name":"Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-2220","authenticated-orcid":false,"given":"Camilla","family":"Buarque","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pontifical Catholic University of Rio de Janeiro (PUC-Rio), Rio de Janeiro 22435-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-9359","authenticated-orcid":false,"given":"Miqu\u00e9ias","family":"Lopes-Pacheco","sequence":"additional","affiliation":[{"name":"Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1126\/science.256.5058.774","article-title":"Cystic Fibrosis: Molecular Biology and Therapeutic Implications","volume":"256","author":"Collins","year":"1992","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1126\/science.2997931","article-title":"Cystic Fibrosis Locus Defined by a Genetically Linked Polymorphic DNA Marker","volume":"230","author":"Tsui","year":"1985","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.3389\/fphar.2019.01662","article-title":"CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine","volume":"10","year":"2020","journal-title":"Front. 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