{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:13:01Z","timestamp":1760058781295,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Portuguese Foundation for Science and Technology (FCT, Portugal) through CQ-UM","award":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"],"award-info":[{"award-number":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"]}]},{"name":"CIMO","award":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"],"award-info":[{"award-number":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"]}]},{"name":"SusTEC","award":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"],"award-info":[{"award-number":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"]}]},{"name":"the European Social Fund within the Human Potential Operating Programme","award":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"],"award-info":[{"award-number":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"]}]},{"name":"One Health Drugs against Parasitic Vector-Borne Diseases in Europe and Beyond (OneHealthDrugs)","award":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"],"award-info":[{"award-number":["UID\/00686\/2020","UIDB\/00690\/2020","UIDP\/00690\/2020","LA\/P\/0007\/2021","2021.04285.CEECIND\/CP1663\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd\/Cu-catalyzed Sonogashira coupling using Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 &lt; 10 \u00b5M in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 &lt; 11 \u00b5M, though some level of cytotoxicity was observed in THP-1\u2014derived macrophages.<\/jats:p>","DOI":"10.3390\/molecules30091999","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T07:00:21Z","timestamp":1745996421000},"page":"1999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of Tricyclic and Tetracyclic Lactone Derivatives of Thieno[2,3-b]pyrazine or Thieno[2,3-b]quinoline: Preliminary Antitumor and Antiparasitic Activity Evaluation"],"prefix":"10.3390","volume":"30","author":[{"given":"Maria F.","family":"Martins","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica, Universidade do Minho (CQ-UM), Campus de Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0369-3370","authenticated-orcid":false,"given":"Francisco","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica, Universidade do Minho (CQ-UM), Campus de Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8809-0541","authenticated-orcid":false,"given":"Ana","family":"Borges","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o de Montanha (CIMO), Instituto Polit\u00e9cnico de Bragan\u00e7a, Campus de Santa Apol\u00f3nia, 5300-253 Bragan\u00e7a, Portugal"},{"name":"Laborat\u00f3rio Associado para a Sustentabilidade e Tecnologia em Regi\u00f5es de Montanha (SusTEC), Instituto Polit\u00e9cnico de Bragan\u00e7a, Campus de Santa Apol\u00f3nia, 5300-253 Bragan\u00e7a, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-4578","authenticated-orcid":false,"given":"Ricardo C.","family":"Calhelha","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o de Montanha (CIMO), Instituto Polit\u00e9cnico de Bragan\u00e7a, Campus de Santa Apol\u00f3nia, 5300-253 Bragan\u00e7a, Portugal"},{"name":"Laborat\u00f3rio Associado para a Sustentabilidade e Tecnologia em Regi\u00f5es de Montanha (SusTEC), Instituto Polit\u00e9cnico de Bragan\u00e7a, Campus de Santa Apol\u00f3nia, 5300-253 Bragan\u00e7a, Portugal"}]},{"given":"Nuno","family":"Santar\u00e9m","sequence":"additional","affiliation":[{"name":"Host-Parasite Interactions, IBMC\/I3S, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"}]},{"given":"Anabela","family":"Cordeiro-da-Silva","sequence":"additional","affiliation":[{"name":"Host-Parasite Interactions, IBMC\/I3S, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"},{"name":"Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4322-8035","authenticated-orcid":false,"given":"Maria-Jo\u00e3o R. P.","family":"Queiroz","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica, Universidade do Minho (CQ-UM), Campus de Gualtar, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","unstructured":"Folmer, B.J.B., Man, A.P.A., Gernette, E.S., Azevedo, R.C.R.G., and Ibrahim, H. (2011). Thieno[2,3-b]pyrazine Compounds as B-RAF Inhibitors. (2011147764, A1), WO."},{"key":"ref_2","unstructured":"Gong, Y.D., Kwak, S., and Lee, E.S. (2016). Substituted Thieno[3,2-b]Pyrazines for Inhibiting Cancer Cell Proliferation and Inducing Cancer Cell Apoptosis. (2016093554, A1), WO."},{"key":"ref_3","unstructured":"Lim, J., Altman, M.D., and Gibeau, C.R. (2016). Thienopyrazine Inhibitors of IRAK4 Activity. (2016144849, A1), WO."},{"key":"ref_4","unstructured":"Guerin, D.J., Bair, K.W., Caravella, J.A., Ioannidis, S., Lancia, D.R., Li, H., Mischke, S., Ng, P.Y., Richard, D., and Sciller, S.E.R. (2017). 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