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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

2025Journal article Open access
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datacite.subject.fosCiências Médicas::Ciências da Saúde
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorMartins, Maria F.
dc.contributor.authorRibeiro, Francisco
dc.contributor.authorBorges, Ana Margarida
dc.contributor.authorCalhelha, Ricardo C.
dc.contributor.authorSantarém, Nuno
dc.contributor.authorCordeiro-da-Silva, Anabela
dc.contributor.authorQueiroz, Maria João R.P.
dc.date.accessioned2025-05-29T13:15:32Z
dc.date.available2025-05-29T13:15:32Z
dc.date.issued2025
dc.description.abstractTricyclic 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 < 10 µM 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 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages.eng
dc.description.sponsorshipThis research was funded by the Portuguese Foundation for Science and Technology (FCT, Portugal) through CQ-UM (strategic funding UID/00686/2020), CIMO (UIDB/00690/2020 and UIDP/00690/2020) and SusTEC (LA/P/0007/2021); the institutional scientific employment program-contract for RCC; NS is funded by national funds through FCT and co-funded through the European Social Fund within the Human Potential Operating Programme 2021.04285.CEECIND/CP1663/CT0004. The work on anti-parasitic activity is performed under the scope of COST Action CA21111: One Health Drugs against Parasitic Vector-Borne Diseases in Europe and Beyond (OneHealthDrugs)
dc.identifier.citationMartins, Maria F.; Ribeiro, Francisco; Borges, Ana Margarida; Calhelha, Ricardo C.; Santarém, Nuno; Cordeiro-da-Silva, Anabela; Queiroz, Maria-João R.P. (2025). 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. Molecules. ISSN 1420-3049. 30:9, p. 1-27
dc.identifier.doi10.3390/molecules30091999
dc.identifier.issn1420-3049
dc.identifier.urihttp://hdl.handle.net/10198/34504
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationMountain Research Center
dc.relationMountain Research Center
dc.relation.ispartofMolecules
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectC-H activation
dc.subjectLactonization
dc.subjectMetal-catalyzed cycloaddition
dc.subject2H-pyrones
dc.subjectSonogashira coupling
dc.subjectthieno[2
dc.subject3-b]pyrazines
dc.subject3-b]quinolines
dc.titleSynthesis of Tricyclic and Tetracyclic Lactone Derivatives of Thieno[2,3-b]pyrazine or Thieno[2,3-b]quinoline: Preliminary Antitumor and Antiparasitic Activity Evaluationeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMountain Research Center
oaire.awardTitleMountain Research Center
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00690%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00690%2F2020/PT
oaire.citation.endPage27
oaire.citation.issue9
oaire.citation.startPage1
oaire.citation.titleMolecules
oaire.citation.volume30
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameBorges
person.familyNameCalhelha
person.givenNameAna Margarida
person.givenNameRicardo C.
person.identifier.ciencia-idCA13-636E-7820
person.identifier.ciencia-idF313-E3CE-554E
person.identifier.orcid0009-0009-8809-0541
person.identifier.orcid0000-0002-6801-4578
person.identifier.ridJ-2172-2014
person.identifier.scopus-author-id6507978333
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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