Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones
Resumen:
The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):<10). With the aim to identify the paullones’ moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 :150 nM; Trypanosoma brucei bloodstream form EC50: 4.3 μM and SI: 2.4). However, several of them retained potency (T. b. brucei EC50: 2.4–12.0 μM) and improved selectivity (SI: 5 to >25).
| 2023 | |
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TRYPANOSOMA BRUCEI ANTIPROTOZOARIOS ANTIPARASITARIOS |
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| Inglés | |
| Universidad de la República | |
| COLIBRI | |
| https://hdl.handle.net/20.500.12008/41453 | |
| Acceso abierto | |
| Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| _version_ | 1877554935759896576 |
|---|---|
| author | Lindhof, Jens C. |
| author2 | Ihnatenko, Irina Müller, Marco J. Orban, Oliver C. F. Ortíz, Cecilia Benítez, Diego Dibello, Estefanía Seidl, Leonardo L. Comini, Marcelo A. Kunick, Conrad |
| author2_role | author author author author author author author author author |
| author_facet | Lindhof, Jens C. Ihnatenko, Irina Müller, Marco J. Orban, Oliver C. F. Ortíz, Cecilia Benítez, Diego Dibello, Estefanía Seidl, Leonardo L. Comini, Marcelo A. Kunick, Conrad |
| author_role | author |
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| collection | COLIBRI |
| dc.contributor.filiacion.none.fl_str_mv | Lindhof Jens C., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ) Ihnatenko Irina, Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ) Müller Marco J., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ) Orban Oliver C. F., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ) Ortíz Cecilia, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas Benítez Diego, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas Dibello Estefanía, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas; Universidad de la República (Uruguay). Facultad de Química, Departamento de Química Orgánica Seidl Leonardo L., Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas Comini Marcelo A., Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas Kunick Conrad, Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ) |
| dc.creator.none.fl_str_mv | Lindhof, Jens C. Ihnatenko, Irina Müller, Marco J. Orban, Oliver C. F. Ortíz, Cecilia Benítez, Diego Dibello, Estefanía Seidl, Leonardo L. Comini, Marcelo A. Kunick, Conrad |
| dc.date.accessioned.none.fl_str_mv | 2023-11-22T21:33:32Z |
| dc.date.available.none.fl_str_mv | 2023-11-22T21:33:32Z |
| dc.date.issued.none.fl_str_mv | 2023 |
| dc.description.abstract.none.fl_txt_mv | The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):<10). With the aim to identify the paullones’ moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 :150 nM; Trypanosoma brucei bloodstream form EC50: 4.3 μM and SI: 2.4). However, several of them retained potency (T. b. brucei EC50: 2.4–12.0 μM) and improved selectivity (SI: 5 to >25). |
| dc.format.mimetype.es.fl_str_mv | application/pdf |
| dc.identifier.citation.es.fl_str_mv | Lindhof, J, Ihnatenko, I, Müller, M, y otros. "Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones"ChemMedChem. [en línea] 2023, e202300036. DOI: .doi.org/10.1002/cmdc.202300036 |
| dc.identifier.doi.none.fl_str_mv | doi.org/10.1002/cmdc.202300036 |
| dc.identifier.uri.none.fl_str_mv | https://hdl.handle.net/20.500.12008/41453 |
| dc.language.iso.none.fl_str_mv | en eng |
| dc.publisher.es.fl_str_mv | Wiley-VCH GmbH |
| dc.relation.none.fl_str_mv | ChemMedChem 2023. -- e202300036 |
| dc.rights.license.none.fl_str_mv | Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.subject.other.es.fl_str_mv | TRYPANOSOMA BRUCEI ANTIPROTOZOARIOS ANTIPARASITARIOS |
| dc.title.none.fl_str_mv | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| dc.type.es.fl_str_mv | Artículo |
| dc.type.none.fl_str_mv | info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv | info:eu-repo/semantics/publishedVersion |
| description | The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):<10). With the aim to identify the paullones’ moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 :150 nM; Trypanosoma brucei bloodstream form EC50: 4.3 μM and SI: 2.4). However, several of them retained potency (T. b. brucei EC50: 2.4–12.0 μM) and improved selectivity (SI: 5 to >25). |
| eu_rights_str_mv | openAccess |
| format | article |
| id | COLIBRI_8db24901b472c2d5c4d8d6a1d536cf2f |
| identifier_str_mv | Lindhof, J, Ihnatenko, I, Müller, M, y otros. "Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones"ChemMedChem. [en línea] 2023, e202300036. DOI: .doi.org/10.1002/cmdc.202300036 doi.org/10.1002/cmdc.202300036 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | COLIBRI |
| network_name_str | COLIBRI |
| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/41453 |
| publishDate | 2023 |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | karina.camps@seciu.edu.uy |
| repository.name.fl_str_mv | COLIBRI - Universidad de la República |
| repository_id_str | 4771 |
| rights_invalid_str_mv | Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| spelling | Lindhof Jens C., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ)Ihnatenko Irina, Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ)Müller Marco J., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ)Orban Oliver C. F., Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ)Ortíz Cecilia, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de TripanosomasBenítez Diego, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de TripanosomasDibello Estefanía, Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de Tripanosomas; Universidad de la República (Uruguay). Facultad de Química, Departamento de Química OrgánicaSeidl Leonardo L., Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de TripanosomasComini Marcelo A., Institut Pasteur de Montevideo (Uruguay). Laboratorio de Biología Redox de TripanosomasKunick Conrad, Technische Universität Braunschweig (Alemania). Institut für Medizinische und Pharmazeutische Chemie; Zentrum für Pharmaverfahrenstechnik (PVZ)2023-11-22T21:33:32Z2023-11-22T21:33:32Z2023Lindhof, J, Ihnatenko, I, Müller, M, y otros. "Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones"ChemMedChem. [en línea] 2023, e202300036. DOI: .doi.org/10.1002/cmdc.202300036https://hdl.handle.net/20.500.12008/41453doi.org/10.1002/cmdc.202300036The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):<10). With the aim to identify the paullones’ moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 :150 nM; Trypanosoma brucei bloodstream form EC50: 4.3 μM and SI: 2.4). However, several of them retained potency (T. b. brucei EC50: 2.4–12.0 μM) and improved selectivity (SI: 5 to >25).Submitted by Silvana González (sgz@adinet.com.uy) on 2023-11-22T20:31:36Z No. of bitstreams: 2 license_rdf: 25790 bytes, checksum: 489f03e71d39068f329bdec8798bce58 (MD5) AA Lindhof, J. C. et al ChemMedChem 2023.pdf: 3631960 bytes, checksum: a216acd3d63c909fae063ff60ae8b26c (MD5)Made available in DSpace by Seroubian Mabel (mabel.seroubian@seciu.edu.uy) on 2023-11-22T21:33:32Z (GMT). No. of bitstreams: 2 license_rdf: 25790 bytes, checksum: 489f03e71d39068f329bdec8798bce58 (MD5) AA Lindhof, J. C. et al ChemMedChem 2023.pdf: 3631960 bytes, checksum: a216acd3d63c909fae063ff60ae8b26c (MD5) Previous issue date: 2023application/pdfenengWiley-VCH GmbHChemMedChem 2023. -- e202300036Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0)TRYPANOSOMA BRUCEIANTIPROTOZOARIOSANTIPARASITARIOSDiscovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullonesArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaLindhof, Jens C.Ihnatenko, IrinaMüller, Marco J.Orban, Oliver C. F.Ortíz, CeciliaBenítez, DiegoDibello, EstefaníaSeidl, Leonardo L.Comini, Marcelo A.Kunick, ConradLICENSElicense.txtlicense.txttext/plain; charset=utf-84267http://localhost:8080/xmlui/bitstream/20.500.12008/41453/5/license.txt6429389a7df7277b72b7924fdc7d47a9MD55CC-LICENSElicense_urllicense_urltext/plain; charset=utf-850http://localhost:8080/xmlui/bitstream/20.500.12008/41453/2/license_urla006180e3f5b2ad0b88185d14284c0e0MD52license_textlicense_texttext/html; charset=utf-814674http://localhost:8080/xmlui/bitstream/20.500.12008/41453/3/license_text6eed504571858d3e58aeed5ad67e191aMD53license_rdflicense_rdfapplication/rdf+xml; charset=utf-825790http://localhost:8080/xmlui/bitstream/20.500.12008/41453/4/license_rdf489f03e71d39068f329bdec8798bce58MD54ORIGINALAA Lindhof, J. C. et al ChemMedChem 2023.pdfAA Lindhof, J. C. et al ChemMedChem 2023.pdfapplication/pdf3631960http://localhost:8080/xmlui/bitstream/20.500.12008/41453/1/AA+Lindhof%2C+J.+C.+et+al+ChemMedChem+2023.pdfa216acd3d63c909fae063ff60ae8b26cMD5120.500.12008/414532025-02-14 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- Universidad de la Repúblicafalse |
| spellingShingle | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones Lindhof, Jens C. TRYPANOSOMA BRUCEI ANTIPROTOZOARIOS ANTIPARASITARIOS |
| status_str | publishedVersion |
| title | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| title_full | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| title_fullStr | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| title_full_unstemmed | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| title_short | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| title_sort | Discovery of antitrypanosomal indolylacetamides by a deconstruction–optimization strategy applied to paullones |
| topic | TRYPANOSOMA BRUCEI ANTIPROTOZOARIOS ANTIPARASITARIOS |
| url | https://hdl.handle.net/20.500.12008/41453 |
