Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study

Autores
Zidar, Nace; Emanuel Cotman, Andrej; Sinnige, Wessel; Benek, Ondrej; Barančokova, Michaela; Zega, Anamarija; Peterlin Mašič, Lucija; Tomašič, Tihomir; Ilaš, Janez; Henderson, Sara R.; Mundy, Julia E. A.; Maxwell, Anthony; Stevenson, Clare E. M.; Lawson, David M.; Jan Sterk, Geert; Tosso, Rodrigo David; Gutierrez, Lucas Joel; Enriz, Ricardo Daniel; Kikelj, Danijel
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2- carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.
Fil: Zidar, Nace. University of Ljubljana; Eslovenia
Fil: Emanuel Cotman, Andrej. University of Ljubljana; Eslovenia
Fil: Sinnige, Wessel. Vrije Universiteit Amsterdam; Países Bajos. University of Ljubljana; Eslovenia
Fil: Benek, Ondrej. University of Ljubljana; Eslovenia
Fil: Barančokova, Michaela. University of Ljubljana; Eslovenia
Fil: Zega, Anamarija. University of Ljubljana; Eslovenia
Fil: Peterlin Mašič, Lucija. University of Ljubljana; Eslovenia
Fil: Tomašič, Tihomir. University of Ljubljana; Eslovenia
Fil: Ilaš, Janez. University of Ljubljana; Eslovenia
Fil: Henderson, Sara R.. John Innes Institute; Reino Unido. University of Bradford; Reino Unido
Fil: Mundy, Julia E. A.. John Innes Institute; Reino Unido
Fil: Maxwell, Anthony. John Innes Institute; Reino Unido
Fil: Stevenson, Clare E. M.. John Innes Institute; Reino Unido
Fil: Lawson, David M.. John Innes Institute; Reino Unido
Fil: Jan Sterk, Geert. Vrije Universiteit Amsterdam; Países Bajos
Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Kikelj, Danijel. University of Ljubljana; Eslovenia
Materia
Antibacterial agent
DNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide Inhibitor
molecular modelling
QTAIM analysis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/267339
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/267339
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM studyZidar, NaceEmanuel Cotman, AndrejSinnige, WesselBenek, OndrejBarančokova, MichaelaZega, AnamarijaPeterlin Mašič, LucijaTomašič, TihomirIlaš, JanezHenderson, Sara R.Mundy, Julia E. A.Maxwell, AnthonyStevenson, Clare E. M.Lawson, David M.Jan Sterk, GeertTosso, Rodrigo DavidGutierrez, Lucas JoelEnriz, Ricardo DanielKikelj, DanijelAntibacterial agentDNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide Inhibitormolecular modellingQTAIM analysishttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2- carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.Fil: Zidar, Nace. University of Ljubljana; EsloveniaFil: Emanuel Cotman, Andrej. University of Ljubljana; EsloveniaFil: Sinnige, Wessel. Vrije Universiteit Amsterdam; Países Bajos. University of Ljubljana; EsloveniaFil: Benek, Ondrej. University of Ljubljana; EsloveniaFil: Barančokova, Michaela. University of Ljubljana; EsloveniaFil: Zega, Anamarija. University of Ljubljana; EsloveniaFil: Peterlin Mašič, Lucija. University of Ljubljana; EsloveniaFil: Tomašič, Tihomir. University of Ljubljana; EsloveniaFil: Ilaš, Janez. University of Ljubljana; EsloveniaFil: Henderson, Sara R.. John Innes Institute; Reino Unido. University of Bradford; Reino UnidoFil: Mundy, Julia E. A.. John Innes Institute; Reino UnidoFil: Maxwell, Anthony. John Innes Institute; Reino UnidoFil: Stevenson, Clare E. M.. John Innes Institute; Reino UnidoFil: Lawson, David M.. John Innes Institute; Reino UnidoFil: Jan Sterk, Geert. Vrije Universiteit Amsterdam; Países BajosFil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Kikelj, Danijel. University of Ljubljana; EsloveniaPergamon-Elsevier Science Ltd2024-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/267339Zidar, Nace; Emanuel Cotman, Andrej; Sinnige, Wessel; Benek, Ondrej; Barančokova, Michaela; et al.; Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 109; 117798; 7-2024; 1-160968-0896CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0968089624002128info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2024.117798info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-11T12:35:48Zoai:ri.conicet.gov.ar:11336/267339instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-02-11 12:35:48.447CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
title Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
spellingShingle Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
Zidar, Nace
Antibacterial agent
DNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide Inhibitor
molecular modelling
QTAIM analysis
title_short Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
title_full Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
title_fullStr Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
title_full_unstemmed Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
title_sort Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study
dc.creator.none.fl_str_mv Zidar, Nace
Emanuel Cotman, Andrej
Sinnige, Wessel
Benek, Ondrej
Barančokova, Michaela
Zega, Anamarija
Peterlin Mašič, Lucija
Tomašič, Tihomir
Ilaš, Janez
Henderson, Sara R.
Mundy, Julia E. A.
Maxwell, Anthony
Stevenson, Clare E. M.
Lawson, David M.
Jan Sterk, Geert
Tosso, Rodrigo David
Gutierrez, Lucas Joel
Enriz, Ricardo Daniel
Kikelj, Danijel
author Zidar, Nace
author_facet Zidar, Nace
Emanuel Cotman, Andrej
Sinnige, Wessel
Benek, Ondrej
Barančokova, Michaela
Zega, Anamarija
Peterlin Mašič, Lucija
Tomašič, Tihomir
Ilaš, Janez
Henderson, Sara R.
Mundy, Julia E. A.
Maxwell, Anthony
Stevenson, Clare E. M.
Lawson, David M.
Jan Sterk, Geert
Tosso, Rodrigo David
Gutierrez, Lucas Joel
Enriz, Ricardo Daniel
Kikelj, Danijel
author_role author
author2 Emanuel Cotman, Andrej
Sinnige, Wessel
Benek, Ondrej
Barančokova, Michaela
Zega, Anamarija
Peterlin Mašič, Lucija
Tomašič, Tihomir
Ilaš, Janez
Henderson, Sara R.
Mundy, Julia E. A.
Maxwell, Anthony
Stevenson, Clare E. M.
Lawson, David M.
Jan Sterk, Geert
Tosso, Rodrigo David
Gutierrez, Lucas Joel
Enriz, Ricardo Daniel
Kikelj, Danijel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Antibacterial agent
DNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide Inhibitor
molecular modelling
QTAIM analysis
topic Antibacterial agent
DNA gyrase ATP-binding site N-(benzothiazol-2-yl)pyrrolamide Inhibitor
molecular modelling
QTAIM analysis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2- carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.
Fil: Zidar, Nace. University of Ljubljana; Eslovenia
Fil: Emanuel Cotman, Andrej. University of Ljubljana; Eslovenia
Fil: Sinnige, Wessel. Vrije Universiteit Amsterdam; Países Bajos. University of Ljubljana; Eslovenia
Fil: Benek, Ondrej. University of Ljubljana; Eslovenia
Fil: Barančokova, Michaela. University of Ljubljana; Eslovenia
Fil: Zega, Anamarija. University of Ljubljana; Eslovenia
Fil: Peterlin Mašič, Lucija. University of Ljubljana; Eslovenia
Fil: Tomašič, Tihomir. University of Ljubljana; Eslovenia
Fil: Ilaš, Janez. University of Ljubljana; Eslovenia
Fil: Henderson, Sara R.. John Innes Institute; Reino Unido. University of Bradford; Reino Unido
Fil: Mundy, Julia E. A.. John Innes Institute; Reino Unido
Fil: Maxwell, Anthony. John Innes Institute; Reino Unido
Fil: Stevenson, Clare E. M.. John Innes Institute; Reino Unido
Fil: Lawson, David M.. John Innes Institute; Reino Unido
Fil: Jan Sterk, Geert. Vrije Universiteit Amsterdam; Países Bajos
Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Kikelj, Danijel. University of Ljubljana; Eslovenia
description N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2- carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.
publishDate 2024
dc.date.none.fl_str_mv 2024-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/267339
Zidar, Nace; Emanuel Cotman, Andrej; Sinnige, Wessel; Benek, Ondrej; Barančokova, Michaela; et al.; Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 109; 117798; 7-2024; 1-16
0968-0896
CONICET Digital
CONICET
url http://hdl.handle.net/11336/267339
identifier_str_mv Zidar, Nace; Emanuel Cotman, Andrej; Sinnige, Wessel; Benek, Ondrej; Barančokova, Michaela; et al.; Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 109; 117798; 7-2024; 1-16
0968-0896
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0968089624002128
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2024.117798
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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