Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains

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dc.contributor.authorFernandes, Guilherme F. S. [UNESP]
dc.contributor.authorManieri, Karyn F. [UNESP]
dc.contributor.authorBonjorno, Andressa F. [UNESP]
dc.contributor.authorCampos, Debora L. [UNESP]
dc.contributor.authorRibeiro, Camila M. [UNESP]
dc.contributor.authorDemarqui, Fernanda M. [UNESP]
dc.contributor.authorRuiz, Daniel A. G. [UNESP]
dc.contributor.authorNascimento-Junior, Nailton M. [UNESP]
dc.contributor.authorDenny, William A.
dc.contributor.authorThompson, Andrew M.
dc.contributor.authorPavan, Fernando R. [UNESP]
dc.contributor.authorDos Santos, Jean L. [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionThe University of Auckland
dc.contributor.institutionUniversity College London
dc.date.accessioned2023-07-29T16:11:47Z
dc.date.available2023-07-29T16:11:47Z
dc.date.issued2023-01-01
dc.description.abstractThe emergence of multidrug-resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18–1.63 μM against Mtb H37Rv. Compounds 47–49, 51–53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 μM. In Mtb-infected macrophages, several compounds demonstrated a 1-log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1-b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin-dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1-b][1,3]oxazines and their promising potential against MDR-TB.en
dc.description.affiliationSchool of Pharmaceutical Sciences São Paulo State University, Rod. Araraquara-Jaú
dc.description.affiliationAuckland Cancer Society Research Centre Faculty of Medical and Health Sciences The University of Auckland, Private Bag 92019
dc.description.affiliationInstitute of Chemistry São Paulo State University, Rua Professor Francisco Degni, 55
dc.description.affiliationDepartment of Chemistry University College London, 20 Gordon Street
dc.description.affiliationUnespSchool of Pharmaceutical Sciences São Paulo State University, Rod. Araraquara-Jaú
dc.description.affiliationUnespInstitute of Chemistry São Paulo State University, Rua Professor Francisco Degni, 55
dc.identifierhttp://dx.doi.org/10.1002/cmdc.202300015
dc.identifier.citationChemMedChem.
dc.identifier.doi10.1002/cmdc.202300015
dc.identifier.issn1860-7187
dc.identifier.issn1860-7179
dc.identifier.scopus2-s2.0-85153112345
dc.identifier.urihttp://hdl.handle.net/11449/249879
dc.language.isoeng
dc.relation.ispartofChemMedChem
dc.sourceScopus
dc.subject2-nitroimidazooxazine
dc.subjectImidazo[2,1-b][1,3]oxazine
dc.subjectmultidrug-resistant tuberculosis
dc.subjectpretomanid derivatives
dc.subjecttuberculosis
dc.titleSynthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strainsen
dc.typeArtigo
unesp.author.orcid0000-0002-7644-5466[1]
unesp.author.orcid0000-0001-6461-2098[2]
unesp.author.orcid0000-0002-8666-008X[3]
unesp.author.orcid0000-0003-2250-8342[4]
unesp.author.orcid0000-0001-6402-7147[5]
unesp.author.orcid0000-0003-2054-9511[6]
unesp.author.orcid0000-0001-6233-3036[7]
unesp.author.orcid0000-0002-1543-419X[8]
unesp.author.orcid0000-0001-7997-1843[9]
unesp.author.orcid0000-0003-2593-8559[10]
unesp.author.orcid0000-0002-6969-3963[11]
unesp.departmentCiências Biológicas - FCFpt

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Araraquara - FCF - Faculdade de Ciências Farmacêuticas