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In vitro Evaluation of Isoniazid Derivatives as Potential Agents Against Drug-Resistant Tuberculosis

2022-05-04Artigo científico Acesso aberto
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dc.contributor.authorMarquês, Joaquim Trigo
dc.contributor.authorFrazão De Faria, Catarina
dc.contributor.authorReis, Marina
dc.contributor.authorMachado, Diana
dc.contributor.authorSantos, Susana
dc.contributor.authorSantos, Maria da Soledade
dc.contributor.authorViveiros, Miguel
dc.contributor.authorMartins, Filomena
dc.contributor.authorDe Almeida, Rodrigo F.M.
dc.contributor.institutionTB, HIV and opportunistic diseases and pathogens (THOP)
dc.contributor.institutionGlobal Health and Tropical Medicine (GHTM)
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.pblFrontiers Media
dc.date.accessioned2022-08-25T22:21:15Z
dc.date.available2022-08-25T22:21:15Z
dc.date.issued2022-05-04
dc.descriptionFunding Information: Financed by Fundação para a Ciência e a Tecnologia, I.P./MCTES through national funds (PIDDAC, PT2020) under projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, EXPL/BIA-BFS/1034/2021, UIDB/00100/2020, UIDP/00100/2020, LA/P/0056/2020, UID/Multi/04413/2020, CEECIND/03247/2018 and DL57/CEECIND/0256/2017. Publisher Copyright: Copyright © 2022 Marquês, Frazão De Faria, Reis, Machado, Santos, Santos, Viveiros, Martins and De Almeida.
dc.description.abstractThe upsurge of multidrug-resistant tuberculosis has toughened the challenge to put an end to this epidemic by 2030. In 2020 the number of deaths attributed to tuberculosis increased as compared to 2019 and newly identified multidrug-resistant tuberculosis cases have been stably close to 3%. Such a context stimulated the search for new and more efficient antitubercular compounds, which culminated in the QSAR-oriented design and synthesis of a series of isoniazid derivatives active against Mycobacterium tuberculosis. From these, some prospective isonicotinoyl hydrazones and isonicotinoyl hydrazides are studied in this work. To evaluate if the chemical derivatizations are generating compounds with a good performance concerning several in vitro assays, their cytotoxicity against human liver HepG2 cells was determined and their ability to bind human serum albumin was thoroughly investigated. For the two new derivatives presented in this study, we also determined their lipophilicity and activity against both the wild type and an isoniazid-resistant strain of Mycobacterium tuberculosis carrying the most prevalent mutation on the katG gene, S315T. All compounds were less cytotoxic than many drugs in clinical use with IC50 values after a 72 h challenge always higher than 25 µM. Additionally, all isoniazid derivatives studied exhibited stronger binding to human serum albumin than isoniazid itself, with dissociation constants in the order of 10−4–10−5 M as opposed to 10−3 M, respectively. This suggests that their transport and half-life in the blood stream are likely improved when compared to the parent compound. Furthermore, our results are a strong indication that the N′ = C bond of the hydrazone derivatives of INH tested is essential for their enhanced activity against the mutant strain of M. tuberculosis in comparison to both their reduced counterparts and INH.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent3539281
dc.identifier.doi10.3389/fphar.2022.868545
dc.identifier.issn1663-9812
dc.identifier.otherPURE: 45881212
dc.identifier.otherPURE UUID: 7e90fcc5-d278-4e85-8e49-99afc8f6052d
dc.identifier.otherScopus: 85130522883
dc.identifier.otherORCID: /0000-0003-2375-2726/work/117747082
dc.identifier.otherORCID: /0000-0001-9676-6251/work/117747546
dc.identifier.urihttp://hdl.handle.net/10362/143306
dc.identifier.urlhttps://www.scopus.com/pages/publications/85130522883
dc.language.isoeng
dc.peerreviewedyes
dc.subjectantimycobacterial activity
dc.subjectcytotoxicity
dc.subjecthuman serum albumin binding
dc.subjectisoniazid resistance
dc.subjectlipophilicity
dc.subjectMycobacterium tuberculosis
dc.subjectPharmacology
dc.subjectPharmacology (medical)
dc.subjectSDG 3 - Good Health and Well-being
dc.titleIn vitro Evaluation of Isoniazid Derivatives as Potential Agents Against Drug-Resistant Tuberculosisen
dc.typejournal article
degois.publication.titleFrontiers in Pharmacology
degois.publication.volume13
dspace.entity.typePublication
rcaap.rightsopenAccess

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