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Design, synthesis and biologival evaluation of novel isoniazid derivatives with potente antitubercular activity

2014-06Journal article Open access
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dc.contributor.authorMartins, Filomena
dc.contributor.authorSantos, Susana
dc.contributor.authorVentura, Cristina
dc.contributor.authorElvas Leitao, Ruben
dc.contributor.authorSantos, Lídia
dc.contributor.authorVitorino, Susana
dc.contributor.authorReis, Marina
dc.contributor.authorMiranda, Vanessa
dc.contributor.authorCorreia, Henrique E.
dc.contributor.authorAires-de-Sousa, João
dc.contributor.authorKovalishyn, Vasyl
dc.contributor.authorLatino, Diogo A. R. S.
dc.contributor.authorRamos, Jorge
dc.contributor.authorViveiros, Miguel
dc.date.accessioned2015-08-24T10:50:32Z
dc.date.available2015-08-24T10:50:32Z
dc.date.issued2014-06
dc.description.abstractThe disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N-N distances and lengthy substituents lead to more active compounds. Compounds I, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC <= 0.28 mu M), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (Le., 6.9 vs. 43.8 mu M). All compounds were ineffective against H37Rv(INH) (Delta katG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC. (C) 2014 Elsevier Masson SAS. All rights reserved.por
dc.identifier.citationMARTINS, Filomena; [et al] – Design, synthesis and biologival evaluation of novel isoniazid derivaatives with potente antitubercular activity. European Journal of Medicinal Chemistry. ISSN: 0223-5234. Vol. 81 (2014), pp. 119-138por
dc.identifier.doi10.1016/j.ejmech.2014.04.077
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttp://hdl.handle.net/10400.21/4932
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherElsevier France – Editions Scientifiques Medicales Elsevierpor
dc.subjectAntitubercular Activitypor
dc.subjectIsoniazid Derivativespor
dc.subjectMycobacterium Tuberculosispor
dc.subjectResistancepor
dc.subjectQSARspor
dc.subjectSynthesispor
dc.titleDesign, synthesis and biologival evaluation of novel isoniazid derivatives with potente antitubercular activitypor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceParispor
oaire.citation.endPage138por
oaire.citation.startPage119por
oaire.citation.titleEuropean Journal of Medicinal Chemistrypor
oaire.citation.volume81por
person.familyNameElvas Leitao
person.givenNameRuben
person.identifier.ciencia-idF41B-8A26-88D4
person.identifier.orcid0000-0002-2196-412X
person.identifier.ridD-2452-2009
person.identifier.scopus-author-id55667178200
rcaap.rightsclosedAccesspor
rcaap.typearticlepor
relation.isAuthorOfPublication440b7129-d4d9-4225-a936-ca694c0984b6
relation.isAuthorOfPublication.latestForDiscovery440b7129-d4d9-4225-a936-ca694c0984b6

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