Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.21/4932
Título: Design, synthesis and biologival evaluation of novel isoniazid derivatives with potente antitubercular activity
Autor: Martins, Filomena
Santos, Susana
Ventura, Cristina
Leitão, Rúben Elvas
Santos, Lídia
Vitorino, Susana
Reis, Marina
Miranda, Vanessa
Correia, Henrique E.
Aires-de-Sousa, João
Kovalishyn, Vasyl
Latino, Diogo A. R. S.
Ramos, Jorge
Viveiros, Miguel
Palavras-chave: Antitubercular Activity
Isoniazid Derivatives
Mycobacterium Tuberculosis
Data: Jun-2014
Editora: Elsevier France – Editions Scientifiques Medicales Elsevier
Citação: MARTINS, 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. 119-138
Resumo: The 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.
Peer review: yes
URI: http://hdl.handle.net/10400.21/4932
DOI: 10.1016/j.ejmech.2014.04.077
ISSN: 0223-5234
Aparece nas colecções:ISEL - Eng. Quim. Biol. - Artigos

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