Publication Type Journal Article
Title Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity
Authors F. Martins Susana Santos Cristina Ventura R. Elvas-Leitão Lidia Santos Susana Vitorino Marina Reis Vanessa Miranda Henrique E. Correia Joao Aires-de-Sousa Vasyl Kovalishyn Diogo A. R. S. Latino Jorge Ramos Miguel Viveiros
Groups HC MET
Journal EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Year 2014
Month June
Volume 81
Number
Pages 119-138
Abstract 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.
DOI http://dx.doi.org/10.1016/j.ejmech.2014.04.077
ISBN
Publisher
Book Title
ISSN 0223-5234
EISSN 1768-3254
Conference Name
Bibtex ID ISI:000338598400012
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