BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity

Participants in the publication
Filomena Martins (Author)
Dep. Química e Bioquímica
CQB
Susana Santos (Author)
Cristina Ventura (Author)
Ruben Elvas-Leitão (Author)
Lídia Santos (Author)
Susana Vitorino (Author)
Marina Reis (Author)
Vanessa Miranda (Author)
Henrique F. Correia (Author)
João Aires-de-Sousa (Author)
Vasyl Kovalishyn (Author)
Diogo A.R.S. Latino (Author)
Jorge Ramos (Author)
Miguel Viveiros (Author)

Summary
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 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 μM), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 μM). All compounds were ineffective against H37RvINH (ΔkatG), 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.


Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
European Journal of Medicinal Chemistry

Publication Identifiers

Publisher
Elsevier BV



Document Identifiers
DOI - https://doi.org/10.1016/j.ejmech.2014.04.077
URL - http://dx.doi.org/10.1016/j.ejmech.2014.04.077

Rankings
SCIMAGO Q1 (2014) - 1.079 - Drug Discovery
Web Of Science Q1 (2014) - 3.447 - Medicinal Chemistry

Keywords
Antitubercular activity Isoniazid derivatives Mycobacterium tuberculosis Resistance QSARs Synthesis