2. Academic Validation
  3. Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity

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

  • Eur J Med Chem. 2014 Jun 23:81:119-38. doi: 10.1016/j.ejmech.2014.04.077.
Filomena Martins 1,  Susana Santos 2,  Cristina Ventura 3,  Ruben Elvas-Leitão 4,  Lídia Santos 2,  Susana Vitorino 2,  Marina Reis 3,  Vanessa Miranda 2,  Henrique F Correia 2,  João Aires-de-Sousa 5,  Vasyl Kovalishyn 5,  Diogo A R S Latino 6,  Jorge Ramos 7,  Miguel Viveiros 7
Affiliations

Affiliations

  • 1 Centro de Química e Bioquímica (CQB), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal. Electronic address: filomena.martins@fc.ul.pt.
  • 2 Centro de Química e Bioquímica (CQB), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal.
  • 3 Centro de Química e Bioquímica (CQB), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal; Instituto Superior de Educação e Ciências, Alameda das Linhas de Torres 179, 1750-142 Lisboa, Portugal.
  • 4 Centro de Química e Bioquímica (CQB), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal; Área Departamental de Engenharia Química, Instituto Superior de Engenharia de Lisboa (ISEL), Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro, 1959-007 Lisboa, Portugal.
  • 5 REQUIMTE and CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Monte de Caparica, 2829-516 Caparica, Portugal.
  • 6 REQUIMTE and CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Monte de Caparica, 2829-516 Caparica, Portugal; Centro de Ciências Moleculares e Materiais (CCMM), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal.
  • 7 Grupo de Micobactérias, Unidade de Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
PMID: 24836065 DOI: 10.1016/j.ejmech.2014.04.077
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 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.

Keywords

Antitubercular activity; Isoniazid derivatives; Mycobacterium tuberculosis; QSARs; Resistance; Synthesis.

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