Synthesis, Inhibition of Mycobacterium tuberculosis Enoyl-acyl Carrier Protein Reductase and Antimycobacterial Activity of Novel Pentacyanoferrate(II)-isonicotinoylhydrazones

• Autor(a) principal: Gazzi,Thais P.
• Data de Publicação: 2017
• Outros Autores: Rotta,,Mariane, Villela,Anne D., Rodrigues-Junior,Valnês, Martinelli,Leonardo K. B., Sales,Francisco Adilson M., Sousa,Eduardo Henrique Silva de, Campos,Maria Martha, Basso,Luiz Augusto, Santos,Diógenes S., Machado,Pablo
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Journal of the Brazilian Chemical Society (Online)
• Texto Completo: http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532017001002028
• topic: metallodrugs; tuberculosis; isoniazid; coordination complex

Tuberculosis remains among the top causes of death triggered by a single pathogen. Herein, a greener synthetic approach for isonicotinoylhydrazones is described using ultrasound energy. These compounds were used as starting materials for synthesizing pentacyanoferrate(II)-isonicotinoylhydrazones, which inhibited the reaction catalyzed by Mycobacterium tuberculosis 2-trans-enoyl-ACP(CoA) reductase (MtInhA) in a time-dependent manner. The most active coordination complex showed an increase of more than ten-fold in the MtInhA inhibition rate constant compared with lead pentacyano(isoniazid)ferrate(II) (IQG607). Additionally, the new series of metal-based compounds demonstrated antitubercular activity against a drug-susceptible Mycobacterium tuberculosis (Mtb) strain and was devoid of toxicity to mammalian cells (IC50 > 20 µmol L-1, half maximal inhibitory concentration). Finally, one of the synthesized compounds showed intracellular activity similar to isoniazid in a macrophage model of Mtb infection, indicating that this chemical class may furnish novel structures to embark on the preclinical phase of anti-tuberculosis drug development.