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

Abstract

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 (IC 50 > 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.

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

“…On the other hand, these compounds showed significant structural differences that could aid their interaction with InhA enzyme. Interestingly, we found that some of these complexes were better in vitro inhibitors of InhA than IQG-607 with inhibition rate values 10-fold larger, though with similar MIC values (Gazzi et al, 2017 ).…”

“…A series of cyanoferrate(II) complexes containing isonicotinoylhydrazone ligands (Figure 4 ) was prepared and measurements of InhA enzyme inhibition and antitubercular activity against a drug-susceptible M. tuberculosis strain were carried out (Gazzi et al, 2017 ). There was a modest difference in electrochemical potential among all of those complexes, ranging from 337 to 426 mV vs. Ag|AgCl, which is expected as they are bound through an analogous pyridinic nitrogen.…”