Novel isoniazid derivative as promising antituberculosis agent

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Tuberculosis drug discovery prioritizes novel antibiotics against resistant Mycobacterium tuberculosis strains.
• Isoniazid resistance is a significant challenge in tuberculosis treatment.
• Developing new drugs is crucial to combat multidrug-resistant tuberculosis.

Purpose of the Study:

• To synthesize and evaluate novel isoniazid derivatives for activity against Mycobacterium tuberculosis.
• To identify compounds effective against isoniazid-resistant strains.
• To assess the preliminary safety and pharmacokinetic properties of active compounds.

Main Methods:

• Synthesis of ten isoniazid derivatives.
• Antimicrobial susceptibility testing against M. tuberculosis H37Rv and an isoniazid-resistant strain (SRI 1369).
• Cytotoxicity assay using HepG2 cells and permeability assessment using Caco-2 cells.
• Plasma protein binding assay.

Main Results:

• One compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide (compound 1), exhibited potent activity against the isoniazid-resistant strain (MIC = 0.14 μM).
• Compound 1 showed no cytotoxicity to HepG2 cells (IC50 >100 μM) and good Caco-2 cell permeability.
• The unbound fraction of compound 1, relevant for pharmacological effects, was determined to be 57.9%.

Conclusions:

• Isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising candidate for further preclinical development.
• The compound's favorable activity profile against resistant tuberculosis and good preliminary safety/permeability data support its potential.
• Further studies are warranted to explore its efficacy and safety in preclinical models of tuberculosis.