Synthesis, Characterisation and Antitubercular Activity of Novel Schiff Base Derivatives of Isoniazid Against Drug-Resistant Mycobacterium tuberculosis Strains

Tuberculosis remains a leading infectious disease cause of death in Nigeria, and the emergence of multidrug-resistant and extensively drug-resistant strains has rendered standard first-line treatment with isoniazid increasingly ineffective. Structural modification of isoniazid through Schiff base formation offers a well-established medicinal chemistry strategy to enhance potency and overcome resistance. This study synthesised a series of eight novel Schiff base derivatives of isoniazid by condensation with substituted aromatic aldehydes under reflux conditions. All synthesised compounds were characterised by melting point, IR spectroscopy, proton NMR, carbon NMR, and mass spectrometry. Antitubercular activity was evaluated against drug-susceptible H37Rv and two clinically derived MDR-TB strains from the NIMR Strain Library using the microplate Alamar Blue assay. Cytotoxicity was assessed against Vero cells to calculate selectivity indices. Five of the eight derivatives showed MIC values below 1 microgram per millilitre against H37Rv, superior to isoniazid under the same test conditions. Three derivatives retained activity against both MDR-TB strains. The most active compound, bearing a 4-nitrobenzaldehyde substituent, demonstrated MIC of 0.25 micrograms per millilitre with selectivity index above 40. Computational ADMET prediction indicated acceptable drug-likeness for the lead compound. These results identify the synthesised Schiff base series as promising antitubercular lead compounds warranting further in vivo evaluation and structure-activity relationship optimisation. Keywords: isoniazid, Schiff base, antitubercular activity, MDR-TB, synthesis.