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Abstract
Oximes, semicarbazones, thiosemicarbazones, phenylhydrazones and other Schiff bases, which contain the azomethine group (-NH-N=CH), have recently been investigated as potential tuberculosis(TB) drugs due to their anti-inflammatory and anti-oxidant properties. In this study, we map out the two-step mechanism of the reaction between acid hydrazides and aromatic aldehydes using a DFT approach by focusing on the reaction between isoniazid (pyridine-4-carbaldehyde) and different hydrogen-bonding conformations between phenol and INH with benzaldehyde, which involves a rate-determining attack of the nitrogen base on the carbonyl compound under mildly acidic conditions as Jencks et al. initially proposed. The relative thermodynamic favorability and stability of the transition states and intermediates were then interpreted by performing natural bond orbital(NBO) analysis and molecular electrostatic potential(MEP) surface analysis. Our results showed that the terminal phenol moiety contributed significantly to the resonance stabilization of the structures with a lower Gibbs free energy of -307.40326 and -307.38176 Hartrees/particle, hence as promising candidates for novel tuberculosis treatments.
