New series of isoniazid hydrazones linked with electron-withdrawing substituents

A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 μmol L −1) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125–0.250 μmol L −1), high value of selectivity index (SI) and IC 50 between 0.0218 and 0.326 mmol L −1. Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed. [Display omitted] ► New isoniazid derivatives exhibiting in vitro antimycobacterial activity were prepared. ► NMR study confirmed that two different synthetic procedures led to the same tautomer. ► Most active compounds have better activity against Mycobacterium kansasii 325/80 than isoniazid. ► The most active compound, 2o, was stable at neutral pH. ► Stability was quantitatively studied by UV–vis in buffer solutions at pH 2–13.