Novel isoniazid-amidoether derivatives: synthesis, characterization and antimycobacterial activity evaluation

A series of isoniazid-amidoether derivatives was synthesized and screened for their antimycobacterial activity in vitro and in vivo. Most of the compounds exhibited potent in vitro activity against the Mycobacterium tuberculosis H37Rv strain with MIC99 values ranging from 0.39 to 3.125 mu M. Five compounds were equally as potent as the reference compound isoniazid. The most active compound 3b, when evaluated for in vivo activity, exhibited mild reduction in the bacillary load in lungs. However it showed a better effect in spleens. All the compounds were also evaluated for their cytotoxicity against the THP-1 cell line and no toxicity was observed up to 50 mu M concentrations. The calculated ADMET parameters for the compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new anti-tuberculosis agents.