Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity

Abstract

A series of isoniazid derivatives bearing a phenolic or heteroaromatic coupled frame were obtained by mechanochemical means. Their pH stability and their structural (conformer/isomer) analysis were checked. The activity of prepared derivatives against <i>Mycobacterium tuberculosis</i> cell growth was evaluated. Some compounds such as phenolic hydrazine <b>1a</b> and almost all heteroaromatic ones, especially <b>2</b>, <b>5</b> and <b>7</b>, are more active than isoniazid, and their activity against some <i>M. tuberculosis</i> MDR clinical isolates was determined. Compounds <b>1a</b> and <b>7</b> present a selectivity index >1400 evaluated on MRC5 human fibroblast cells. The mechanism of action of selected hydrazones was demonstrated to block mycolic acid synthesis due to InhA inhibition inside the mycobacterial cell.