A library of 143 Schiff bases of isatin derivatives was evaluated for its activity against the differe nt types ofMycobacterium tuberculosis. Ten of the tested der ivatives showed promising activity against the wild -type strain with MIC values range between 10-0.156 μ g/mL. The m ost active derivatives ( A2 , A6 , D5 and D8 ) were further tested against a panel of six single resistant Myco bacterium tuberculosisstrains. The results revealed interesting results regarding derivative D8 which showed enhanced activity against the Streptom ycin resistant strain. Further investigations showed D8 to have equipotent activity to INH against rifampin -resistant strains as well as being 4 times more active than rifampin against the ofloxac in-resistant strains. A pharmacophore modeling stud y was conducted to determine critical molecular component s for activity and to provide insights towards furt her optimization.