A series of novel heterocyclic compounds containing N-acetyl isatine moiety were synthesized. Herein, reaction of N-acetyl isatine with water in the presence of a catalytic amount of glacial acetic acid, via a ring opening route, yielded 2-(2-acetamidophenyl)-2-oxoaceticacid,which acts as an adjustable precursor with different heteroaryl amines such as aniline, 2-amino pyridine, 5-amino-1,3,4-thiadiazole-2-thiol,phenylhydrazeine, for the preparation of different schiff bases. Furthermore, acetamide derivatives were prepared via the ring opening path of N-acetyl isatin, by the interaction of it with 2-aminomethylpyridine, aniline, and hydrazine hydrate. All prepared samples were confirmed by their spectral data such as FTIR, 1H-NMR, 13C-NMR, Mass spectrometry, and elemental analysis. Furthermore, all the obtained compounds were evaluated as antibacterial agents and gave promising results.