Phthalimide derivatives were synthesized using the concept of molecular hybridization or combination of two pharmacophores in one drug. In this paper, the concept was utilized to synthesize new antimycobacterial compounds to combat emerging resistant Mycobacterium tuberculosis strains. Four new phthalimides were successfully prepared using a single-step condensation reaction between phthalic anhydride and four different sulfonamides: sulfadimethoxine, sulfathiazole, sulfamethizole, and sulfamethoxypyridazine. IR and 1H NMR spectroscopic and mass spectrometric data verified the identity and structure of the synthesized compounds. The antimycobacterial activity of the synthesized phthalimides and their starting materials was evaluated according to CLSI standard procedures using the agar proportion method. The calculated LogP of both starting materials and phthalimides were also compared. Sulfathiazole, sulfadimethoxine, and sulfamethizole showed significant activity against Mycobacterium tuberculosis H37Rv strain at 0.01 mg/ml, the lowest concentration at which they were tested. One of the four new compounds, 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)benzenesulfonamide, which was synthesized from sulfathiazole also exhibited the same activity. The derivatives from sulfadimethoxine and sulfamethizole, however, showed a decrease in activity. The phthalimides overall gave higher LogP values. The active new compound demonstrates that molecular hybridization may be used to design antimycobacterial compounds with improved activity and pharmacokinetic properties.