Abstract: Tuberculosis (TB) remains a leading infectious cause of death, and drug-resistant strains make new antitubercular scaffolds and targets necessary. Glutamine synthetase 1 (GS1, GlnA1) of Mycobacterium tuberculosis forms glutamine from glutamate and ammonia and is linked to nitrogen metabolism and to the poly-L-glutamate/glutamine component of the cell wall. Five Schiff bases of 2-aminobenzothiazole (C1–C5) were chosen from a designed library on the basis of docking against GS1 (PDB ID: 4ACF) and were synthesized by microwave-assisted condensation of 2-aminobenzothiazole with cinnamaldehyde, 4-nitrobenzaldehyde, 3-methyl-4-nitrobenzaldehyde, 5-chlorosalicylaldehyde and 5-fluoro-4-nitrobenzaldehyde (350 W, 75 °C, 3–5 min; yields 81–88%). The products were characterized by melting point, TLC, IR, 1H NMR and mass spectrometry. All five compounds satisfied Lipinski’s rule of five, and OSIRIS Property Explorer flagged no mutagenic, tumorigenic, irritant or reproductive-effect risk. Docking scores ranged from −7.6 to −8.5 kcal/mol (highest for C3, −8.5; C5, −8.4). In the Microplate Alamar Blue Assay (MABA) against M. tuberculosis H37Rv the MIC values were 100 (C1), 6.25 (C2), 3.12 (C3), 25 (C4) and 1.6 µg/mL (C5). C5 was the most active compound; its MIC equals the values reported for isoniazid and ethambutol (1.6 µg/mL) and is twofold higher than those for rifampicin and streptomycin (0.8 µg/mL). Docking scores ranked the compounds only weakly in agreement with MIC (Spearman ρ = 0.6, n = 5), and no enzyme-inhibition assay was performed, so GS1 inhibition remains a hypothesis. C5 is regarded as a candidate for further optimization, enzyme assays and cytotoxicity testing.