Various substituted benzothiazole-thiadiazole-based ketones 4a-i and 6a-c were synthesized and characterized by the IR, NMR, and MS spectral data. The DFT study of the synthesized ketones 4 and 6 displayed matched configurations of their HOMO and LUMO, with the exception of the nitrophenyl derivatives, whose HOMO extended over the entire molecule. Meanwhile, the antiproliferative effectiveness of the produced ketones was evaluated against diverse cell lines and compared with the reference drug Erlotinib. The ketones exhibited variable inhibitory effects, for example, the ketone 6a has the most potent activity versus Panc-1 (IC