Mechanochemical Solvent-Free Synthesis and Biological Profiling of Novel 2-Hydrazone-Bridged Benzothiazoles as Potent Anticancer Agents

This study reports the solvent-free mechanochemical synthesis of a novel series of 2-hydrazone-bridged benzothiazole derivatives 19&ndash:52 via the reaction of 2-hydrazinylbenzothiazole derivatives 4&ndash:6 with O-alkylated benzaldehydes 7&ndash:18. The stereostructure of the E-isomers was confirmed by 2D NOESY spectroscopy. The antiproliferative potential of these newly prepared 2-hydrazone derivatives of benzothiazole 19&ndash:52 was evaluated in vitro against eight human cancer cell lines. Several compounds demonstrated low micromolar IC50 values, with some outperforming the reference drug etoposide. Among the most potent compounds, the 6-chloro-2-hydrazone(3-fluorophenyl)benzothiazole derivative 38 exhibited remarkable activity against pancreatic adenocarcinoma (Capan-1, IC50 = 0.6 &micro:M) and non-small cell lung cancer (NCI-H460, IC50 = 0.9 &micro:M). Structure&ndash:activity relationship analysis revealed that derivatives 45&ndash:52, featuring a methoxy group at position 6 of the benzothiazole ring and either a methoxy or fluorine substituent at position 3 of the phenyl ring, showed consistently strong antiproliferative effects across all tested cell lines (IC50 = 1.3&ndash:12.8 &micro:M). Furthermore, compounds bearing N,N-diethylamino or N,N-dimethylamino groups at position 4 of the phenyl ring generally exhibited superior activity compared to those with morpholine or piperidine moieties. However, as this study represents an initial screening, further mechanistic investigations are required to confirm specific anticancer pathways and therapeutic relevance. In addition to their in vitro anticancer properties, the antibacterial activity of the compounds was assessed against both Gram-positive and Gram-negative bacteria. Notably, compound 37 demonstrated selective antibacterial activity against Pseudomonas aeruginosa (MIC = 4 &micro:g/mL). Overall, this work highlights the efficiency of a green, mechanochemical approach for synthesizing E-isomer hydrazone-bridged benzothiazoles and underscores their potential as promising scaffolds for the development of potent antiproliferative agents.