Synthesis and Cytotoxic Activity Study of Conjugates of N-Acyl Derivatives of 3,5-Bis(benzylidene)-4-piperidones and Phenothiazine

In this study, a simple and efficient method for the synthesis of conjugates of N-acyl derivatives of 3,5-bis(benzylidene)-4-piperidones and phenothiazine was developed. The method was based on the acylation of 3,5-bis(benzylidene)-4-piperidones with chloroacetic acid chloride, followed by treatment of the product with sodium azide and an azide-alkyne [3+2] cycloaddition reaction between the resulting azide and 10-(prop-2-yn-1-yl)-10H-phenothiazine in the final step. Using this method, a series of seven compounds 23–29 were synthesized. The structure of synthesized compounds 23–29 was studied using 1H, 13C, and 19F NMR spectroscopy and ESI-MS mass spectrometry. The cytotoxicity of compounds 23–29 and their hydrochloride salts 30–36 towards pancreatic adenocarcinoma Panc-1, bladder cancer T-24, glioblastoma T98G, breast adenocarcinoma BT-20, and normal dermal fibroblast DF-1 cells was studied using an MTT assay. Compound 29, containing 3,4,5-trimethoxyl radicals at the aromatic ring, and its hydrochloride salt 36, demonstrated the best cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells. Hydrochloride salts were found to exhibit superior cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells compared to the original 3,5-bis(benzylidene)-4-piperidones and free bases. Selective cytotoxic action against Panc-1, T-24, T98G, and BT-20 cancer cells compared to normal DF-1 cells was also observed for all the obtained compounds and their salts.