One-Pot Synthesis of New Bipyridine and Yerpyridine Derivatives: Anti-proliferative Evaluation, DNA Flow Cytometry Analysis, and Molecular Docking Study

Some new bipyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile 1a. While terpyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carbonitrile 1b as starting material. Alkylation of compounds 1a, b gave the alkyl derivatives 2a, b which converted into aceto hydrazides 3a,b. Treating the aceto hydrazides with ethyl cyanoacetate afforded 2'-(2-(3,5-dioxopyrazolidin-1-yl)-2-oxoethoxy)-6'-(thiophen-2-yl)-3,4'-bipyridine-3'-carbonitrile 4a and 6'-2-(3,5-dioxopyrazolidin-1-yl)-2-oxoethoxy-(3,4':2',4''-terpyridine)-5'-carbonitrile 4b. While treatment of 3a, b with ethyl benzoylacetate afforded the carboniltrile derivatives 2'-(2-oxo-2-(5-oxo-3-phenyl-4,5-dihydropyrazol-1-yl)ethoxy)-6'-(thiophen-2-yl)-3,4'-bipyridine-3'-carbonitrile 5a and 6'-2-oxo-2-(5-oxo-3-phenyl-4,5-dihydropyrazol-1-yl)ethoxy-(3,4':2',4''-terpyridine)-5' carbonitrile 5b. Treating compounds 3a, and b with two aromatic aldehydes (3,4-dihydroxy benzaldehyde, 4-chlorobenzaldehyde) afforded Schiff bases 6a-d. Finally, treatment of 3a, b with p-toluenesulfonyl chloride (Tosyl chloride) afforded the corresponding benzene sulfonohydrazide 7a, b. IR, 1HNMR, 13CNMR, MS, and elemental analysis confirmed the synthesized compounds. The anti-cancer activity of the compounds was investigated against the breast cancer (MCF-7) cell line. Compound 6b demonstrated the strongest cytotoxic activity among the tested compounds and it is more active than the reference drug 5-fluorouracil (5-FU), so that, it is subjected to further investigations, where its effect on the cell cycle distribution in the MCF-7 cell line, its ability to inhibit Topoisomerase II, the level of Caspase‐3/7 green flow cytometry assay was investigated. Also, Molecular operating environmental docking (MOE) has been studied and found that the inhibition efficiency could be organized as follows (S, Kcal/mol) values: 5b ˃ 6d ˃ 3a ˃ 3b ˃ 6b, while compound 5a did not show any interaction data belonging to the shaped complex with 1cca. Hence, most synthesized compounds can be used as anti-cancer and anti-oxidant agents.