ONE-POT SYNTHESIS OF NEW BIPYRIDINE AND TERPYRIDINE DERIVATIVES: ANTI-PROLIFERATIVE EVALUATION, DNA FLOW CYTOMETRY ANALYSIS, AND MOLECULAR DOCKING STUDY

New bipyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile 1a. Terpyridine derivatives were synthesized using 2-oxo-4-(pyridin-3-yl)-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carbonitrile 1b as the starting material. Alkylation of compounds 1a, b gave the alkyl derivatives 2a, b which converted into acetohydrazides 3a,b. Treating the acetohydrazides with ethyl cyanoacetate obtained 2'-[2-(3,5-dioxopyrazolidin-1-yl)-2-oxoethoxy]-6'-(thiophen-2-yl)-3,4'-bipyridine-3'-carbonitrile4a 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 obtained the carbonitrile 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, b with two aromatic aldehydes (3,4-dihydroxy benzaldehyde, 4-chlorobenzaldehyde) obtained Schiff bases 6a-d. Finally, the treatment of 3a, b with p-toluenesulfonyl chloride (Tosyl chloride) obtained the corresponding benzene sulfonohydrazide 7a, b. IR, 1HNMR, 13CNMR, MS, and elemental analysis confirmed the of the synthesized compounds. The anticancer activity of the compounds was investigated against breast cancer MCF-7 cell line. Compound6b demonstrated the strongest cytotoxic activity among the tested compounds and was more active than the reference drug 5-fluorouracil (5-FU). Thus, it was 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) was 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 of the synthesized compounds can be used as anticancer and anti-oxidant agents