Synthesis, characterization, and anticancer effect of novel Pyrazolopyranopyrimidines

Abstract

Two novel β-enaminonitrile derivatives 5a,b bearing pyrano[2,3-c]pyrazole moiety were synthesized using Multi Component Reaction (MCR) technique by reacting the ethyl benzoylacetate, phenylhydrazine, malononitrie, and various aldehydes in different conditions. A series of fused pyrazolopyrane derivatives (6–13) was constructed from a compound, 6-amino-4-(2-bromophenyl)-1,3-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5a), as a building block. The novel constructed compounds were analyzed by spectra data as FT-IR, 1H NMR, 13C NMR, mass spectra and elemental analysis. The cytotoxic activity of the prepared compounds was evaluated against three different cancer cell lines and the IC50 was determined for each compound, including MDA-MB-231 (a breast cancer cell line), A549 (a lung cancer cell line) and WI-38 (a lung fibroblast cell line). Ethyl-N-(4-(2-bromophenyl)-5-cyano-1,3-diphenyl-1,4-dihydropyrano[2,3-c]pyrazol-6-yl)formimidate (11) and 4-(2‑bromo phenyl)-1,3-diphenyl-1,4-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidin-5-amine (13) were among the most potent cytotoxic activity against the cancer cells with IC50 values of 18.03 ± 0.98 - 46.23 ± 3.45 µM. Compound (11) showed more potent topoisomerase inhibitory activity than the positive control etoposide as per the IC50 values, 35.05 µM ± 2.1 and 46.54 µM ± 2.8, respectively. The results of the molecular docking studies supported the in vitro assay results for the active compounds.