Spectroscopic, DFT, molecular docking and anti-cancer studies of regioselectively designed 1-aryl-indenopyrazoles

Abstract

L-Proline catalyzed condensation of 1-indanones with DMF-DMA (N,N-dimethylformamide dimethyl acetal) resulted in (Z)-2-((dimethylamino)methylene-2,3-dihydro-1H-inden-1-ones 2 instead of their E-isomers 3, which is further regioselectively transformed into 1-aryl-2,4-dihydroindeno[1,2-c]pyrazole 4 rather than 2-aryl-2,4-dihydroindeno[1,2-c]pyrazoles 5 by condensing with aryl hydrazines. Spectrochemical characterizations and single crystal X-ray diffraction studies were used to resolve syntactic ambiguity between the possible geometric isomers of enaminones (E & Z) and regioisomers 1H-indenopyrazole and 2H-indenopyrazoles. The experimental findings were correlated with computed values and have shown good correlation with the proposed structures. The synthesized indenopyrazoles 4a–f were tested for their ability to inhibit the proliferation of A549 human lung cancer cell lines, and the compound 4b have showed IC50 value 13.77 µM comparable to the reference medication erlotinib (10.26 µM). The complete cell cycle analysis have revealed the accumulation of mitotic cells in G1/S phase. The flow cytometric analysis also revealed the increase in apoptotic cells indicating tumor suppression by the derivative 4b. To get insight into the interactions of the compound and EGFR tyrosine kinase protein molecular docking was performed. Also, pharmacokinetic profiling revealed about the oral compatibility of the synthesized compounds.