An Efficient One-pot Synthesis of Certain Stereoselective Spiro[pyrazole-4,5′-isoxazoline]-5-one Derivatives: In vitro Evaluation of Antitumor Activities, Molecular Docking and In silico ADME Predictions

Alibrary of novel spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives were designed and synthesized using a concise and efficient one-pot reaction protocol through 1,3-dipolar cycloaddition between 4-benzylidene-3-methyl-1-phenyl-1 H -pyrazol-5(4 H )-one and chlorooximes. The synthesized derivatives were elucidated and characterized based on their spectroscopic data, including infrared spectrometry(IR), 1 H NMR, 13 C NMR, and elemental and mass spectral analysis. The synthesized compounds were evaluated for their antitumor inhibition potency against four human cancer cell lines, including human prostatic adenocarcinoma (PC3), human colorectal carcinoma(HCT116), human liver hepatocellular carcinoma(HepG2) and breast adenocarcinoma (MCF7). The outcomes were compared with the standard reference drug Doxorubicin. Among the synthesized chlorooximes, compounds 6 d and 6 e were the most active compounds on all cell lines. The spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives 7 a and 7 c were active on the HepG2 liver cancer cell line. In comparison, compounds 7 f and 7 g were moderately active on the MCF7 cell line. The structure-activity relationship was explored for the synthesized compounds. Besides, in silico analysis of physicochemical, adsorption, distribution, metabolism, excretion and toxicity(ADMET) properties were done to determine the potential capacity of drug candidates. Molecular docking study onto the epidermal growth factor(EGF) tyrosine kinase receptor(3POZ) was done for the most active compounds to validate the reliability of in vitro anticancer screenings.