CRCU

Chemical Research in Chinese Universities ›› 2022, Vol. 38 ›› Issue (4): 1073-1082.doi: 10.1007/s40242-022-1408-3

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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

Ghadah F. ALJOHANI1, Fatma A. A. EL-HAG2, Mohamed S. BEKHEIT3, Ewies F. EWIES4, May A. EL-MANAWATY5   

  1. 1. Chemistry Department, College of Science, Taibah University, P. O. Box 30002, Code 14177, Al-Madinah Al Munawarah, Saudi Arabia;
    2. Department of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt;
    3. Pesticide Chemistry Department, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt;
    4. Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt;
    5. Department of Pharmacognosy, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt
  • Received:2021-10-07 Revised:2022-01-04 Online:2022-08-01 Published:2022-03-17
  • Contact: Ghadah F. ALJOHANI;Fatma A.A. E-mail:gjohani@taibahu.edu.sa; EL-HAGfatmaabdaleem@yahoo.com
  • Supported by:
    This work was supported by the Fund of National Research Centre, Egypt.

Abstract: A library 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-1H-pyrazol-5(4H)-one and chlorooximes. The synthesized derivatives were elucidated and characterized based on their spectroscopic data, including infrared spectrometry(IR), 1H NMR, 13C 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 6d and 6e were the most active compounds on all cell lines. The spiro[pyrazole-4,5'-isoxazoline]-5-one derivatives 7a and 7c were active on the HepG2 liver cancer cell line. In comparison, compounds 7f and 7g 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.

Key words: Spiroisoxazoline, Pyrazole, Chlrooxime, 1,3-Dipolar cycloaddition, Antitumor, Molecular docking