Synthesis, crystal structure, DFT, molecular docking and antitumor activity of 4-(2-chlorobenzyl)-1-(5-fluoro-2-hydroxy-3-((4-methylpiperidin-1-yl)methyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

• Published in: Research on chemical intermediates Vol. 47; no. 9; pp. 3609 - 3627
• Main Authors: Zhou, Zhi-xu, Wu, Qing-mei, Huang, Zhu-yan, Yu, De-hou, Lu, Hong-guang
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.09.2021; Springer Nature; Springer Nature B.V
• Subjects: Absorption spectra; Acetonitrile; Anticancer properties; Catalysis; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Crystal structure; Infrared spectroscopy; Inorganic Chemistry; Molecular docking; Molecular orbitals; Molecular structure; NMR; Nuclear magnetic resonance; Physical Chemistry; Physical Sciences; Science & Technology; Single crystals; X-ray diffraction; DFT calculation; Antitumor activity; Vibrational property; Triazoloquinazolinone; Crystal structure; DESIGN; ALLOSTERIC INHIBITION
• ISSN: 0922-6168; 1568-5675
• DOI: 10.1007/s11164-021-04491-x

In this study, the compound 4-(2-chlorobenzyl)-1-(5-fluoro-2-hydroxy-3-((4-methylpiperidin -1-yl)methyl)phenyl)-[1,2,4]triazolo[4,3- a ]quinazolin-5(4 H )-one ( 1 ) was synthesized for the first time, and its structure was characterized by 1 H NMR, 13 C NMR, MS and FT-IR spectra. Single crystals of compound 1 were grown in acetonitrile and the structure was confirmed by X-ray diffraction. The DFT-optimized structure was consistent with that determined by X-ray diffraction. Geometrical parameter, molecular electrostatic potential and frontier molecular orbital analyses were performed using the DFT/B3LYP/6-311G (2d, p) method. The vibrational assignment was based on the characteristic vibrational absorption band of compound 1 . The theoretical and experimental 13 C NMR chemical shifts exhibited good correlation. Molecular docking suggests favorable interactions between compound 1 and SHP2 protein. The SHP2 enzyme inhibition rate of compound 1 was 12.40% at 10 μM. The antitumor activity of 1 was better than that of the reference compound in human hepatoma cells SMMC7721 (IC 50  = 757 µM) and human melanoma cells A375 (IC 50  = 70.19 µM). Graphic abstract