Novel Pyrazoloquinolin-2-ones: Design,synthesis, docking studies,and biological evaluation as antiproliferative EGFR-TK inhibitors |
| |
Affiliation: | 1. Department of Chemistry, Faculty of Science, Minia University, Minia, Egypt;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt;3. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt;4. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt;5. Program in Chemistry, Florida Institute of Technology, Melbourne, FL, United States;6. Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany;7. Institute of Biological and Chemical Systems (IBCS-FMS), Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany |
| |
Abstract: | Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50 = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds’ activity. |
| |
Keywords: | Quinolin-2-one Pyrazole NCI Antiproliferative Molecular docking EGFR-TK Inhibitors |
本文献已被 ScienceDirect 等数据库收录! |
|