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Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors

by Haiyan Sun 1,*,†, Linsheng Zhuo 2,†, Huan Dong 2, Wei Huang 2,* and Nengfang She 2,*
1
Nanjing Polytechnic Institute, Nanjing 210048, China
2
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Academic Editor: Giuseppe Manfroni
Molecules 2019, 24(24), 4461; https://doi.org/10.3390/molecules24244461
Received: 12 November 2019 / Revised: 30 November 2019 / Accepted: 3 December 2019 / Published: 5 December 2019
The 2,7-naphthyridone scaffold has been proposed as a novel lead structure of MET inhibitors by our group. To broaden the application of this new scaffold, a series of 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one derivatives were designed and synthesized. Preliminary biological screening resulted in the discovery of a new lead of c-Kit and VEGFR-2 kinase inhibitors. Compound 9k exhibited excellent c-Kit inhibitory activity, with an IC50 value of 8.5 nM, i.e., it is 38.8-fold more potent than compound 3 (IC50 of 329.6 nM). Moreover, the compounds 10l and 10r exhibited good VEGFR-2 inhibitory activity, with IC50 values of 56.5 and 31.7 nM, respectively, i.e., they are 5.0–8.8-fold more potent than compound 3 (IC50 of 279.9 nM). Molecular docking experiments provided further insight into the binding interactions of the new lead compounds with c-Kit and VEGFR-2 kinase. In this study, an 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one scaffold was identified as the new lead structure of c-Kit and VEGFR-2 kinase inhibitors. View Full-Text
Keywords: 2,7-naphthyridone; kinase inhibitor; c-Kit; VEGFR-2 2,7-naphthyridone; kinase inhibitor; c-Kit; VEGFR-2
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MDPI and ACS Style

Sun, H.; Zhuo, L.; Dong, H.; Huang, W.; She, N. Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors. Molecules 2019, 24, 4461.

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