Design and synthesis of novel benzo[d]oxazol-2(3H)-one derivatives bearing 7-substituted-4-enthoxyquinoline moieties as c-Met kinase inhibitors
- Eur J Med Chem. 2016 Jun 10:115:191-200. doi: 10.1016/j.ejmech.2016.03.027.
- 1. State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
- 2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China.
- 3. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China. Electronic address: [email protected].
- 4. State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: [email protected].
Analysis of the results of studies of docking 1 and 7a with c-Met kinase led to the identification of benzo[d]oxazol-2(3H)-one-quinolone derivatives as potential inhibitors of this enzyme. A molecular hybrid strategy, using a 4-ethoxy-7-substituted-quinoline core and a benzo[d]oxazol-2(3H)-one scaffold, was employed to design members of this family for study as inhibitors of the kinase and proliferation of EBC-1 cells. Most of the substances were found to display good to excellent c-Met kinase inhibitory activities. The results of a structure-activity relationship (SAR) study led to the discovery of benzo[d]oxazol-2(3H)-one-quinolone 13, which has IC50 values of 1 nM against c-Met kinase and 5 nM against proliferation of the EBC-1 cell line.