Design, synthesis, in-vitro antiproliferative activity and kinase profile of new picolinamide based 2-amido and ureido quinoline derivatives

• Published in: European journal of medicinal chemistry Vol. 101; pp. 754 - 768
• Main Authors: El-Damasy, Ashraf Kareem, Seo, Seon Hee, Cho, Nam-Chul, Kang, Soon Bang, Pae, Ae Nim, Kim, Key-Sun, Keum, Gyochang
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 28.08.2015; Elsevier
• Subjects: Amide; Amides - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; BRAFV600E; C-RAF; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Picolinamide; Picolinic Acids - chemistry; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Quinoline; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Structure-Activity Relationship; Urea; Urea; Picolinamide; BRAFV600E; Antiproliferative activity; Quinoline; C-RAF; Amide; ADVANCED HEPATOCELLULAR-CARCINOMA; OVARIAN-CANCER; SORAFENIB; RENAL-CELL CARCINOMA; MULTIKINASE INHIBITOR; BRAF(V600E); LUNG-CANCER; MELANOMA; CANCER-TREATMENT; GROWTH; B-RAF
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.07.025

New 2-amido and ureido quinoline derivatives substituted with 2-N-methylamido-pyridin-4-yloxy group at the 5-position of quinoline (18 final compounds) have been designed and synthesized as anticancer sorafenib congeners. Among the synthesized derivatives, fourteen compounds were selected for evaluation of their antiproliferative activity over a panel of 60 cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Four compounds, 9b–d and 9f showed promising mean growth inhibitions and thus were further tested at five-dose testing mode to determine their IC50 values. The data revealed that 2,4-difluorophenyl (9b) and 4-chloro-3-trifluoromethylphenyl (9d) urea compounds are the most active derivatives with significant efficacies and superior potencies than sorafenib in 36 and 12 cancer cell lines, respectively, belonging particularly to renal carcinoma cell (RCC), ovarian, and non small cell lung cancer (NSCL). Compound 9b and 9d were found to be six and two times more potent than sorafenib against A498 RCC line, with IC50 values of 0.42 μM and 1.36 μM, respectively. Accordingly, compound 9d was screened over a panel of 41 oncogenic kinases at a single dose concentration of 10 μM to profile its kinase inhibitory activity. Interestingly, the compound showed highly selective inhibitory activities ( 81.8% and 96.3%) against BRAFV600E and C-RAF kinases with IC50 values of 316 nM and 61 nM, respectively. In addition, molecular docking, cell cycle analysis, compliance to Lipinski's rule of five, and in silico toxicity assessment have been reported. [Display omitted] •Synthesis and in vitro antiproliferative activities of new picolinamide based 2-amido and ureido quinolines are reported.•Compounds 9b and 9d are the most potent derivatives with superior potencies than sorafenib over multiple cancer cell lines.•Against A498 renal cancer cell line, compounds 9b and 9d showed IC50 values of 0.418 and 1.36 μM, respectively.•Compound 9b is a C-RAF kinase inhibitor with IC50 value of 807 nM.•Compound 9d is a selective dual BRAFV600E and C-RAF inhibitor with IC50 values of 316 and 61 nM, respectively.