Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies

• Published in: Bioorganic & medicinal chemistry 2019-05, Vol.27 (10), p.2083-2089
• Main Authors: Zeinyeh, Wael, Esvan, Yannick J., Josselin, Béatrice, Baratte, Blandine, Bach, Stéphane, Nauton, Lionel, Théry, Vincent, Ruchaud, Sandrine, Anizon, Fabrice, Giraud, Francis, Moreau, Pascale
• Format: Article
• Language: English
• Subjects: Chemical Sciences; CLK1; Cyclin-Dependent Kinase 5 - antagonists & inhibitors; Cyclin-Dependent Kinase 5 - metabolism; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Humans; Molecular Docking Simulation; Organic chemistry; Protein kinase inhibition; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyridines - chemistry; Pyrido[3,4-g]quinazolines; Pyrido[4,3-h]quinazoline; Quinazolines - chemistry; Quinazolines - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.04.005

[Display omitted] •2-Alkylaminomethylamino substituted 10-nitropyrido[3,4-g]quinazolines were prepared.•First synthesis of pyrido[4,3-h]quinazoline-2-amine 11 was described.•Most active compound 4 exhibited nanomolar potencies toward CLK1.•A putative binding mode of 11 within CLK1-ATP binding pocket was determined. New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.