Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines

• Published in: European journal of medicinal chemistry 2012-11, Vol.57, p.85-101
• Main Authors: Ihmaid, Saleh K., Al-Rawi, Jasim M.A., Bradley, Christopher J., Angove, Michael J., Robertson, Murray N.
• Format: Article
• Language: English
• Subjects: 2-Amino-substituted-1,3-benzoxazines; Anti-platelet activity; Benzoxazines - chemical synthesis; Benzoxazines - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Collagen - pharmacology; Crystallography, X-Ray; DNA-Activated Protein Kinase - antagonists & inhibitors; DNA-Activated Protein Kinase - chemistry; DNA-PK; Homology modelling; Humans; Inhibitory Concentration 50; Medical sciences; Miscellaneous; Molecular Docking Simulation; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - chemistry; PI3K inhibition; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Protein Subunits - antagonists & inhibitors; Protein Subunits - chemistry; Structure-Activity Relationship; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.08.035

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a–g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs2CO3 to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a–i, 13a–c, and 15a–f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19–31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC50 of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a–b, 15a–b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC50 for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K. Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19–31 within the binding pocket and structure–activity relationships (SAR) analyses were performed with results agreeing well with observed activities. DNA-PK and PI3K inhibition data of 2-morpholino substituted-1,3-benzoxazines and 2-(N-substituted (pyridin-3-ylmethyl)amino)-substituted-1,3-benzoxazines compounds were measured and showed high to moderate activity. [Display omitted] ► Synthesis of novel 2-amino-substituted-1,3-benzoxazines. ► DNA-PK inhibition data for 2-amino-substituted-1,3-benzoxazines. ► 2-(Pyridin-3-ylmethyl)-1,3-benzoxazines showed significant DNA-PK inhibitio