Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b–c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17–22, 24, and 25) and angular compounds 14–16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23–25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC50 = 55 ± 4 and 85 ± 4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC50 = 0.091 μM, 24 IC50 = 0.191 μM, and 22 IC50 = 0.331 μM.Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure–activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.

Twelve new O-substituted-morpholino-naphtho-oxazines were synthesised, characterised and used for DNA-PK IC50 evaluation. The compound 18 is the most potent inhibitor. Docking of compound 18 within the binding pocket and SAR analyses of the poses support the observed activity.Figure optionsDownload as PowerPoint slide