Abstract
Twelve new
O-substituted-morpholino-naphtho-oxazines were synthesised, characterised and used for DNA-PK IC
50 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.
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 IC
50
=
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 IC
50
=
0.091
μM,
24 IC
50
=
0.191
μM, and
22 IC
50
=
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.