Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

Figures & data

Figure 1. Potent CK2 inhibitor representing fused pyrimidinone family.

Figure 2. 2-Aminopyrimidinone scaffold.

Table 1. Chemical structures of building-blocks 2a–2u.

Table 2. Chemical structures and in vitro activities of compounds 3–15.

No	R1	R2	R3	X	Y	Z	R4	COOH position	IC50 (μM)
3	H	Me	–	C	C	N	H	4	>30
4	H	Me	–	C	C	N	6-Me	3	28
5	H	n-Pr	–	C	C	N	H	4	>30
6	–(CH2)4–		–	C	C	N	H	4	>30
7			–	C	C	N	H	3	24
8	Me	–	–	C	N	N	H	4	>30
9	Me	–	–	C	N	N	H	3	>30
10	–	–	H	N	N	C	H	4	>30
11	–	–	H	N	N	C	H	3	>30
12	–	–	H	N	N	C	6-Me	3	>30
13	–	–	Me	N	N	C	H	4	>30
14	–	–	Me	N	N	C	H	3	>30
15	–	–	Me	N	N	C	5-COOH	3	>30

Table 3. Chemical structures and in vitro activities of compounds 16–34.

No	R1	R2	R3	X	Y	Z	IC50 (μM)
16	H	H	–	C	C	N	>30
17	H	Me	–	C	C	N	20
18	H	Et	–	C	C	N	>30
19	H	n-Pr	–	C	C	N	>30
20	H	i-Pr	–	C	C	N	>30
21	H	n-Bu	–	C	C	N	9,5
22	Me	Me	–	C	C	N	17
23	–(CH2)4–		–	C	C	N	12
24			–	C	C	N	>30
25	H	4-MeO-Ph	–	C	C	N	1,1
26	Bn	Me	–	C	C	N	>30
27	4-Me-Bn	Me	–	C	C	N	>30
28	4-Cl-Bn	Me	–	C	C	N	>30
29			–	C	C	N	19
30	H	–	–	C	N	N	>30
31	Me	–	–	C	N	N	>30
32	t-Bu	–	–	C	N	N	>30
33	Ph	–	–	C	N	N	>30
34	–	–	Me	N	N	C	>30

Table 4. Chemical structures and in vitro activities of compounds 35–62.

No	R1	R2	R3	X	Y	Z	R4	OH position	IC50 (μM)
35	H	Me	–	C	C	N	H	4	23
36	H	Me	–	C	C	N	2-Me	4	>30
37	H	Me	–	C	C	N	H	3	>30
38	H	n-Pr	–	C	C	N	H	4	20
39	H	n-Pr	–	C	C	N	2-Me	4	>30
40	H	n-Pr	–	C	C	N	4-Me	3	>30
41	H	i-Pr	–	C	C	N	2-Me	4	>30
42	–(CH2)4–		–	C	C	N	2-Me	4	>30
43	H	Ph	–	C	C	N	2-Me	4	15
44			–	C	C	N	H	4	27
45			–	C	C	N	H	3	>30
46	H	–	–	C	N	N	H	4	>30
47	H	–	–	C	N	N	2-Me	4	>30
48	Me	–	–	C	N	N	H	4	>30
49	Me	–	–	C	N	N	2-Me	4	>30
50	Me	–	–	C	N	N	H	3	>30
51	Me	–	–	C	N	N	4-Me	3	>30
52	Ph	–	–	C	N	N	H	4	>30
53	Ph	–	–	C	N	N	H	3	>30
54	–	–	H	N	N	C	H	4	>30
55	–	–	H	N	N	C	H	3	>30
56	–	–	H	N	N	C	H	2	>30
57	–	–	H	N	N	C	4-Me	2	>30
58	–	–	H	N	N	C	5-Me	2	>30
59	–	–	H	N	N	C	5-Cl	2	>30
60	–	–	Me	N	N	C	H	4	>30
61	–	–	Me	N	N	C	2-Me	4	>30
62	–	–	Me	N	N	C	H	3	>30

Scheme 1. Combinatorial synthesis of 2-aminopyrimidinones and their 6-aza-analogs.

Figure 3. Complex “compound 7-CK2” obtained by the molecular docking method. Intermolecular H-bonds are shown as dotted lines.

Figure 4. Structure of the most active CK2 inhibitor obtained as a result of chemical optimization.

Figure 5. Calculated electronegative charges at the oxygen atoms for (a) 2-aminopyrimidin-4-one, (b) 2-amino-6-azapyrimidin-4-one and (c) 4-amino-6-azapyrimidin-2-one.

Figure 6. Complex of ligand 25 with CK2. Complex is obtained using a molecular docking method. Intermolecular H-bonds are shown as dotted lines.