Design, synthesis and evaluation of 2-phenylisothiazolidin-3-one-1,1-dioxides as a new class of human protein kinase CK2 inhibitors

Figures & data

Figure 1. Compound 1 in ATP-binding site of CK2 (2D-model).

Scheme 1. Combinatorial synthesis of (1,1-dioxido-3-oxoisothiazolidin-2-yl)benzamides.

Table 1. Compounds 21–39 with para-position of the thiazolidine cycle relative to carboxylamide fragment and the data related to their in vitro screening.

No.	R1	R2	R3	R4	R5	R6	IC50 (μM)	Molecular formula
21	H	H	H	COOH	H	H	1.8	C17H14N2O6S
22	H	H	H	COOH	OH	H	8	C17H14N2O7S
23	H	H	H	OH	COOH	H	14	C17H14N2O7S
24	Me	H	H	COOH	H	H	3.1	C18H16N2O6S
25	Me	H	H	COOH	OH	H	>30	C18H16N2O7S
26	Me	H	H	COOH	H	OH	16	C18H16N2O7S
27	Me	H	H	OH	COOH	H	19.5	C18H16N2O7S
28	Me	Me	H	COOH	H	H	8	C19H18N2O6S
29	Me	Me	H	COOH	OH	H	>30	C19H18N2O7S
30	Me	Me	H	OH	COOH	H	>30	C19H18N2O7S
31	H	H	Cl	COOH	H	H	1.5	C17H13ClN2O6S
32	H	H	Cl	COOH	OH	H	9	C17H13ClN2O7S
33	H	H	Cl	OH	COOH	H	3.0	C17H13ClN2O7S
34	H	H	Cl	H	COOH	H	>30	C17H13ClN2O6S
35	Me	H	Cl	COOH	H	H	3.6	C18H15ClN2O6S
36	Me	H	Cl	COOH	OH	H	6	C18H15ClN2O7S
37	Me	H	Cl	COOH	H	OH	3.7	C18H15ClN2O7S
38	Me	H	Cl	OH	COOH	H	3.5	C18H15ClN2O7S
39	Me	H	Cl	COOMe	OH	H	>30	C19H17ClN2O7S

Table 2. Compounds 40–42 containing the fragments of amino acids with aliphatic chains and the data related to their in vitro screening.

No.	n	IC50 (μM)	Molecular formula
40	1	>30	C13H14N2O6S
41	2	>30	C14H16N2O6S
42	3	>30	C15H18N2O6S

Table 3. Residual activity of protein kinases (%) with added inhibitor (10 μM) and ATP (100 μM).

No.	CK2	Aurora А	FGFR1	ASK1
Compound 31	23%	106%	96%	112%

Figure 2. Compound 1 (a) and compound 35 (b) bound to the active site of the CK2 catalytic subunit. The complex has been obtained with molecular docking. Intermolecular hydrogen bonds are shown as dotted lines.

Figure 3. Compound 31 (a) and compound 34 (b) bound to the active site of the CK2 catalytic subunit. The complex has been obtained with molecular docking. Intermolecular hydrogen bonds are shown as dotted lines.