Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2

Figures & data

Scheme 1. Synthesis of 3-quinoline carboxylic acids.

Scheme 2. Synthesis of phenyl substituted 3-quinoline carboxylic acids.

Scheme 3. Synthesis of 5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylic acid derivatives.

Figure 1. Schematic representation of the complex of compound 93 with active site of protein kinase CK2 (green line indicates amino acid residues involved in hydrophobic contacts; dotted lines indicate hydrogen bonds).

Table 1. Structure of 2-chloro- and 2-aminoquinoline-3-carboxylic acid derivatives and the data related to their in vitro screening.

Compounds	R1	R2	R3	R4	R5	IC50 (μM)
3a	Cl	H	H	–OCH3	H	>30
3b	Cl	H	–OCH3	H	H	6.1
3c	Cl	H	–OCH3	–OCH3	H	>30
3d	Cl	H	H	–OPh	H	>30
3e	Cl	H	Br	–OCH3	H	>30
3k	Cl	–CH = CH–CH = CH–		H	H	1.5
3l	Cl	H	H	–CH = CH–CH = CH–		>30
5a	NH2	H	H	–OCH3	H	>30
5b	NH2	H	–OCH3	H	H	1.2
5c	NH2	H	Br	H	H	0.7
5d	NH2	H	H	Br	H	>30
5e	NH2	H	H	–OPh	H	>30
5f	NH2	H	Br	–OCH3	H	18.2
5k	NH2	–CH = CH-CH = CH–		H	H	0.65

Table 2. Structure of 2-oxo-1,2-dihydroquinoline-3-carboxylic acid derivatives and the data related to their in vitro screening.

Compounds	R1	R2	R3	R4	R5	IC50 (μM)
4a	H	H	H	–OCH3	H	>30
4b	H	H	–OCH3	H	H	>30
4c	H	H	–OCH3	–OCH3	H	>30
4d	H	H	H	–OPh	H	>30
4k	H	–CH = CH–CH = CH–		H	H	6.8
4l	H	H	H	–CH = CH–CH = CH–		>30
4.1.a	H	H	H	Ph	H	5.8
4.1.b	H	H	Ph	H	H	13.7
4.1.c	H	H	H	4-MeO-Ph-	H	5.0
4.1.d	H	H	H	3-MeO-Ph-	H	2.6
4.1.e	H	H	H	4-Cl-Ph-	H	5.9
4.1.f	H	H	H	3-Cl-Ph-	H	5.6
4.1.j	H	H	H	3-CF3-Ph-	H	13
11	–(CH2)3–		H	H	H	>30
13	–(CH2)3–		H	Br	H	>30
14a	–(CH2)3–		H	Ph	H	11.2
14b	–(CH2)3–		H	3-Cl-Ph-	H	10

Table 3. Structure of tetrazolo[1,5-a]quinoline-4-carboxylic acid derivatives and the data related to their in vitro screening.

Compounds	R1	R2	R3	R4	IC50 (μM)
6a	H	H	–OCH3	H	>30
6b	H	–OCH3	H	H	0.8
6c	H	–OCH3	–OCH3	H	>30
6d	H	H	–OPh	H	>30
6e	H	Br	–OCH3	H	>30
6f	H	H	Br	H	>30
6j	H	Br	H	H	4.2
6k	–CH = CH–CH = CH–		H	H	1.0
6l	H	H	–CH = CH–CH = CH–		>30
6.1a	H	H	Ph	H	15.1
6.1b	H	H	3-MeO-Ph-	H	13.2
6.1c	H	H	3-Cl-Ph-	H	2.5

Figure 2. Compound 5k (violet) in ATP-binding site of CK2 (the complex was obtained with molecular docking, hydrogen bonds are indicated by green dotted lines).

Figure 3. Compounds 6а (green) and 6b (blue) in ATP-binding site of CK2 (the complex was obtained by molecular docking, hydrogen bonds are indicated by green dotted lines).

Figure 4. Compounds 6b (blue) and 6с (purple) in ATP-binding site of CK2 (the complex was obtained by molecular docking, hydrogen bonds are indicated by green dotted lines).

Figure 5. Compounds 4.1а (yellow) and 4.1b (pale gray) in ATP-binding site of CK2 (the complex was obtained by molecular docking, hydrogen bonds are indicated by green dotted lines).