S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors

Figures & data

Figure 1. Structures of AAZ, SLC-0111, A–C, and the designed quinazoline derivatives (2–20) as CAIs.

Scheme 1. Synthesis of the designed quinazoline derivatives (2–20).

Table 1. Inhibition data of hCA isoforms hCA I, II, IX and XII for sulphonamides using AAZ as standard drug.

Comps	R	R1	KI (nM)^a				Selectivity analysis
			hCA I	hCA II	hCA IX	hCA XII	hCA I/IX	hCA I/XII	hCA II/IX	hCA II/XII
1	–	–	31.5	0.62	–	0.59	–	53.12	–	1.05
2	COPh	H	592.7	140.8	40.7	13.0	15	46	3.5	11
3	CO(4-Br-Ph)	H	1447	174.7	75.2	69.6	19	21	2.3	2.5
4	CO(4-Cl-Ph)	H	758.7	186.6	8.0	10.8	95	70	23	17
5	CO(4-F-Ph)	H	399.5	95.4	16.5	9.1	24	44	5.8	10
6	CO(4-CH3-Ph)	H	471.0	116.2	25.1	85.1	19	5.5	4.6	1.4
7	CO(4-Br-Ph)	CH3	978.3	202.6	63.2	76.8	15	13	3.2	2.6
8	CONH2	H	114.5	25.4	34.5	2.4	3.3	48	0.7	11
9	CONHPh	H	459.7	69.7	27.3	38.4	17	12	2.6	1.8
10	CONH(4-Br-Ph)	H	697.1	119.3	64.9	61.0	11	11	1.8	2
11	CONH(4-Cl-Ph)	H	726.4	92.0	66.8	31.6	11	23	1.4	2.9
12	CONH(4-F-Ph)	H	548.6	87.6	12.7	8.7	43	63	6.9	10
13	CONH(4-CH3-Ph)	H	878.1	304.6	37.4	45.2	23	19	8.1	6.7
14	CONH(4-OCH3-Ph)	H	2567	266.1	84.0	49.1	31	52	3.2	5.4
15	CONH(4-OC2H5-Ph)	H	3654	684.2	35.9	59.7	102	61	19	11
16	CONH(4-COCH3-Ph)	H	1697	200.1	24.1	22.5	70	75	8.3	8.9
17	CONH(3,4,5-tri-OCH3-Ph)	H	2672	519.4	100.4	16.9	27	158	5.2	31
18	CONH(4-F-Bn)	H	2048	975.4	256.4	113.4	8	18	3.8	8.6
19	CONH(3,4-diOCH3-Bn)	H	5467	1099	145.1	97.3	38	56	7.6	11
20	CONH(4-Cl-Ph)	CH3	3628	75.4	18.6	66.7	195	54	4.1	1.1
AAZ	–		250.0	12.0	25.0	5.7	10	44	0.5	2.1

^a Mean from 3 different assays, obtained using a stopped flow technique (errors were in the range of ±5–10% of the reported values).

Figure 2. Docking modes of active compounds 17 and 20 in the binding pockets of CA isoenzyme IX (PDB 5FL4). Predicted binding mode of compounds 17 (2D and 3D in upper panel), and 20 (2D and 3D in lower panel) with the hCA-IX target.

Figure 3. Docking modes of the active compounds 17 and 20 in the binding pockets of CA isoenzyme XII (PDB 1JCZ). Predicted binding mode of compounds 17 (2D and 3D in upper panel) and 20 (2D and 3D in lower panel) with hCA-XII target.

Figure 4. Molecular orbital spatial distribution and localisation for the HOMO and LUMO of three representative compounds, 4 (left panel), 17 (middle panel), and 20 (right panel).