Synthesis and inhibition potency of novel ureido benzenesulfonamides incorporating GABA as tumor-associated carbonic anhydrase IX and XII inhibitors

Figures & data

Chart 1. Structure of compounds A–D and the clinically used sulfonamide acetazolamide AAZ.

Scheme 1. Preparation of sulfonamides 6–20 by reaction of 4-amino-N-(4-sulfamoyl-benzyl)-butyramide hydrochloride (n = 1) (4) or 4-amino-N-[2-(4-sulfamoyl-phenyl)-ethyl]-butyramide hydrochloride (n = 2) (5) with arylisocyanates A1–8 (R-NCO) in presence of diisopropylethylamine (DIPEA), in acetonitrile (dry).

Table 1. Isocyanates used for the preparation of compounds 6–20.

Table 2. Inhibition data of human CA isoforms hCA I, II, IX and XII with ureido-sulfonamides 6–20 reported here and the standard sulfonamide inhibitor acetazolamide (AAZ) by a stopped flow CO₂ hydrase assay26. .

			KI (nM)*
Compound	n	R	hCA I	hCA II	hCA IX	hCA XII
6†	1	C6H5	373.4	6.01	46	37.4
7†	2	C6H5	32.2	4.87	41.6	6.2
8†	1	C6H5CH2	359	6.1	456.6	58.3
9†	2	C6H5CH2	214.4	41	106.4	50.7
10†	1	C6H5(CH2)2	52.6	6.9	300.9	43.5
11†	2	4-NO2C6H4	41.8	6.8	138.7	43
12	2	C6H5(CH2)2	286.1	93.4	5.5	10.4
13	1	C5H9	254.1	70.5	42.2	10
14	2	C5H9	240.4	60	45.3	28.5
15	1	4-C2H5Ph	247.9	71.4	289	5.4
16	2	4-C2H5Ph	232.4	57.5	53.4	6
17	1	4-CH3PhCH2	203.2	73.5	50.2	4.9
18	2	4-CH3PhCH2	192.7	64.3	328.2	6.2
19	1	4-IC6H4	217.8	6.8	370.4	6.1
20	2	4-IC6H4	213.4	6.3	46.7	5.1
AAZ	–	–	250	12	25	5.7
A‡	–	C6H5	760	3730	575	67.3
B‡	–	C6H5CH2	92	2200	41.4	49.5
C‡	–	C5H9	470	226	7.3	7.0
D‡	–	4-IC6H4	5500	2634	24.5	4.3

†From reference 24; ‡From reference 23; *Mean from three different assay, by a stopped flow technique (errors were in the range of ±5–10% of the reported values).

Figure 1. Graphical comparison of inhibition constants of the new ureido-sulfonamides 6–20 reported here and the standard drug AAZ against hCA I, II, IX and XII.

Figure 2. Graphical comparison of inhibition constants of the ureido-sulfonamides A–D previously reported and the standard drug AAZ against hCA I, II, IX and XII.

Khalifah RG. The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J Biol Chem 1971;246:2561–73

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