Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation

Figures & data

Figure 1. Structures of some CAIs, and the target benzofuran-based sulphonamides 4a, b, 5a, b, 9b–d and 10a–d.

Scheme 1. Reagent and conditions: (i) Glacial Acetic acid, reflux 4 h.

Scheme 2. Reagent and conditions: (i) Br₂/Acetic Acid, Stirring at r.t 4 h; (ii) Abs.Ethanol, reflux 4 h; (iii) Ethanol/Acetic acid, reflux 4 h.

Table 1. Inhibition data of human CA isoforms hCA I, II, IX and XII for the target sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d), using (AAZ) as a standard drug.

Compound	R	R1	KI (nM)*
			hCA I	hCA II	hCA IX	hCA XII
4a	H	–	162.8	12.3	33.3	26.9
4b	Br	–	92.7	73.5	48.4	38.8
5a	H	–	37.4	33.6	60.4	10.1
5b	Br	–	63.9	44.2	27.7	32.5
9a	H	CH3	1292	643.7	32.8	49.7
9b	Br	H	2159	888.2	44.6	33.4
9c	Br	CH3	2503	571.1	10.0	16.7
10a	H	H	4625	353.9	76.6	71.8
10b	H	CH3	3921	228.5	51.1	38.9
10c	Br	H	1822	438.8	85.4	66.8
10d	Br	CH3	827.6	727.1	97.5	27.5
AAZ	–	–	250.0	12.0	25.0	5.7

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

Table 2. Selectivity ratios for the inhibition of hCA IX and XII over hCA I and II for targeted compounds 4a, b, 5a, b, 9a–c and 10a–d.

Compound	I/IX	II/IX	I/XII	II/XII
4a	4.9	0.4	6.1	0.5
4b	1.9	1.5	2.4	1.9
5a	0.6	0.6	3.7	3.3
5b	2.3	1.6	2.0	1.4
9a	39.4	19.6	26.0	13.0
9b	48.4	19.9	64.6	26.6
9c	250.3	57.1	149.9	34.2
10a	60.4	4.6	64.4	4.9
10b	76.7	4.5	100.8	5.9
10c	21.3	5.1	27.3	6.6
10d	8.5	7.5	30.1	26.4
AAZ	10.0	0.5	43.9	2.2

Figure 2. The most susceptible NCI cancer cell lines towards the impact of target sulphonamides 5b and 10b according to the GI%.