4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

Figures & data

Figure 1. Selected examples of the guanidine-containing sulfonamide CAIs.

Figure 2. General structure of 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides discussed in the paper.

Scheme 1. Reagents and conditions: (i) KSCN, aq. 3.5 M HCl, reflux, 3 h, 31%; (ii) MeI, DMF, 40 °C, 2.5 h, 70%; (iii) HNR¹R² (8 equiv.), DMSO, 130 °C, 2–6 h.

Table 1. Inhibition data of human CA isoforms I, II and VII using AAZ as standard drug.

Compound	R1	R2	Ki (nM)^a
			CA I	CA II	CA VII
7a		H	746.5	7.7	10.1
7b		H	698.7	17.7	25.1
7c		H	989.1	59.1	15.0
7d		H	781.7	1.6	60.7
7e		H	2988.8	3.2	44.9
7f		H	2932.2	0.3	0.9
7g		H	3163.0	0.07	0.4
7h		H	1319.0	9.6	1.1
7i		CH3	1137.7	0.08	0.7
7j			5845.5	0.6	3.2
7k		H	4183.3	6.9	8.7
7l		H	729.8	0.9	2.2
7m		H	930.3	0.4	0.2
7n		H	2154.0	0.06	0.08
7o			3676.8	0.1	0.06
AAZ	–	–	250.0	12.0	2.5

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

Table 2. Selectivity indexes for hCA VII over hCA I and II inhibition with compounds 7a–7o and acetazolamide as standard inhibitor.

	Selectivity index^a
Compound	hCA VII/hCA I	hCA VII/hCA II
7°	73.9	0.76
7b	27.8	0.70
7c	65.9	3.94
7d	12.8	0.02
7e	66.5	0.07
7f	3257	0.33
7g	7907	0.17
7h	1199	8.72
7i	1625	0.11
7j	1826	0.18
7k	480	0.79
7l	331	0.41
7m	4651	2.00
7n	26,925	0.75
7o	61,300	1.66
AAZ	100	4.80

^aCalculated as the ratio K_I(CA I or II)/K_I(CA VII).