2-((1H-Benzo[d]imidazol-2-yl)amino)benzo[d]thiazole-6-sulphonamides: a class of carbonic anhydrase II and VII-selective inhibitors

Figures & data

Figure 1. Chemical structures of acetazolamide, methazolamide, ethoxzolamide, brinzolamide, and dorzolamide.

Figure 2. (a) General structure of 4-(3-alkyl/benzyl-guanidino)benzenesulphonamides developed by our group as hCA VII selective inhibitors; (b) general structure of cyclic guanidine incorporated benzothiazole-6-sulphonamides discussed in the paper.

Scheme 1. Reagents and conditions: (i) KSCN (1 equiv.), 3.5 M HCl, 90 °C, 3 h; (ii) Br₂ (1.5 equiv.), CHCl₃, reflux, 4.5 h; (iii) DMF-DMA (1 equiv.), DMF, 0 °C, 2.5 h; (iv) CS₂ (1.7 equiv.), KOH (2.5 equiv.), MeI (2.5 equiv.), DMF/H₂O (3:1); (v) aliphatic diamine (10 equiv.), DMSO, 120 °C, 15 h; (vi) 1,2-phenylenediamine (8 equiv.), DMSO, 120 °C, 20 h; (vii) N₂H₄.H₂O, r.t., 1 h; (viii) CS₂ (4 equiv.), KOH (5 equiv.), MeI (5 equiv.), DMF/H₂O (3:1); (ix) aliphatic diamine (15 equiv.), DMSO, 120 °C, 15 h.

Table 1. Inhibition data of human CA isoforms CAI, II, IV and VII with benzothiazole-6-sulphonamide substituted five-membered (bi)cyclic guanidines 6, 7, 9 using acetazolamide (AAZ) as standard drug.

Compound	R^1	R^2	KI (nM)^a
			hCA I	hCA II	hCA IV	hCA VII
6a	–H		422.4	37.6	>100 000	56.3
6b	–H		568.5	48.1	>100 000	37.4
6c	–H		7590	65.6	>100 000	82.5
7a	–H		4927	84.0	>100 000	66.9
7b	–H		8102	375.0	>100 000	451.9
7c	–H		9533	577.6	>100 000	694.4
9a			>100 000	>100 000	>100 000	>100 000
9b			>100 000	>100 000	>100 000	>100 000
9c			>100 000	>100 000	>100 000	>100 000
9d			>100 000	>100 000	>100 000	>100 000
AAZ	–	–	250	12.5	74	2.5

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