Carbonic Anhydrases inhibitory effects of new benzenesulfonamides synthesized by using superacid chemistry

Figures & data

Table 1.  Inhibition data of chlorthalidone 1, indapamide 2 and furosemide 3 against isoforms hCA I, II, IX and XII.

Compound	Ki^a (µm)
	hCA I^b	hCA II^b	hCA IX^c	hCA XII^c
1	348	138	23	4.5
2	51,900	2 520	36	10
3	62	65	420	261

^aErrors in the range of ± 5% of the reported data from three different assay.

^bRecombinant isoforms^16,17.

^cCatalytic domain, recombinant enzymes^16,17.

Figure 1.  Comparison of interactions in which the thiazide/high-celling diuretics chlorthalidone 1 (A), indapamide 2 (B) and furosemide 3 (C) participate when bound to the hCA II active site, as observed in the corresponding X-ray crystal structures (PDB files 3F4X, 3BL1 and 1Z9Y).

Scheme 1.  Synthesis of benzofuzed sultams A and β-fluorinated benzenesulfonamides B in superacid HF/SbF₅. Condition A: 10 min, −20°C, substrate concentration c = 0.16 mol·L⁻¹, % mol SbF₅ = 13.6; Condition B: 10 min, −20°C, substrate concentration c = 0.33 mol·L⁻¹, % mol SbF₅ = 3.8.

Scheme 2.  Synthesis of 4-aminobenzofuzed sultams 4, 5, 6 and 9. (a) HF/SbF₅ (% mol SbF₅ = 3.8), −20°C, 10 min, 42%. (b) CH₃I, K₂CO₃, DMF, rt, 12 h, >95% (c) CuI, L-proline, octylamine, K₃PO₄, DMSO, 90°C, 24 h, 62%. (d) HF/SbF₅ (% mol SbF₅ = 13.6), −20°C, 10 min, 62%.(e) CuI, L-proline, 2-aminobutanol, Cs₂CO₃, DMSO, 90°C, 24 h, 70%. (f) CuI, L-proline, aq. NH₃, K₃PO₄, DMSO, 90°C, 24 h, 81%. (g) allylbromide, K₂CO₃, DMF, rt, 12 h, 83%. (h) CuI, L-proline, morpholine, K₃PO₄, DMSO, 90°C, 24 h, 70%. (i) HF/SbF₅ (% mol SbF₅ = 3.8), −20°C, 10 min, 69%.

Table 2.  hCA I and II inhibition data with sulfonamides A1–A10, by the CO₂ hydrase method¹⁵.

Compound	Ki^a (µm)
	hCA I^b	hCA II^b
A1	20	21
A2	23	85
A3	18	21
A4	34	38
A5	3.2	4.4
A6	9	8.6
A7	3.4	9.8
A8	51	24
A9	30	8.5
A10	39	9.5

^aErrors in the range of ± 5% of the reported data from three different assay.

^bRecombinant isoforms^16,17.

Table 3.  CA inhibition data with β-fluorinated derivatives B1–B18 and 4-aminobenzenesulfonamides 4–6, 9 and SA as standard inhibitor, against isozymes I, II, IX and XII, by a stopped-flow CO₂ hydrase assay.

Compound	Ki^a (µm)
	hCA I^b	hCA II^b	hCA IX^c	hCA XII^c
B1	4.4	4.2	3.9	3.6
B2	4.6	2.2	4.2	4.1
B3	3.3	3.9	4.8	3.4
B4	4.2	4.4	4.3	3.2
B5	4.4	3.3	3.4	2.5
B6	3.1	4.5	3.3	3.0
B7	4.6	4.5	3.9	3.1
B8	4.8	4.6	4.4	1.1
B9	4.5	2.4	2.2	4.2
B10	4.8	4.1	4.6	1.4
B11	4.7	4.3	4.9	1.1
B12	4.5	4.4	3.8	4.1
B13	4.8	2.7	5.7	4.3
B14	4.5	4.3	3.0	4.6
B15	4.2	3.0	2.1	4.0
B16	4.6	2.1	2.9	4.6
B17	4.6	2.3	2.7	3.8
B18	4.8	2.0	2.5	4.5
4	>500^d	>500^d	ND	ND
5	>500^d	>500^d	ND	ND
6	0.637	0.431	0.136	0.298
9	>500^d	>500^d	ND	ND
SA	25	0.24	0.294	0.037

^aErrors in the range of ± 5% of the reported data from three different assay.

^bRecombinant isoforms^16,17.

^cCatalytic domain

^dNot active.

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