1,2,3-Benzoxathiazine-2,2-dioxides – effective inhibitors of human carbonic anhydrases

Figures & data

Figure 1. Structure of CA inhibitors.

Table 1. Inhibition data of human CA isoforms hCA I, II, IX, XII with compounds JI reported here and the standard inhibitor acetazolamide (AAZ) by a stopped flow CO₂ hydrase assay.

cmp	R	KI (nM)^a,b
		hCA I	hCA II	hCA IX	hCA XII
2a	6-Me	25690	115.6	72.0	98.2
2b	6-MeO	>100,000	168.5	62.8	75.1
2c	6-F	3324	71.8	58.3	120.8
2d	6-Br	>100,000	8315	27.4	186.4
2e	7-Me	657.1	78.9	53.1	58.0
2f	7-MeO	986.5	55.2	39.7	83.1
2g	7-F	447.6	86.7	55.4	111.7
2h	7-Br	46520	45.1	22.3	70.1
2i	8-MeO	1523	39.0	73.6	63.4
2j	8-F	465.8	89.2	65.9	34.7
2k	8-Br	788.1	112.8	41.8	86.3
5a	5-Ph	>100,000	9865	5247	12630
5b	5-(4-F-C6H4)	>100,000	14,830	4139	7465
5c	5-(4-OMe-C6H4)	>100,000	36,870	10,870	17,960
5d	5-(3,4-Cl2-C6H3)	>100,000	>100,000	>100,000	45,320
5e	5-(4-CO2Et-C6H4)	>100,000	>100,000	>100,000	>100,000
5f	7-Ph	5682	7.7	28.6	78.3
5g	7-(4-F-C6H4)	15,230	2.1	69.8	8.2
5h	7-(4-OMe-C6H4)	30,310	14.3	45.2	36.4
5i	7-(4-CO2Et-C6H4)	356.3	0.8	38.0	90.5
5j	8-Ph	668.4	0.5	49.1	61.8
5k	8-(4-F-C6H4)	1852	5.6	32.3	12.4
5l	8-(4-OMe-C6H4)	4259	12.3	62.7	7.3
5m	8-(3,4-Cl2-C6H3)	6708	9.5	40.8	4.8
AAZ	–	250.0	12.5	25.0	5.7

^aMean from three different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values); ^b15 min incubation.

Scheme 1. Reagents and conditions: (i) HCOOH, 0 °C, 15 min, then RT, 45 min; (ii) ClSO₂NH₂, DMA, RT, 24–72 h.

Scheme 2. Reagents and conditions: (i) K₂CO₃, Pd(PPh₃)₄, toluene/H₂O (5:1), 90 °C, 24–48 h; (ii) ClSO₂NH₂, DMA, RT, 24–48 h.