Derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide as selective inhibitors of human carbonic anhydrases IX and XII over the cytosolic isoforms I and II

Figures & data

Figure 1. Structures of 1,2,3-benzoxathiazine-2,2-dioxide and its methyl derivative.

Table 1. Inhibition data of human CA isoforms hCA I, II, IX, XII with compounds 2a-j and 5a-j 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	5-Ome	>100000	>100000	75320	>100000
2b	6-Me	21020	456.8	72.1	42.0
2c	6-F	12360	228.7	53.4	15.7
2d	6-Cl	45690	634.1	49.1	29.6
2e	6-Br	>100000	5568	25.8	116.2
2f	7-Me	33210	788.2	48.0	34.8
2g	7-Ome	24890	558.6	63.4	22.9
2h	7-F	10450	284.0	59.7	19.3
2i	7-Cl	82050	1659	75.9	78.1
2j	7-Br	>100000	11450	99.8	152.9
5a	6-Ph	60590	936.4	28.5	390.4
5b	6-(4-F-C6H4)	24510	1529	22.6	53.7
5c	6-(4-Ome-C6H4)	70513	7118	30.4	10.5
5d	6-(3,4-Cl2-C6H3)	>100000	4527	30.8	130.7
5e	6-(4-CO2Et-C6H4)	19630	8254	93.6	12.2
5f	7-Ph	>100000	2364	7.0	230.6
5g	7-(4-F-C6H4)	>100000	5374	52.7	13.8
5h	7-(4-Ome-C6H4)	>100000	3165	57.3	180.4
5i	7-(3,4-Cl2-C6H3)	>100000	10020	42.1	15.6
5j	7-(4-CO2Et-C6H4)	>100000	6781	12.9	52.0
AAZ	–	250.0	12.5	25.0	5.7

^aMean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values); b. 15 min incubation.

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

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