Fluorinated pyrrolidines and piperidines incorporating tertiary benzenesulfonamide moieties are selective carbonic anhydrase II inhibitors

Figures & data

Table 1. Inhibition data of selected tertiary benzenesulfonamides and saccharins against isoforms hCA I, II, IX and XII.

			Ki (µM)*
Entry	Substrate		hCA I†	hCA II†	hCA IX‡	hCA XII‡
1¶	A		0.637	0.431	0.136	0.298
2¶	B		6.796	4.995	0.073	0.080
3§	C		0.073	>50	0.009	0.033
4||	D		>100	>100	0.451	>100
5#	E		>50	>50	>50	1.780
6#	F		>50	0.042	0.150	0.440

*Errors in the range of ±5% of the reported data from three different assays.

†Recombinant isoforms35–37.

‡Catalytic domain.

¶Values from Ref. 29.

§Values from Ref. 27.

||Values from Ref. 28.

#Values from Ref. 34.

Figure 1. (A) Binding of sulpiride to hCA II active site. Figures represent distances in Å. (B) Representation of the π-stacking between the phenyl ring of Phe131 and the N-methylpyrrolidone fragment of the drug.

Scheme 1. Synthesis of carbonic anhydrase inhibitors.

Table 2. Inhibition data of tertiary (fluorinated) benzenesulfonamides.

		Ki (µM)*
Entry	Compound	hCA I†	hCA II†	hCA IX‡	hCA XII‡
1	2	>100	>100	>100	>100
2	4	>100	0.5	>100	>100
3	5	>100	6.3	>100	>100
4	6	>100	7.3	>100	>100
5	7	>100	4.7	>100	>100
6	8	>100	3.9	>100	>100
7	9	>100	4.8	>100	>100
8	10	>100	3.4	>100	>100
9	11	>100	7.6	>100	>100
10	12	>100	6.3	>100	>100
11	13	>100	6.6	>100	>100
12	18	>100	11.0	>100	>100
13	19	>100	10.0	>100	>100

*Errors in the range of ±5% of the reported data from three different assays.

†Recombinant isoforms.

‡Catalytic domain.

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