Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold

Figures & data

Figure 1. Changes performed on the 2-(benzylsulfinyl)benzoic acid scaffold.

Scheme 1. Synthesis and structures of compounds 1–12 and 16–21.

Scheme 2. Synthesis and structures of compounds 13–15.

Scheme 3. Synthesis and structures of compounds 22–38.

Scheme 4. Synthesis of the amide 42, esters 44–46, hydroxyamide 51 and amides 47–49.

Scheme 5. Synthesis of amide 50 and ketones 52–53.

Table 1 Inhibitory activity of derivatives 1–53 and the reference drug (acetazolamide, AAZ) against the four selected hCA isoforms by a stopped-flow CO₂ hydrase assay²⁸.

Compound	Structure	Ki (μM)^a
		hCA I	hСа II	hСа IX	hСа XII
1		>100	>100	1.1	nt
2		>100	63.2	2.0	nt
3		>100	>100	16.4	nt
4		>100	>100	21.8	nt
(R)-5		>100	0.21	1.4	nt
(S)-5		>100	0.093	1.2	nt
6		>100	>100	2.3	nt
7		>100	75.2	15.0	nt
(R)-8		>100	84.9	15.3	nt
(S)-8		>100	65.7	20.0	nt
9		>100	>100	11.4	nt
10		>100	45.7	1.0	nt
(R)-11		>100	>100	1.4	nt
(S)-11		>100	>100	18.1	nt
12		>100	40.1	21.1	nt
13		>100	>100	>100	nt
14		>100	>100	>100	nt
15		>100	>100	>100	nt
16		>10	8.22	0.046	2.66
(R)-17		>100	52.2	2.2	nt
(S)-17		>100	51.9	1.9	nt
18		>10	2.67	>10	0.066
19		>100	86.3	19.8	nt
(R)-20		>100	52.2	22.8	nt
(S)-20		>100	38.9	24.6	nt
21		>100	68.2	25.8	nt
22		>100	>100	>100	nt
23		>100	>100	>100	nt
24		>100	>100	6.5	>100
25		>100	>100	34.5	>100
26		>100	>100	14.0	>100
27		>100	>100	16.7	>100
28		>100	>100	40.9	>100
29		>100	>100	22.7	>100
30		>100	90.9	>100	>100
31		>100	>100	38.2	>100
32		>100	>100	2.3	>100
33		>100	>100	2.5	>100
34		>100	>100	36.4	>100
35		>100	>100	13.5	>100
36		>100	>100	2.7	>100
37		>100	>100	27.3	>100
38		>100	>100	8.7	>100
39		>100	>100	>100	>100
40		>100	>100	>100	>100
41		>100	>100	>100	>100
42		>100	>100	>100	>100
43		>100	>100	>100	>100
44		>100	>100	>100	>100
45		>100	>100	>100	>100
46		>100	>100	>100	>100
47		>100	>100	>100	>100
48		>100	>100	>100	>100
49		>100	>100	>100	>100
50		>100	>100	>100	>100
51		>100	>100	>100	>100
52		>100	>100	>100	>100
53		>100	>100	>100	>100
AAZ		0.25	0.012	0.25	0.006

^a Mean from three different determinations (errors in the range of 5–10% of the reported values). nt: not tested.

Figure 2. The docked poses of compound 16 (purple) in the active site of hCA IX forming an interaction with either the active site Zn²⁺-ion (panel A) or the zinc-bound water molecule (panel B). Zn²⁺ is indicated with a turquoise sphere, the water molecule is indicated with a red sphere, hydrogen bonds and interactions to the Zn²⁺-ion are indicated in red dashed lines and arene-H interactions are indicated in yellow dashed lines.

Figure 3. The docked poses of compound 18 (turquoise, left) and compound 16 (purple, right) in the active site of hCA XII forming interactions with the active site Zn²⁺-ion. Zn²⁺ is indicated with a turquoise sphere, hydrogen bonds and interactions to the Zn²⁺-ion are indicated in red dashed lines.

Khalifah RG. The carbon dioxide hydration activity of carbonic anhydrase. I. Stop flow kinetic studies on the native human isoenzymes B and C. J Biol Chem 1971;246:2561–73.

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