Synthesis and carbonic anhydrase activating properties of a series of 2-amino-imidazolines structurally related to clonidine¹

Figures & data

Chart 1. Chemical structure of CA activators.

Table 1. Activation constants of Clonidine (CLO) and histamine (HST) on selected human CA isoforms, measured by means of a stopped-flow, CO₂ hydrase assay.^a

Compound	hCA KA (µM)
	I	II	IV	VA	VII	IX	XII	XIII
CLO	73.6	>200	132	42.6	8.4	54.1	126	7.8
HST^b	2.1	125	25.3	0.01	37.5	35.1	27.9	4.6

^aErrors (data not shown) are in the range of ±5–10% of the reported values from three different assays.

^bFrom Ref. [4].

Table 2. Synthetic details for the preparation of compounds 2–20 (see general formula in Scheme 1) starting from 1a (R₁ = H) or 1 b (R₁ = Me) and amines R₂R₃NH.

N	Starting material	R2	R3	Solvent	Reaction time (h)^a	Yields (%)^b
2	1a	H	–CH2Ph	THF	7	94
3	1a	H	–(CH2)2Ph	THF	16	90
(S)-4	1a	H	(S)–CH(Me)Ph	Amine^c	2	36^d
(R)-4	1a	H	(R)–CH(Me)Ph	Amine^c	2	74^d
5	1a	H	–(CH2)3Ph	THF	3	88
6	1a	Me	–CH2Ph	THF	22	32^d
7	1a	Me	–(CH2)2Ph	THF	2	88
8	1b	H	–(CH2)2Ph	Amine^c	2	86
9	1b	Me	–(CH2)2Ph	Amine^c	2	97
10	1b	Me	–CH2Ph	Amine^c	3	70^d
11	1b	H	–CH2Ph	Amine^c	2	81
12	1b	H	–(CH2)3Ph	Amine^c	2	45^d
13	1b	H	–CH2C6H4Cl(4)	THF	16	97
14	1b	H	–CH2C6H4OCH3(4)	THF	4	89^d
15	1b	H	–CH2C6H4F(4)	Amine^c	6	89
16	1b	H	–CH2C6H4Cl(3)	Amine^c	6	88^d
17	1b	H	–CH2C6H4OCH3(3)	Amine^c	24	92
18	1b	H	–CH2C6H4 F(3)	Amine^c	16	87
19	1a	H	–(CH2)2NHCH2Ph	Amine^c	3	56^d
20	1b	H	–(CH2)2NHCH2Ph	Amine^c	4	57^d

^a Heating at 70 °C; all amines were commercially available.

^b Unless otherwise stated, yields are given after trituration with diethyl ether.

^c The amine was used in excess (5 eq).

^d After chromatographic separation.

Scheme 1. Synthesis of compounds 2-20.

Scheme 2. Synthesis of compounds 22 and 23.

Table 3. Activation constant (K_A) of the synthesised compounds and Clonidine (CLO) for human I, II, VA, VII and XIII Carbonic Anhydrase isoforms.

N	R1	X	R2	KA (μM)^b
				hCA I	hCA II	hCA VA	hCA VII	hCA XIII
1a	H	S	–CH3	9.61	>150	38.3	41.9	>100
2	H	NH	–CH2Ph	4.18	>150	45.7	35.2	>100
3	H	NH	–(CH2)2Ph	>150	>150	16.7	18.9	>100
S-4	H	NH	(S)–CH(Me)Ph	>150	>150	12.4	31.5	>100
R-4	H	NH	(R)–CH(Me)Ph	>150	>150	4.92	24.2	>100
5	H	NH	–(CH2)3Ph	36.7	>100	9.9	11.4	24.3
6	H	NMe	–CH2Ph	>150	>150	40.5	11.0	>100
7	H	NMe	–(CH2)2Ph	68.6	>100	14.9	2.4	6.5
8	CH3	NH	–(CH2)2Ph	95.4	>100	14.6	16.2	31.0
9	CH3	NMe	–(CH2)2Ph	20.2	>100	14.9	2.6	36.9
10	CH3	NMe	–CH2Ph	30.2	>100	0.9	6.5	17.4
11	CH3	NH	–CH2Ph	16.9	>100	3.7	0.9	19.1
12	CH3	NH	–(CH2)3Ph	10.9	>100	17.2	3.1	10.9
13	CH3	NH	–CH2C6H4Cl(4)	17.7	>100	10.5	22.7	22.9
14	CH3	NH	–CH2C6H4OCH3(4)	37.6	>100	15.3	30.2	19.3
15	CH3	NH	–CH2C6H4F(4)	59.7	>100	9.3	17.4	24.4
16	CH3	NH	–CH2C6H4Cl(3)	99.2	>100	10.4	24.0	37.0
17	CH3	NH	–CH2C6H4OCH3(3)	>100	>100	13.1	29.4	14.7
18	CH3	NH	–CH2C6H4 F(3)	>100	>100	14.9	19.4	23.3
19	H	NH	–(CH2)2NHCH2Ph	>100	>100	11.0	41.7	20.1
20	CH3	NH	–(CH2)2NHCH2Ph	>100	>100	11.9	29.0	16.3
21	H	NH	–CH2CH2NH2	3.87	>150	31.2	91.6	>100
22	H	NH	–Ph	>150	>150	52.7	32.6	>100
23	COCH3	S	–CH3	12.7	>150	15.0	30.9	>100
24	H	S	–CH2Ph	>150	>150	11.1	46.7	>100
CLO	H	NH	(2,6-dichloro)Ph	76.3	>200	42.6	8.4	7.8

^a All compounds have been tested as HI salts, with the exception of 21 (oxalate), 22 and 23 (free bases), 24 (HBr), and CLO (HCl).

^b Mean from 3 different determinations (errors in the range of 5–10% of the reported values, data not shown).

Supuran CT. Carbonic anhydrase activators. Future Med Chem 2018;10:561–73.

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