Synthesis and biological evaluation of histamine Schiff bases as carbonic anhydrase I, II, IV, VII, and IX activators

Figures & data

Figure 1. Superimposed ribbon diagram (a) and active site detail (b) of the CA II isozyme (PDB codes 1AVN²² and 3HS4³⁷) with the activator histamine and the well known CAI 5-acetamido-1,3,4-thiadiazole-2-sulphonamide (acetazolamide, AZM). Acetazolamide is coordinated to the zinc ion being bound deep within the active site, whereas histamine does not interact with the metal ion and is bound at the entrance of the cavity. The zinc ion (magenta) is coordinated by three histidine residues (His 94, His 96, and His 119, in orange) and some key amino acids on active site were shown (in red). The proton shuttle residue His 64 is also shown (in cyan). Figure made using PyMol (DeLano Scientific).

Scheme 1. General synthetic route for the synthesis of histamine Schiff bases H(1–20).

Table 1. In vitro hCA I, hCA II, hCA IV, hCA VII, and hCA IX activation data with histamine Schiff bases H(1–20) by a stopped-flow CO₂ hydrase assay.

	KA (µM)^a
Comp.H	hCA I	hCA II	hCA IV	hCA VII	hCA IX
1	18.4	54.2	47.1	20.6	31.4
2	1.60	21.7	0.0018	21.9	7.81
3	0.85	36.8	1.24	0.81	15.8
4	0.24	37.9	1.03	0.052	39.9
5	1.17	34.2	2.15	0.061	26.4
6	1.02	25.8	1.70	0.012	41.7
7	0.94	14.5	1.86	0.038	20.5
8	0.80	8.62	0.93	0.006	31.8
9	2.83	9.27	0.96	0.012	30.0
10	4.14	10.4	1.51	0.007	62.6
11	10.7	21.9	36.8	12.6	65.4
12	8.52	11.2	18.9	24.6	47.9
13	11.2	24.3	25.7	7.13	48.1
14	12.7	21.2	33.5	11.4	51.2
15	20.4	45.2	29.1	8.23	49.0
16	24.3	30.7	20.0	7.16	47.9
17	14.1	58.9	24.1	6.26	31.6
18	9.64	63.4	28.3	9.51	47.9
19	17.8	44.5	29.0	8.44	58.2
20	10.4	41.8	30.5	0.78	57.6
HST	2.10	125	4.03	37.6	35.2

Histamine (HST) has been used as standard activator⁴².

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

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