Investigation of piperazines as human carbonic anhydrase I, II, IV and VII activators

Figures & data

Figure 1. Complex of hCA II (green, ribbon diagram, Zn(II) ion as violet sphere) with L-adrenaline, in magenta, PDB file 2HKK¹⁴ and d-Trp, in yellow, PDB file 3EFI^13b in the activator binding sites A and B, respectively. His64, in red, is shown both in its “in” and “out” conformations. The two structures were superimposed.

Figure 2. 4-Aminoethyl-piperazine. A: histamine; B: piperazine; C: used as leads for the CAAs investigated in this paper.

Figure 3. Piperazines 1–24 included in the CA activation study. For the meaning of R₁ and R₂ see Table 1.

Table 1. CA activation of isoforms hCA I, II, and VII (cytosolic) and IV (membrane-associated) with compounds 1-24, by a stopped-flow CO₂ hydrase assay²¹.

				KAa (µM)
Compound	Structure	R1	R2	hCA I	hCA II	hCA IV	hCA VII
A^b	I	CH2CH2NH2	–	7.41	2.30	24.9	32.5
B^b	–	–	–	2.10	125.0	25.3	37.5
C	I	H	–	>150	>150	>150	>150
1	I	Phenyl	–	>150	74.9	>150	121.3
2	I	4-F-phenyl	–	88.2	38.7	>150	47.8
3	I	4-Cl-phenyl	–	104.0	110.3	>150	126.1
4	I	4-MeO-phenyl	–	48.6	50.1	>150	80.4
5	I	4-COMe-phenyl	–	83.7	97.9	>150	>150
6	I	3-Cl-phenyl	–	95.2	82.7	>150	104.0
7	I	3-MeO-phenyl	–	119.2	80.1	>150	>150
8	I	3-CF3-phenyl	–	110.2	77.6	>150	114.5
9	I	2-Pyridyl	–	131.0	75.2	>150	95.2
10	I	Methyl	–	>150	78.4	>150	97.0
11	I	Benzyl	–	>150	85.3	>150	98.4
12	I	Acetyl	–	127.4	109.0	>150	96.4
13	I	CH2CH2OH	–	102.1	91.6	>150	124.2
14	I	2-Piperidinyl	–	62.5	16.2	>150	49.2
15	II	H	Methyl	>150	84.0	>150	131
16^c	II	H	Phenyl	80.3	49.7	>150	>150
17^c	II	Benzoyl	Phenyl	75.2	84.5	>150	35.2
18^c	II	H	Benzyl	73.7	116	>150	17.1
19^c	II	Propionyl	Benzyl	32.6	36.1	>150	84.0
20^c	II	Benzoyl	Benzyl	85.2	82.4	>150	48.5
21	II	H	COOH	47.9	46.8	>150	93.6
22	III	H	CO	115.0	>150	>150	37.1
23	III	H	CH2CH2	79.4	44.6	>150	98.5
24	III	Benzyl	CH2CH2	48.1	33.2	>150	127

Aminoethylpiperazine A and histamine B were used as standard activators.

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

^b Data for A,B from Vullo et al.¹⁸.

^c Prepared as described in Guandalini et al.²⁰.

Temperini C, Innocenti A, Scozzafava A, et al. Carbonic anhydrase activators: l - adrenaline plugs the active site entrance of isozyme II, activating better isoforms I, IV, VA, VII, and XIV. Bioorg Med Chem Lett 2007;17:628–35.

 PubMed Web of Science ®Google Scholar

(a) Temperini C, Scozzafava A, Vullo D, Supuran CT. Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with l- and d-phenylalanine and crystallographic analysis of their adducts with isozyme II: stereospecific recognition within the active site of an enzyme and its consequences for the drug design. J Med Chem 2006;49:3019–27. (b) Temperini C, Innocenti A, Scozzafava A, Supuran CT. Carbonic anhydrase activators: kinetic and X-ray crystallographic study for the interaction of D- and L-tryptophan with the mammalian isoforms I–XIV. Bioorg Med Chem 2008;16:8373–8.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

(a) Vullo D, Innocenti A, Nishimori I, et al. Carbonic anhydrase activators: activation of the human isoforms VII (cytosolic) and XIV (transmembrane) with amino acids and amines. Bioorg Med Chem Lett 2007;17:4107–12.(b) Vullo D, Nishimori I, Scozzafava A, Supuran CT. Carbonic anhydrase activators: activation of the human cytosolic isozyme III and membrane-associated isoform IV with amino acids and amines. Bioorg Med Chem Lett 2008;18:4303–7.

 PubMed Web of Science ®Google Scholar

Guandalini L, Martino MV, Di Cesare Mannelli L, et al. Substituted piperazines as nootropic agents: 2- or 3-phenyl derivatives structurally related to the cognition-enhancer DM235. Bioorg Med Chem Lett 2015;25:1700–4.

 PubMed Web of Science ®Google Scholar