New isoxazolidinyl-based N-alkylethanolamines as new activators of human brain carbonic anhydrases

Figures & data

Figure 1. General structures of some reported CAAs.

Table 1. Activation data of human CA isoforms I, II, IV and VII with isoxazoline amino alcohols 2–23 and histamine as reference CAA by a stopped-flow CO₂ hydrase assay³⁸.

Compound				KA (µM)^a
Code	R	R1	Stereoisomer	hCA I	hCA II	hCA IV	hCA VII
2	CH3-	i-Pr	syn	12.4	4.15	15.6	0.86
3	CH3-	i-Pr	anti	27.6	3.89	7.61	0.52
4	CH3-	t-Bu	syn	11.9	3.06	9.08	0.69
5	CH3-	t-Bu	anti	48.1	3.52	14.9	0.53
6		i-Pr	syn	11.7	2.6	6.36	4.98
7		t-Bu	syn	25.8	3.51	7.93	5.12
8		i-Pr	syn	47.5	2.8	25.5	5.97
9		i-Pr	anti	>100	2.85	19.2	6.15
10		t-Bu	syn	49.6	1.74	35.7	8.26
11		t-Bu	anti	63.5	2.01	24.8	7.06
12		i-Pr	syn	40.6	3.75	11.1	1
13		i-Pr	anti	53.1	3.03	10	1.23
14		t-Bu	syn	29.8	2.9	9.67	2.3
15		t-Bu	anti	43.6	2.67	5.98	2.84
16		i-Pr	syn	38.1	1.53	6.23	2.82
17		t-Bu	syn	47.8	2.09	5.8	2.67
18		t-Bu	anti	>100	2.54	7.93	2.89
19		i-Pr	syn	49.1	2.77	17.6	5.8
20		i-Pr	anti	48	1.93	6.05	5.69
21		t-Bu	syn	47.3	2.69	6.02	6
22		i-Pr	syn	>100	1.84	4.35	3.8
23		i-Pr	anti	>100	3.05	12.7	6.51
Histamine	–	-	–	2.1	125	25.3	37.5

^aFrom three different assays (errors within ± 10% of the reported values).

Scheme 1. Reactions and conditions: (i) N-Chlorosuccinimide, DMF 15 min, rt; (ii) Et₃N, 1,3-butadiene, CHCl_3, 0 °C-rt, 3 h; (iii) m-Cl-perbenzoic acid, DCM, 0 °C-rt, 72 h; (iv) iPrNH₂, tBuNH₂, Benzene/EtOH, rt, 72 h.

Figure 2. Superimposition of 12 (left) and 13 (right) to identify the different chemical shifts of methylene D protons.

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(8):2561–2573.

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