Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide–hydantoin hybrids

Figures & data

Figure 1. (a) General structure of furagin derivatives developed by our group as isoform-selective CAIs; (b) selected examples of phthalimide-based CAIs.

Figure 2. General structure of phthalimide–hydantoin hybrids investigated in the paper.

Scheme 1. Reagents and conditions: (i) ClCO₂Et (1 equiv.), 0–20 °C, 4 h, 31%; (ii) 1-aminohydantoin hydrochloride (1 equiv.), K₂CO₃ (2 equiv.), 100 °C, 20 h; (iii) H₂O/HCO₂H (10:1), 70 °C, 2 h; (iv) H₂O/HCO₂H (10:1), 50 °C, 30 min; (v) (a) K₂CO₃, DMF, 100 °C, 1.5 h; (b) Bn-Br (1.5 equiv.), DMSO, 100 °C, 5 h.

Table 1. Inhibition data of human CA I, II, VI, VII, and IX with phthalimide–hydantoin hybrids (3–6) and the reference drug (AAZ) by a stopped-flow CO₂ hydrase assay [16].

Cmpd	R^1	R^2	KI (μM)a
			hCA I	hCA II	hCA VI	hCA VII	hCA IX
3a	H	–	>100	6.94	0.405	0.075	0.331
3b	NO2	–	>100	8.99	0.701	0.163	0.488
5	–	–	>100	58.58	10.54	13.88	4.06
6a	H	Bn	>100	>100	57.67	33.72	3.73
6b	NO2	Bn	>100	>100	40.19	45.94	2.73
6c	H	4-NO2-Bn	>100	>100	50.18	37.63	5.68
6d	NO2	4-NO2-Bn	>100	>100	49.81	26.27	4.58
6e	H	4-CN-Bn	>100	>100	48.45	59.13	4.82
6f	NO2	4-CN-Bn	>100	>100	64.33	50.45	6.49
AAZ	–	–	0.25	0.012	0.011	0.0025	0.025

^a Mean from three different assays, by a stopped-flow technique (errors were in the range of ±5–10% of the reported values).

Figure 3. Predicted binding mode of ligands 3a (cyan) and 3b (orange) within the human: (A) CA II, (B) CA VI, (C) CA VII, and (D) CA IX active site. H-bonds and π–π stacking interactions are represented as black and cyan dashed lines, respectively.

Figure 4. Predicted binding mode of ligand 5 (green) within the human: (A) CA II, (B) CA VI, (C) CA VII, and (D) CA IX active site. H-bonds and π–π stacking interactions are represented as black and cyan dashed lines, respectively.

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.

 PubMed Web of Science ®Google Scholar

Data availability statement

Additional data may be requested from the authors.