Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII

Figures & data

Figure 1. Carbonic anhydrase activity of previously reported coumarin derivatives.

Scheme 1. Reagents and conditions: (i) diethyl malonate, Piperidine, EtOH, 70–80 °C, 4–6 h, 82% (ii) NaOH, H₂O, MeOH, rt., 2 h, 74% (iii) N-Boc piperazine, EDC.HCl, HOBt, DIPEA, DMF, rt, 8-12 h, 61% (iv) TFA, DCM, 0–5 °C to rt., 1 h, 69% (v) substituted sulphonyl chlorides, DIPEA, DCM, rt., 2–3 h, 75–81%. (vi) substituted phenylisothiocyanates, ACN, reflux, 2–3 h, 65–75%.

Scheme 2. Reagents and conditions: (i) diethyl malonate, piperidine, glacial acetic acid (Cat.), reflux, 80 °C, 4–6 h, 79% (ii) NaOH, H₂O, MeOH, rt.,2 h, 70% (iii) substituted sulphonyl piperazines, EDC.HCl, HOBt, DIPEA, DMF, rt,8–12 h, 60–75% (iv) TFA, 90–100 °C 8 h, 88% ²⁷.

Scheme 3. Reagents and conditions: (i) ethyl acetoacetate, piperidine, EtOH, rt, 4–6 h, 70% (ii) cat. AcOH, DMF, rt, 2–3 h, 70–73%.

Table 1. Inhibition data for hCA isozymes I, II, IX and XII for synthesised compounds using AAZ as a standard CAI (K_i in µM).^a,b

S.No.	Code	Structure	hCA I	hCA II	hCA IX	hCA XII
1.	6a		>100	>100	7.1	9.1
2.	6b		>100	>100	6.7	42.3
3.	6c		>100	>100	4.1	66.7
4.	6d		>100	>100	5.56	9.8
5.	6e		>100	>100	37.8	26.1
6.	7a		>100	>100	72.0	47.8
7.	7b		>100	>100	9.2	8.0
8.	7c		>100	>100	5.1	31.8
9.	12a		>100	>100	>100	86.6
10.	12b		>100	>100	>100	9.3
11.	12c		>100	>100	50.7	>100
12.	16a		>100	>100	>100	92.2
13.	16b		>100	>100	90.9	9.5
14.	16c		>100	>100	>100	36.5
15.	20a		>100	>100	62.1	9.2
16.	20b		>100	>100	8.9	9.4
17.	AAZ		0.25	0.012	0.026	0.006

^aValues are mean from three different assays using the stopped-flow technique (errors were in the range of ± 5–10% of the reported values).

^b6 h incubation.

Figure 2. (A) Docking pose of compound 6c (green) (B) docking pose of compound 7c (grey) in the active site of hCA IX (PDB ID: 5DVX) Zn²⁺ is represented as grey sphere.

Figure 3. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA IX (PDB ID: 5DVX) (A) change in conformations of 6c. (B) change in conformations of 7c.

Figure 4. (A) Docking pose of compound 6d (purple) (B) docking pose of compound 7b (teal) in the active site of hCA IX (PDB ID: 1JD0) Zn²⁺ is represented as grey sphere.

Figure 5. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA XII (PDB ID: 1JD0) (A) change in conformations of 6d. (B) change in conformations of 7b.

Woods LL, Johnson D. Coumarins from 2-hydroxyaryl acids and malonic acid. J Org Chem. 1965;30(12):4343–4344.

 Web of Science ®Google Scholar