Isatin: a privileged scaffold for the design of carbonic anhydrase inhibitors

Figures & data

Figure 1. Carbonic anhydrase inhibitors in clinical use: (1) acetazolamide, (2) (methazolamide, (3) ethoxzolamide, (4) dichlorphenamide, (5) dorzolamide, (6) brinzolamide, and (7) topiramate.

Table 1. Chemical, analytical, and physical data of derivatives EMAC 10020.

Compound	R	R.F.*	C--H--N		M.P. °C	Yield %	Mass fragments
			Calc.	Found
			EMAC 10020 a	H				0.52	C, 52.16; H, 3.40; N, 13.52	C, 52.19; H, 3.39; N, 13.50	320d	38	414; 386; 373
EMAC 10020 c	5-Cl	0.38	C, 48.16; H, 2.92; N, 12.48;	C, 48.19; H, 2.90; N, 12.46;	320-1	71	448; 420; 407
EMAC 10020 d	5-F	0.42	C, 49.99; H, 3.03; N, 12.96;	C, 50.01; H, 3.00; N, 12.93;	310-2	66	432; 404; 391
EMAC 10020 l	5-CH3	0.50	C, 53.26; H, 3.76; N, 13.08;	C, 53.29; H, 3.73; N, 13.05;	320-2	67	428; 400; 387
EMAC 10020 m	7-F	0.65	C, 49.99; H, 3.03; N, 12.96;	C, 50.00; H, 3.01; N, 12.95;	288d	43	432; 404; 391
EMAC 10020 n	5-CF3	0.51	C, 47.30; H, 2.72; N, 11.61;	C, 47.33; H, 2.70; N, 11.59;	314d	41	482; 454; 441
EMAC 10020 o	7-Br	0.69	C, 43.82; H, 2.66; N, 11.36;	C, 43.85; H, 2.64; N, 11.33;	320d	75	492; 464; 451

* R.F. values were obtained on silica gel plates using a mixture of ethyl acetate/n-hexane 2/1.

Table 2. ¹H NMR and ¹³C NMR data of derivatives EMAC 10020.

Compound	^1H NMR δ (ppm)
EMAC 10020 a	^1H NMR (500 MHz, DMSO-d6) δ (ppm): 3.32- 3.36 (3H, s, CH3, N-CH3); 7.05- 7.09 (1H, s, CH, Isat.); 6.91-6.93 (1H, d, J = 7.6 Hz, CH, Isat.); 7.20 (2H, d, CH, J = 8.8 Hz, 4-SO2NH2 phenyl); 7.35- 7.39 (3H, m, CH + NH2, Isat.+ SO2NH2)7.86- 7.89 (2H, d, CH, J = 8.8 Hz, 4-SO2NH2 phenyl); 8.84- 8.86 (1H, d, CH, J = 8 Hz, Isat.); 11.20 (1H, s, NH, Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 29.10, 109.93, 120.10, 121.46, 123.55, 127.19, 128.05, 124.30, 130.80, 132.37, 140.16, 140.98, 150.52, 154.32, 165.46, 168.40.
EMAC 10020 c	^1H NMR (500 MHz, DMSO-d6) δ (ppm): 3.29- 3.37 (3H, s, CH3, N-CH3); 6.93- 6.95 (1H, d, CH, J = 8.5 Hz, 5-Cl Isat.); 7.16- 7.20 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 7.33 (2H, s, NH2, SO2NH2); 7.41- 7.43 (1H, d, CH, Jo = 8.5 Hz, Jm=  2, 5 Hz -Cl Isat.); 7.86- 7.88 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 8,89 (1H, d, CH, J = 2 Hz, 5-Cl Isat.); 11.32 (1H, s, NH, 5-Cl Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 28.88, 111.47, 121.23, 121.41, 123.79, 125.81, 127.10, 127.31, 131.08, 132.55, 140.32, 141.89, 150.32, 153.96, 165.44, 168.05.
EMAC 10020 d	^1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.33 (3H, s, CH3, N-CH3); 6.88 (1H, m, CH, 5-F Isat.); 7.18- 7.22 (2H, d, CH, J = 8.4 Hz, 4-SO2NH2 phenyl); 7.22-7.25 (1H, d, CH, 5-F Isat.); 7.37 (2H, s, NH2, SO2NH2); 7.87- 7.90 (2H, d, CH, J = 8.8 Hz, 4-SO2NH2 phenyl); 8.58 (1H, m, CH, 5-F Isat.); 11.20 (1H, s, NH, 5-F Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 28.91, 111.08, 114.54, 118.16, 120.70, 121.38, 124.46, 127.28, 132.35, 140.34, 150.35, 154.06, 156.30, 158.63, 165.58, 168.35.
EMAC 10020 l	^1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.30 (3H, s, CH3, 5-CH3 Isat.); 3.30- 3.35 (3H, s, CH3, N-CH3); 6.79 (1H, d, CH, 5-CH3 Isat.); 7.16-7.19 (3H, m, CH, 4-SO2NH2 phenyl +5-CH3 Isat); 7.33 (2H, s, NH2, SO2NH2); 7.87 (2H, d, CH, J = 8 Hz, 4-SO2NH2 phenyl); 8.67 (1H, s, CH, 5-CH3 Isat.); 11.05 (1H, s, NH, 5-CH3 Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 21.14, 29.12, 109.94, 120.06, 121.47, 123.50, 127.20, 128.03, 130.12, 130.70, 132.36, 140.15, 140.97, 150.52, 154.32, 165.45, 168.39.
EMAC 10020 m	^1H NMR (500 MHz, Acetone-d6) δ (ppm): 3.48 (3H, s, CH3, N-CH3); 7.13-7.15(1H, m, 7-F Isat.); 7.21-7.23 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 7.25-7.29 (3H, m, CH + NH2,7-F Isat.+ SO2NH2), 7.96 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 8.85 (1H, d, CH, J = 8 Hz, 7-F Isat.); 10.43 (1H, s, NH, 7-F Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 28.91, 111.10, 114.54, 118.16, 120.70, 121.38, 122.90, 125.90, 127.28, 132.35, 150.35, 154.06, 156.30, 162.90, 165.58, 168.35.
EMAC 10020 n	^1H NMR (400 MHz, Acetone-d6) δ (ppm): 3.35 (3H, s, CH3, N-CH3); 7.04- 7.08 (1H, m, CH, 5-CF3 Isat.); 7.12 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 7.27- 7.31 (1H, t, CH, J = 8 Hz, 5-CF3 Isat.); 7.31 (2H, weak s, NH2, SO2NH2); 7.99 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 8.67 (1H, d, CH, J = 8 Hz, 5-CF3 Isat.); 11.67 (1H, NH, 5-CF3 Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 29.13, 109.95, 120.07, 121.47, 123.50, 124.60, 127.20, 128.04, 130.12, 130.71, 132.36, 140.16, 140.97, 150.53, 154.32, 165.45, 168.39.
EMAC 10020 o	^1H NMR (500 MHz, DMSO-d6) δ (ppm): 3.34 (3H, s, CH3, N-CH3); 6.99- 7.02 (1H, t, CH, J = 8 Hz, 7-Br Isat); 7.19- 7.20 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 7.34 (2H, s, NH2, SO2NH2); 7.54- 7.55 (1H, d, J = 8 Hz, CH, 7-Br Isat.); 7.87- 7.89 (2H, d, CH, J = 8.5 Hz, 4-SO2NH2 phenyl); 8.81- 8.83 (1H, d, CH, J = 8 Hz, 7-Br. Isat.); 11.43 (1H, s, NH, 7-Br Isat.). ^13C NMR (100 MHz, DMSO-d6) δ (ppm): 29.02, 102.69, 121.45, 121.68, 123.37, 124.44, 126.71, 127.26, 132.79, 134.27, 140.30, 142.17, 150.38, 153.97, 165.31, 168.26.

Table 3. Inhibition data towards hCA I, II, IX, and XII of compounds EMAC 10020.

KI (nM)
Compound	Structure	hCA I	hCA II	hCA IX	hCA XII
EMAC 10020 a		95.5	40.7	40.1	841
EMAC 10020 c		958	8300	55.7	865
EMAC 10020 d		50.3	274	50.7	85.0
EMAC 10020 l		87.6	79.1	3.0	440
EMAC 10020 m		44.3	139	4.1	90.7
EMAC 10020 n		945	5720	2660	873
EMAC 10020 o		877	8780	126	824
Acetazolamide		250	12	25	5.7

Figure 2. Synthetic pathway to compounds EMAC 10020. Reagents and conditions: (i) 2-propanol, methyl isothiocyanate; (ii) ethanol, ethyl bromoacetate, dry sodium acetate; (iii) R-isatin, acetic anhydride, dry sodium acetate, acetic acid.