Exploring new structural features of the 4-[(3-methyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzenesulphonamide scaffold for the inhibition of human carbonic anhydrases

Figures & data

Figure 1. Carbonic anhydrase inhibitors in clinical use and previously reported EMAC derivatives: (1) acetazolamide (2) ethoxzolamide, (3) dichlorphenamide, (4) dorzolamide, (5) EMAC10020⁴⁷, (6) EMAC8001³¹, (7) EMAC8000⁴⁸, (8) EMAC10153⁵⁰, (9) EMAC10111⁴⁹.

Table 1. Chemical, analytical, and physical data of derivatives EMAC8002 a–m.

Compound	R	R.F.^a	C–H–N		M.P. °C	Yield %	Mass fragments
			Calc.	Found
EMAC8002a	4-Br	0.78	C, 45.29; H, 3.33; N, 9.90	C, 44.87; H, 3.28; N, 9.83	256-259	55	425; 423
EMAC8002b	4-Cl	0.70	C, 50.59; H, 3.71; N, 11.06	C, 50.61; H, 3.67; N, 11.02	241-242	76	379
EMAC8002c	4-F	0.63	C, 52.88; H, 3.88; N, 11.56	C, 52.90; H, 3.83; N, 11.51	230-233	58	363
EMAC8002d	3-NO2	0.74	C, 49.22; H, 3.61; N, 14.35;	C, 49.30; H, 3.58; N, 14.28;	235-236	73	390
EMAC8002e	2,4-Cl	0.83	C, 46.38; H, 3.16; N, 10.14	C, 46.42; H, 3.13; N, 10.09	256-257	79	413
EMAC8002f	4-CN	0.72	C, 55.12; H, 3.81; N, 15.12	C, 55.08; H, 3.77; N, 15.04	237-238	85	370
EMAC8002g	2,4-F	0.67	C, 50.38; H, 3.44; N, 11.02	C, 50.31; H, 3.40; N, 10.97	239-240	45	381
EMAC8002h	4-NO2	0.72	C, 49.22; H, 3.61; N, 14.35	C, 49.00; H, 3.58; N, 14.29	244-245	63	390
EMAC8002i	4-C6H5	0.76	C, 62.68; H, 4.54; N, 9.97	C, 62.68; H, 4.52; N, 9.98	254-255	72	421
EMAC8002j	4-CH3	0.77	C, 56.80; H, 4.77; N, 11.69	C, 56. 75; H, 4.80; N, 11.61	252-254	67	359
EMAC8002k	4-OCH3	0.65	C, 54.38; H, 4.56; N, 11.19	C, 54.37; H, 4.57; N, 11.17	243-244	77	375
EMAC8002l	//	0.69	C, 47.84; H, 3.73; N, 11.96	C, 47.80; H, 3.75; N, 11.89	233-235	74	351
EMAC8002m	H	0.74	C, 55.63; H, 4.38; N, 12.16	C, 55.55; H, 4.34; N, 12.13	252-253	67	345

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

Table 2. 1H NMR data of derivatives EMAC8002a–m.

Compound	^1H NMR δ (ppm)
EMAC8002a	^1H-NMR: (300 MHz, DMSO) 3.57 (3H, s, CH3), 7.10 (1H, s, CH thiazole), 7.45 (2H, s, NH2, D2O), 7.54 (2H, d, J = 7.9 Hz, CH Ar), 7.61 (2H, d, J = 7.7 Hz, CH Ar), 7.78 (2H, d, J = 7.8 Hz, CH Ar), 7.95 (2H, d, J = 7.7 Hz, CH Ar)
EMAC8002b	^1H-NMR: (300 MHz, DMSO) 3.46 (3H, s, CH3), 6.83 (1H, s, CH thiazole), 7.36 (2H, s, NH2, D2O), 7.44 (2H, d, J = 8.4 Hz, CH Ar), 7.58 (2H, d, J = 8.7 Hz, CH Ar), 7.63 (2H, d, J = 8.4 Hz, CH Ar), 7.88 (2H, d, J = 8.5 Hz, CH Ar)
EMAC8002c	^1H-NMR: (300 MHz, DMSO) 3.65 (3H, s, CH3), 7.01 (1H, s, CH thiazole), 7.50 (2H, t, J = 8.5 Hz, CH Ar), 7.56 (2H, s, NH2, D2O), 7.67 (2H, d, J: 8.7 CH Ar), 7.74 (2H, dd, JH-H: 8.5, JH-F: 5.5, CH Ar), 8.02 (2H, d, J: 9.0, CH Ar)
EMAC8002d	^1H-NMR: (300 MHz, DMSO) NH2 not detected, 3.34 (3H, s, CH3), 6.59 (1H, s, CH thiazole), 7.18 (2H, d, J = 8.5 Hz, CH Ar), 7.24 (1H, s, CH Ar), 7.78 (2H, d, J = 8.5 Hz, CH Ar), 7.83 (1H, d, J = 7.8 Hz, CH Ar), 8.01 (1H, d, J = 7.8 Hz, CH Ar), 8.34 (1H, d, J = 2.0 Hz, CH Ar)
EMAC8002e	^1H-NMR: (500 MHz, DMSO) 3.25 (3H, s, CH3), 6.68 (1H, s, CH thiazole), 7.29 (2H, s, NH2, D2O), 7.34 (2H, d, J = 8 Hz, CH Ar), 7.59 (1H, d, J = 8 Hz, CH Ar), 7.63 (1H, dd, J = 8.5, 2 Hz), 7.83 (2H, d, J = 8.5 Hz, CH Ar), 7.88 (1H, d, J = 2 Hz, CH Ar)
EMAC8002f	^1H-NMR: (300 MHz, DMSO) 3.46 (3H, s, CH3), 6.83 (1H, s, CH thiazole), 7.36 (2H, s, NH2, D2O), 7.44 (2H, d, J = 8.4 Hz, CH Ar), 7.58 (2H, d, J = 8.7 Hz, CH Ar), 7.63 (2H, dd, J = 8.4 Hz, CH Ar), 7.88 (2H, d, J = 8.5 Hz, CH Ar)
EMAC8002g	^1H-NMR: (300 MHz, DMSO) 3.55 (3H, s, CH3), 7.13 (1H, s, CH thiazole), 7.34 (1H, td, J = 8.4, 1.5 Hz, CH Ar), 7.45 (2H, s, NH2, D2O), 7.67-7.53 (4H, m, CH Ar), 7.93 (2H, d, J = 7.6 Hz, CH Ar)
EMAC8002h	1H-NMR: (300 MHz, DMSO) 3.36 (3H, s, CH3), 6.61 (1H, s, CH thiazole), 7.17 (2H, d, J = 8.2 Hz, CH Ar), 7.25 (2H, s, NH2, D2O), 7.79 (2H, d, J = 8.5 Hz, CH Ar), 7.83 (2H, d, J = 8.7 Hz, CH Ar), 8.33 (2H, d, J = 8.0 Hz, CH Ar)
EMAC8002i	^1H-NMR: (500 MHz, DMSO) 3.59 (3H, s, CH3), 7.0 (1H, s, CH thiazole), 7.40 (2H, s, NH2), 7.43 (1H, m, CH Ar), 7.52 (2H, m, CH Ar), 7.56 (2H, d, J = 8 Hz, CH Ar), 7.66 (2H, d, J = 8 Hz, CH Ar), 7.75 (2H, m,CH Ar), 7.87 (2H, d, J = 8.5 Hz, CH Ar), 7.93 (2H, d, J = 8.5 Hz)
EMAC8002j	^1H-NMR: (300 MHz, DMSO) 2.40 (3H, s, CH3), 3.53 (3H, s, CH3), 6.91 (1H, s, CH thiazole), 7.46-7.36 (6H, m, CH Ar), 7.55 (2H, s, NH2, D2O), 7.92 (2H, d, J = 8.5 Hz, CH Ar)
EMAC8002k	^1H-NMR: (300 MHz, DMSO) 3.64 (3H, s, CH3), 3.96 (3H, s, OCH3), 6.98 (1H, s, CH thiazole), 7.23 (2H, d, J = 8.5 Hz, CH Ar), 7.54 (2H, s, NH2, D2O), 7.63-7.60 (4H, m, CH Ar), 8.04 (2H, d, J = 8.1 Hz, CH Ar)
EMAC8002l	^1H-NMR: (300 MHz, DMSO) 3.61 (3H, s, CH3), 7.15 (1H, s, CH thiazole), 7.48 (2H, s, NH2, D2O), 7.59 (5H, m, CH Ar), 7.67 (2H, d, J = 8.5 Hz, CH Ar), 7.97 (2H, d, J = 8.5 Hz, CH Ar)
EMAC8002m	^1H-NMR: (300 MHz, DMSO) 3.61 (3H, s, CH3), 7.15 (1H, s, CH thiazole), 7.48 (2H, s, NH2, D2O), 7.59 (5H, m, CH Ar), 7.67 (2H, d, J = 8.5 Hz, CH Ar), 7.97 (2H, d, J = 8.5 Hz, CH Ar)

Table 3. Inhibition data towards hCA I, II, IX, and XII of compounds EMAC8002 a–m.

		Ki (nM)
Compound	R	hCA I	hCA II	hCA IX	hCA XII
EMAC8002a	4-Br	4457	45.8	58.1	778
EMAC8002b	4-Cl	1548	13.1	1213	97.9
EMAC8002c	4-F	4845	5.3	2482	40.0
EMAC8002d	3-NO2	2456	17.8	1821	271
EMAC8002e	2,4-Cl	>10,000	398	1605	10.5
EMAC8002f	4-CN	2650	17.9	2064	94.7
EMAC8002g	2,4-F	>10,000	37.7	1648	9.0
EMAC8002h	4-NO2	2239	19.9	142	9.5
EMAC8002i	4-C6H5	8910	503	1389	9.5
EMAC8002j	4-CH3	2603	4.5	23.3	3.1
EMAC8002k	4-OCH3	5580	3.8	25.4	4.6
EMAC8002l	//	1650	30.3	1874	36.9
EMAC8002m	H	2305	5.3	620	9.4
AAZ	//	250	12	25	5.7

Scheme 1. Synthetic pathway to compounds EMAC8002a–m. Reagents and conditions: (i) ethanol, methylisothiocyanate; (ii) ethanol, α-halogenoarylketone.

Figure 2. (a) ROESY spectrum of compound EMAC8002i; (b) Partial ROESY spectrum of compound EMAC8002i.

Figure 3. Three-dimensional representation of the putative binding mode as obtained by docking experiments of: (a) EMAC8002-i and (b) relative 2D representation of the complex stabilising interactions with the residues of the binding site.

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