Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II and IX with some 1,3,4-oxadiazole- and 1,2,4-triazole-thiols

Figures & data

Table I.  Selected IR data for some of the new compounds 4(a–c) and 5(a–c).

			υ (cm^− 1)
No	X	R	CH aryl	CH2 asym	CH2 sym		SO2		C = S	CH2N	C–O–C	N–N
							asym	sym
4a	H		3060	2936	2853	1593 1441	1291 1321	1157	1248	1223	1067	1009
4b	Cl		3087	2936	2852	1581 1472	1290 1324	1159	1249	1221	1087	1010
5b	Cl		3067	2935	2853	1590 1439	1291 1321	1157	1248	1223	1068	1009
5c	Br		3087	2945	2854	1617 1572	1294 1324	1159	1252	1186	1068	1009

Table II.  NMR data for compounds 4(a–c); 5(a–c)

No	X	A	^1H-NMR (CDCl3) δ (ppm), J (Hz)	^13C-NMR δ (ppm)
4a	H	CH2	8.07s, 2H, H-7,11; 8.07s, 2H, H-8,10;	178.31, C-2; 157.52, C-5; 126.72, C-6;
			7.97dd (7.5, 1.8), 2H, H-13,17;	128.43, C-7, 11; 127.84, C-8, 10;
			7.56t (7.5), 2H, H-14,16;	144.81, C-9; 140.67, C-12;
			7.61tt (7.5, 1.8), 1H, H-15;	127.18, C-13, 17; 129.52, C-14,16;
			5.06s, 2H, H-18;	133.72, C-15; 71.82, C-18; 51.58, C-19,23;
			2.77bt (5.2), 2H, H-19,23;	25.84,C-20,22; 23.58, C-21
			(1.35-1.62)m, 3H, H-20,21,22
4b	Cl	CH2	8.06d, (8.9), 2H, H-7,11;	178.10, C-2; 157.14, C-5; 126.75, C-6;
			8.10d (8.9), 2H, H-8,10;	128.24, C-7, 11; 127.10, C-8, 10;
			7.91d (8.7) 2H, H-13,17;	144.12, C-9; 140.37, C-12;
			7.52d (8.7), 2H, H-14,16;	129.11, C-13,17; 129.71, C-14,16;
			5.06s, 2H, H-18;	138.95, C-15; 71.63, C-18; 51.37, C-19,23;
			2.77t (5.5), 2H, H-19,23;	25.63, C-20,22; 23.37, C-21
			1.58qv (5.5), 2H, H-20, 22;
			1,39m, 1H, H-21
4c	Br	CH2	7.91d, (8.8), 2H, H-7,11;	178.37, C-2; 157.15, C-5; 126.75, C-6;
			7.97d, (8.8), 2H, H-8,10;	128.48, C-7,11; 127.32, C-8,10;
			7.82d (8.7), 2H, H-13,17;	144.55, C-9; 139.70, C-12;
			7.66d (8.7), 2H, H-14,16;	129.36, C-13,17; 132.88, C-14,16;
			5.06s, 2H, H-18;	129.21, C-15; 71.77, C-18; 51.52,C-19,23;
			2.77t (5.5), 2H, H-19,23;	25.46, C-20,22; 23.24, C-21
			(1.35-1.64)m, 3H, H-20,21,22
5a	H	–O–	8.07s, 2H, H-7,11;	178.34, C-2; 157.25, C-5; 126.48, C-6;
			8.07s, 2H, H-8,10;	128.46, C-7,11; 127.85, C-8,10;
			7.97dd, (7.3, 1.5), 2H, H-13,17;	145.14, C-9; 140.63, C-12;
			7.54t, (7.3), 2H, H-14,16;	127.21, C-13,17; 129.51, C-14,16;
			7.62tt, (7.3, 1.5), 1H, H-15;	133.73, C-15; 70.72, C-18; 50.49, C-19,23;
			5.06s, 2H, H-18;	66.70, C-20,22
			2.83t(4.8), 2H, H-19,23;
			3.69t, (4.8), 2H, H-20,22
5b	Cl	–O–	8.06d, (8.1), 2H, H-7,11; 8.08d,	178.35, C-2; 157.13, C-5; 126.73, C-6;
			(8.1), 2H, H-8,10; 7.91d, (8.7),	128.46, C-7,11; 127.31, C-8,10; 144.60,
			2H, H-13,17; 7.52d, (8.7), 2H, H-	C-9; 140.62, C-12; 129.30, C-13,17;
			14,16; 5.06s, 2H, H-18; 2.83t(4.7),	129.87, C-14,16; 139.14 C-15; 70.75,
			2H, H-19,23; 3.70t, (4.7), 2H, H-20,22	C-18; 50.50, C-19,23; 66.70, C-20,22
5c	Br	–O–	8.06s, 2H, H-7,11; 8.07s, 2H, H-	178.37, C-2; 157.15, C-5; 126.75, C-6;
			8,10; 7.83d, (8.1), 2H, H-13,17;	128.48, C-7,11; 127.32, C-8,10; 144.55,
			7.68d, (8.1), 2H, H-14,16; 5.06s,	C-9; 139.69, C-12; 129.36, C-13,17;
			2H, H-18; 2.83bt(4.5), 2H, H-	132.89, C-14,16; 129.21, C-15; 70.77,
			19,23; 3.69bt, (4.5), 2H, H-20,22	C-18; 50.52, C-19,23; 66.71, C-20,22

s = singlet; d = doublet; t = triplet; dd = doublet of doublets; tt = triplet of triplets; qv = quartet; m = multiplet; b = broad

Scheme 1 Synthesis of the heterocycles 2–9

Table III.  Inhibition data for derivatives 2-9 investigated here and the standard sulfonamide CAI (acetazolamide AAZ), against isozymes hCA I, II and IX.

Compound	hCA I^a	KI^† (μM) hCA II^a	hCA IX^b
AAZ	0.250	0.012	0.025
2a	7.4	3.7	13.5
2b	9.3	3.1	32.8
2c	9.2	2.7	14.2
3a	7.5	1.6	57.1
3b	6.4	2.0	59.0
3c	7.2	2.1	54.5
4a	7.5	5.9	32.4
4b	5.1	1.4	52.8
4c	6.2	1.6	31.9
5a	6.4	0.63	1.25
5b	8.0	3.0	9.20
5c	7.6	4.3	6.07
8a	340	11	129
8b	460	12	133
8c	400	31	348
9a	422	67	476
9b	443	78	452
9c	449	85	433

^†Errors in the range of 5-10% of the reported value (from 3 different assays)

^a Human cloned isozyme, by the CO₂ hydration method

^b Catalytic domain of human, cloned isozyme, by the CO₂ hydration method [20].

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: 2561–2573

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