Synthesis and biological evaluation of benzenesulphonamide-bearing 1,4,5-trisubstituted-1,2,3-triazoles possessing human carbonic anhydrase I, II, IV, and IX inhibitory activity

Figures & data

Figure 1. Some clinically used sulphonamide based drugs and 1,2,3-triazole ring containing CA inhibitors.

Scheme 1. Synthetic pathway to the sulphonamides 4a–4d, 5a–5d, 6a–6d, 7a–7d, and 8a–8d. Reagents and conditions: (i) HCl, NaNO₂, H₂O, 0 °C, 15 min; (ii) NaN₃, 0 °C, 30 min; (iii) Piperidine, DMSO, 70 °C, 4 h; (iv) NaOH, reflux, 3 h then H₃O⁺; (v) NH₃ solution, stir, 22 h; (vi) NH₂NH₂.H₂O, EtOH, reflux, 10–12 h; (vii) LiAlH₄, dry THF, reflux, 2 h then H₃O⁺.

Table 1. Inhibitory potency data for compounds 4a–4d, 5a–5d, 6a–6d, 7a–7d, and 8a–8d against isozymes hCAI, hCA II, hCA IV, and hCA IX.

Compound	R	Ki (nM)^a
		hCA I	hCA II	hCA IV	hCA IX
4a	–CH3	9.1	3.2	3.5	6.6
4b	–C6H5	245.5	6	5.1	9.5
4c	4-C6H4–OCH3	63	6.1	4.5	40
4d	2-Naphthyl	68.2	5.8	5	7.1
5a	–CH3	9.6	1.6	269.4	8.5
5b	–C6H5	645.7	97.9	55.3	45.9
5c	4-C6H4–OCH3	489.1	9	2.4	42.3
5d	2-Naphthyl	56.2	8.9	4.1	4.2
6a	–CH3	8.3	1.9	211.9	9.5
6b	–C6H5	69.1	9.1	1.4	28.3
6c	4-C6H4–OCH3	873.7	6.2	1.7	6.8
6d	2-Naphthyl	771.7	6	4	6.7
7a	–CH3	15.1	7.6	227.8	9.3
7b	–C6H5	73.7	38	22.7	26.1
7c	4-C6H4–OCH3	91.2	5.6	4	8.1
7d	2-Naphthyl	82.5	1.6	2	7.2
8a	–CH3	354.2	58.9	359.6	30.6
8b	–C6H5	78.9	9.4	8.4	58.7
8c	4-C6H4–OCH3	811.8	4	1.9	5.8
8d	2-Naphthyl	213.5	8.1	1.9	7.8
AZA		250	12.1	74	25.8

AZA: acetazolamide (reference compound).

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