Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases

Figures & data

Figure 1. Advanced and clinically used hCA inhibitors.

Figure 2. Isoform-selective CAIs derivable by direct sulfochlorination approach.

Figure 3. Celebrex and its tricyclic constrained versions 3a–e reported earlier.

Figure 4. N-Arylpyrazole substrates 6a-t investigated in direct mono- and bis-sulfochlorination reactions (regiochemistry established for the respective mono- and bis-sulfonamides).

Table 1. Inhibitory profile of mono-sulfonamides 7a–o against four hCA isoforms.

			Sulfochlorination step		hCA Ki (μM)
Compound	Substrate 6	Structure	T (°C)	Time (h)	hCA I	hCA II	hCA IV	hCA VII
7a	6a		70	6	4.78	0.072	>10.0	0.80
7b	6c		70	3	>10.0	>10.0	0.56	>10.0
7c	6f		20	22	0.26	0.004	0.033	0.040
7d	6e		70	3	0.096	0.008	3.42	0.014
7e	6h		20	22	4.21	0.381	>10.0	0.194
7f	6g		70	3	1.23	0.059	>10.0	0.059
7g	6j		20	20	>10.0	>10.0	>10.0	>10.0
7h	6i		20	24	>10.0	>10.0	>10.0	>10.0
7i	6l		20	1	8.85	>10.0	>10.0	>10.0
7j	6k		20	24	>10.0	>10.0	>10.0	0.387
7k	6n		10	1	>10.0	>10.0	>10.0	>10.0
7l	6m		20	24	>10.0	6.65	>10.0	>10.0
7m	6q		80	3	0.066	0.085	0.086	0.328
7n	6s		90	5	3.83	0.001	0.004	0.009
7o	–		–	–	0.462	0.004	0.084	0.017
Acetazolamide					0.25	0.012	0.074	0.003

Table 2. Inhibitory profile of mono-sulfonamides 8a–i against four hCA isoforms.

			Sulfochlorination		hCA Ki (μM)
Compound	Substrate 6	Structure	T (°C)	Time (h)	hCA I	hCA II	hCA IV	hCA VII
8a	6p		70	1	0.76	5.33	>10.0	>10.0
8b	6b		70	1	0.54	0.28	>10.0	0.53
8c	6d		20	20	0.76	0.74	>10.0	>10.0
8d	6f		20	22	0.27	0.24	>10.0	0.94
8e	6h		20	22	0.60	0.091	>10.0	>10.0
8f	6o		90	4	0.19	0.082	7.06	>10.0
8g	6r		70	5	0.94	1.08	9.49	0.46
8h	6q		80	3	0.54	0.14	3.74	0.24
8i	6t		70	10	0.62	2.64	7.19	>10.0
Acetazolamide					0.25	0.012	0.074	0.003

Table 3. Inhibitory profile of mono-sulfonamides 9a–s against four hCA isoforms.

			Sulfochlorination		hCA Ki (μM)
Compound	Substrate xx	Structure	T (°C)	Time (h)	hCA I	hCA II	hCA IV	hCA VII
9a	6b		70	7	0.50	0.021	0.065	0.26
9b	6b		70	7	0.33	0.005	0.111	0.035
9c	6a		100	48	0.20	0.002	0.025	0.041
9d	6d		70	7	>10.0	>10.0	0.40	>10.0
9e	6c		100	20	0.30	0.004	0.24	0.068
9f	6f		70	7	0.47	0.002	0.022	0.019
9g	6e		100	20	0.10	0.049	5.80	0.005
9h	6h		70	7	0.87	>10.0	>10.0	>10.0
9i	6g		100	20	0.55	0.030	7.86	0.014
9j	6j		70	4	0.95	0.96	>10.0	0.33
9k	6l		70	4	4.65	0.61	>10.0	0.17
9l	6n		70	4	6.80	0.30	0.95	>10.0
9m	6p		100	24	0.89	0.040	0.077	0.65
9n	6o		120	10	0.62	0.024	0.074	0.099
9o	6r		100	24	0.16	0.008	0.93	0.71
9p	6q		120	20	3.08	0.008	0.075	0.48
9q	6t		100	24	2.12	0.025	4.38	>10.0
9r	6s		120	20	0.55	0.005	0.022	0.60
Acetazolamide					0.25	0.012	0.074	0.003

Scheme 1. Mono- and bis-sulfonamide synthesis via direct sulfochlorination of 6a–t. Reagents and conditions: (a) ClSO₃H (10 equiv.), SOCl₂ (1.1 equiv.), 10–70 °C, 1–24 h; (b) aq. NH₃ (20 equiv.), acetone, 50 °C, 1 h; (c) ClSO₃H (20 equiv.), SOCl₂ (2.2 equiv.), 70–120 °C, 7–48 h.

Scheme 2. Preparation of compound 7o.

Figure 5. Docking of compound 7b (A) and 7h (B) into hCA IV.

Figure 6. Docking of compound 7b into hCA I (A), hCA II (B) and hCA VII (C).

Figure 7. Docking of compound 8h into hCA I (A), hCA II (B), hCA IV (C) and hCA VII (D).

Figure 8. Docking of compound 9r into hCA II.