Diversely substituted sulfamides for fragment-based drug discovery of carbonic anhydrase inhibitors: synthesis and inhibitory profile

Figures & data

Figure 1. CAIs in clinical development and clinical use.

Figure 2. Examples of clinically used sulfamide drugs.

Scheme 1. Synthesis of unsymmetrically substituted primary sulfamides 2a–q.

Scheme 2. Synthesis of unsymmetrically (hetero)aromatic amine-substituted sulfamides 2r–w.

Table 1. Calculated physicochemical properties and hCA I, II, IX and XII inhibitory profile of compounds 2a–w.

Compound	Mw	cLogP^a	Ki (nM)^b
			hCA I	hCA II	hCA IX	hCA XII
2a	180.2	−1.87	75.6	42.7	54.2	25.3
2b	179.2	−1.01	64.2	32.1	58.6	52.5
2c	204.2	0.42	126.2	70.5	30.7	51.7
2d	226.3	1.22	120.7	42.6	36.8	59.7
2e	180.2	−0.77	38.4	63.4	92.7	98.0
2f	208.2	−0.65	52.1	69.8	78.2	83.6
2g	193.3	−0.72	89.7	52.1	63.2	38.4
2h	240.3	1.57	359.5	120.4	58.2	96.7
2i	257.4	0.53	28.4	39.8	65.1	19.7
2j	187.2	−0.98	98.5	90.2	29.5	16.5
2k	192.3	0.15	22.6	48.2	73.2	66.8
2l	209.3	−0.12	59.6	92.3	126.5	72.5
2m	236.3	0.11	62.8	42.8	58.1	25.9
2n	247.4	0.43	497.3	99.3	72.5	35.1
2o	166.2	−1.05	59.2	66.9	82.1	100.9
2p	207.3	−1.39	88.2	59.4	46.2	40.2
2q	165.2	−1.60	68.9	52.9	78.2	100.2
2r	212.3	1.12	867.9	315.7	94.7	116.2
2s	174.2	−1.27	29.6	59.4	68.0	39.3
2t	212.3	1.31	231.4	89.5	34.2	114.2
2u	222.3	1.71	160.1	56.7	25.4	72.3
2v	198.2	0.79	723.5	472.2	102.5	95.7
2w	208.2	0.81	45.7	76.3	38.5	224.0
Acetazolamide			250	125	25	5.7

^aCaclculated using Molinspiration Chemoinformatics [34].

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

Figure 3. Co-crystal structure of fragment sulfamide 2v with hCA II (PDB code 7QSI).

Table 2. Summary of data collection and atomic model refinement statistics for hCAII.^a

	hCAII + 2v
PDB ID	7QSI
Wavelength (Å)	0.999900
Space Group	P21
Unit cell (a, b, c, α, β, γ) (Å,°)	42.363, 41.557, 72.068 90.000, 104.495, 90.000
Limiting resolution (Å)	41.02–1.30 (1.34–1.30)
Unique reflections	52,866 (2056)
Rmerge (%)	6.4 (73.2)
Rmeas (%)	7.0 (84.4)
Redundancy	6.11 (3.98)
Completeness overall (%)	88.9 (46.7)
<I/σ(I)>	19.54 (2.1)
CC (1/2)	99.9 (63.8)
Refinement statistics
Resolution range (Å)	41.02–1.30
Rfactor (%)	16.27
Rfree(%)	18.45
r.m.s.d. bonds(Å)	0.0135
r.m.s.d. angles (°)	1.8542
Ramachandran statistics (%)
Most favoured	96.9
additionally allowed	3.1
outlier regions	0.0
Average B factor (Å^2)
All atoms	15.116
inhibitors	11.348
Solvent	24.123

^aValues in parentheses are for the highest resolution shell.

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