Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

Figures & data

Figure 1. General structure of taurine sulphonamides terminated with thioureido tails¹⁵.

Figure 2. The design for the targeted compounds benzoylthioureido benzenesulfonamide derivatives (7a–f) and their analogues (8a–f) and (9a–f).

Scheme 1. Synthetic pathways for compounds 7a–f, 8a–f, 9a–f. Reagents and conditions: (i) KOH, acetonitrile, R.T, 1–2 h, (ii) SOCl₂, methylene chloride, reflux, 4–5 h, (iii) NH₄SCN, acetone, reflux, 1–3 h, (iv) acetone, reflux, 2–3 h.

Table 1. Carbonic anhydrase inhibitory activity of compounds 7a–f, 8a–f, and 9a–f and the standard sulphonamide inhibitor acetazolamide (AAZ) using a stopped flow CO₂ hydrase assay.

Compound No.	R1	R2	Ki* (nM)
			hCA I	hCA II	hCA IX	hCA XII
7a	H	-NHCOCH3	58.20	2.50	237.50	>100 000
7b	H	-NHCOCH(CH3)2	56.30	2.10	149.30	>100 000
7c	H	-NHCO(4-CH3C6H4)	33.00	56.60	31.20	>100 000
7d	-NHCOCH3	H	5451.10	701.20	168.10	97.00
7e	-NHCOCH(CH3)2	H	333.40	39.60	203.5	94.00
7f	-NHCO(4-CH3C6H4)	H	43.00	39.00	30.00	106.00
8a	H	-NHCOCH3	8177.40	5401.30	209.50	17.00
8b	H	-NHCOCH(CH3)2	>100 000	>100000	207.50	141.60
8c	H	-NHCO(4-CH3C6H4)	9171.50	295.10	264.00	145.20
8d	-NHCOCH3	H	>100 000	855.10	971.10	>100 000
8e	-NHCOCH(CH3)2	H	>100 000	429.60	898.40	101.50
8f	-NHCO(4-CH3C6H4)	H	422.20	>100000	176.00	11.00
9a	H	-NHCOCH3	9036.70	>100000	2127.50	>100 000
9b	H	-NHCOCH(CH3)2	8661.20	57.10	300.0	>100 000
9c	H	-NHCO(4-CH3C6H4)	>100000	546.20	251.50	>100 000
9d	-NHCOCH3	H	>100 000	>100 000	1632.30	>100 000
9e	-NHCOCH(CH3)2	H	8495.20	73.20	29.00	201.50
9f	-NHCO(4-CH3C6H4)	H	>100 000	>100 000	1581.50	155.40
SLC-0111^19	–	–	5080.00	960.00	45.00	4.50
AAZ	–	–	250.00	12.10	25.70	5.70

The reported K_is values of SLC-0111.

*Mean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values);

Table 2. Calculated selectivity indexes (S.I.s) for inhibition of hCA IX over hCA I and hCA II isoforms for compounds 7c, 7f, 9e, SLC-0111, and AAZ.

Compound No.	I/IX	II/IX
7c	1.0	2.0
7f	1.4	1.3
9e	293	2.5
SLC-0111	113	21
AAZ	10	0.5

Table 3. Calculated selectivity indexes (S.I.s) for inhibition of hCA XII over hCA I and hCA II isoforms for compounds 8a, 8f, SLC-0111, and AAZ.

Compound No.	I/XII	II/XII
8a	481	318
8f	38	>9091
SLC-0111^44	1129	213
AAZ	44	2

Figure 3. 2D interaction of compound 7c within the active site of hCAI.

Figure 4. 2D interaction of compound 7a within the active site of hCAII.

Figure 5. 2D interaction of AAZ within the active site of hCAII.

Figure 6. 2D interaction of compound 7f within the active site of hCAIX.

Figure 7. 2D interaction of compound 8f within the active site of hCAXII.

Figure 8. 2D Interaction of SLC-0111 within the active site of hCAXII.

Figure 9. Expected boiled-egg plot from Swiss ADME online web tool for compounds 7a, 7b, 7c, 7f, 8a, 8f, and 9e.

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