Discovery of curcumin inspired sulfonamide derivatives as a new class of carbonic anhydrase isoforms I, II, IX, and XII inhibitors

Figures & data

Figure 1. Structures of some drugs and drug candidates possessing sulfonamide/sulfamate moiety.

Figure 2. Design of curcumin inspired sulfonamide derivatives as hCA inhibitors.

Scheme 1. Synthesis of curcumin inspired sulfonamide derivatives (5a–j); Reagents and conditions: (i) 15% NaOH, ethanol, 0 °C – rt, 2–3 h, 72–85%; (ii) 15% NaOH, ethanol, 0 °C – rt, 1–2 h, 35–45%.

Table 1. In vitro CA I, II, IX, and XII inhibition with compounds 5a–j and acetazolamide (AAZ) as standard, by a stopped-flow, CO₂ hydrase assay.²⁹

	KI (nM)^a				Selectivity ratio^b
Compound	hCA I	hCA II	hCA IX	hCA XII	II/IX	II/XII
5a	417.4	7.9	2.3	6.1	3.43	1.29
5b	286.1	2.1	8.6	6.3	0.24	0.33
5c	848.1	4.7	7.5	7.4	0.62	0.63
5d	703.7	0.89	8.4	8.1	0.10	0.10
5e	294.8	0.75	2.3	52.2	0.32	0.01
5f	191.8	3.0	2.4	71.8	1.25	0.04
5g	904.2	0.87	2.4	7.4	0.36	0.11
5h	594.6	8.8	7.8	25.0	1.12	0.35
5i	372.6	8.1	87.3	31.1	0.09	0.26
5j	246.2	8.2	61.0	68.0	0.13	0.12
AAZ	250	12.1	25.8	5.7	0.46	2.12

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

^b Selectivity as determined by the ratio of K_is for hCA isozyme relative to hCA IX and hCA XII.

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;246:2561–73.

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