Structural effect of phenyl ring compared to thiadiazole based adamantyl-sulfonamides on carbonic anhydrase inhibition.

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Biswas S, Carta F, Scozzafava A, McKenna R, Supuran CT

Structural effect of phenyl ring compared to thiadiazole based adamantyl-sulfonamides on carbonic anhydrase inhibition.

Bioorg Med Chem. 2013 Apr 15;21(8):2314-2318. doi: 10.1016/j.bmc.2013.02.022. Epub 2013 Feb 21.

PubMed ID

23490152 [ View in PubMed

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Abstract

We investigated the inhibitory activity of sulfonamides incorporating adamantyl moieties against the physiologically relevant human (h) CA (EC 4.2.1.1) isoforms hCA I, II III (cytosolic), IX and XII (transmembrane, tumor-associated). The presence of a benzenesulfonamide instead of an 1,3,4-thiadiazole-sulfonamide fragment in the molecule of CA inhibitors (CAIs) drastically affects both inhibition efficacy and binding within the enzyme active site, as rationalized by means of X-ray crystallography of the adduct of hCA II with 4-(1-adamantylcarboxamidomethyl)benzenesulfonamide. Comparing the present X-ray structure with that of the corresponding 1,3,4-thiadiazole-sulfonamide compound possessing the 1-adamantylcarboxamide moiety, important differences of binding emerged, which explain the highly different inhibition profile of the two compounds against the investigated CA isoforms, most of which (CA I, II, IX and XII) are important drug targets.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 12	Ki (nM)	2.5	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 3	Ki (nM)	200000	N/A	N/A	Details