Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives.

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Brzozowski Z, Slawinski J, Gdaniec M, Innocenti A, Supuran CT

Eur J Med Chem. 2011 Sep;46(9):4403-10. doi: 10.1016/j.ejmech.2011.07.011. Epub 2011 Jul 8.

PubMed ID

21820216 [ View in PubMed

]

Abstract

A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K(I)s in the range of 0.089-251 muM, whereas toward hCA II, K(I)s = 50.5-487 nM. Isozyme hCA IX was inhibited with K(I)s in the range of 5.2-18.3 nM, while hCA XII with K(I)s = 6.0-16.4 nM, and hCA XIV with K(I)s = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K(I)s = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	310	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 12	Ki (nM)	5.7	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 14	Ki (nM)	41	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details
Diclofenamide	Carbonic anhydrase 1	Ki (nM)	1200	N/A	N/A	Details
Diclofenamide	Carbonic anhydrase 2	Ki (nM)	38	N/A	N/A	Details
Ethoxzolamide	Carbonic anhydrase 1	Ki (nM)	25	N/A	N/A	Details
Ethoxzolamide	Carbonic anhydrase 2	Ki (nM)	8	N/A	N/A	Details