Quaternary ammonium substituted thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides: Potential membrane-impermeable inhibitors of carbonic anhydrase.
Thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides, which have a quaternary ammonium moiety incorporated into their structures, were synthesized. All of the quaternary ammonium salts prepared in the present study are potent inhibitors of both human carbonic anhydrase-II and recombinant human carbonic anhydrase-IV; they are significantly more potent as inhibitors of these carbonic anhydrase isozymes than the previously reported inhibitor quaternary ammonium homosulfanilamide. By virtue of the permanent cationic charge on these compounds they are anticipated to be membrane-impermeable inhibitors of carbonic anhydrase. Spiro quaternary ammonium compounds, such as 15 and 16, when formed by intracellular cyclization following transport of a suitable precursor molecule, such as 14, may be selective prolonged inhibitors of cytosolic carbonic anhydrase due to intracellular entrapment.
May
Jesse A
JA
Ophthalmology Discovery Research, Alcon Research, Ltd., Fort Worth, TX 76134, USA. jesse.may@alconlabs.com
Namil
Abdelmoula
A
Chen
Hwang-Hsing
HH
Dantanarayana
Anura P
AP
Dupré
Brian
B
Liao
John C
JC
D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors* / Q000235:genetics; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D006801:Humans; D015394:Molecular Structure; D010087:Oxides / Q000737:chemistry* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D010087:Oxides; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; D013843:Thiazines; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV