Abstract
A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. KI values of these sulphonamides were in the range of 21 ± 4–72 ± 2 nM towards hCA I and in the range of 16 ± 6–40 ± 2 nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (KIs of 21 nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.
Highlights
Carbonic anhydrases (CAs, EC 4.2.1.1) are a superfamily of metalloenzymes that catalyse the interconversion reaction between carbon dioxide and bicarbonate[1,2]
Human carbonic anhydrases are targets for the design of new drugs to use in the diagnosis and/or treatment of many diseases
HCA II, IV, XII, and XIV inhibitors are used as diuretics, whereas human carbonic anhydrases (hCAs) II, IV, and XII inhibitors are used as anti-glaucoma drugs1,2,8,9. hCA I plays a role in the regulation of retinal pathologic processes, and its inhibition is a strategy for the treatment of such conditions. hCA II inhibitors are used for the treatment of glaucoma, oedema, and epilepsy[5,8]
Summary
Carbonic anhydrases (CAs, EC 4.2.1.1) are a superfamily of metalloenzymes that catalyse the interconversion reaction between carbon dioxide and bicarbonate[1,2]. The metal ions present within the active site of these enzymes (Zn(II), Cd(II), Co(II), Fe(II) or Mn(II) for the i-CAs) are coordinated by three amino acid residues and a water molecule which is activated by the metal ion and the hydrophobic environment, becoming highly nucleophilic[3,4,5] This metal hydroxide species nucleophilically attacks CO2 and promotes its hydration to bicarbonate very efficiently at almost a neutral pH3–5. There are 12 catalytically active a-CA isoforms which have different catalytic activities[6] These enzymes are distributed in many organs and tissues and they play important roles in many physiological and pathological processes such as acid-base regulation, biosynthetic reactions, electrolyte secretion, and calcification. Some compounds bearing triazene substituted sulphanilamide or metanilamide (3-aminobenzene sulphonamide) were recently reported to possess CA inhibitory effects by one of our groups[13,20], but there are few studies on this class of CA inhibitors.
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