Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold

Abstract

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.

Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation

“…Moreover, considering the esterase activity of hCAs 40 , these molecules, if not active as esters, could undergo the enzyme-mediated hydrolysis in the active site acting as putative prodrugs of the acid compounds. The derivatives belonging to the sub-groups ii and iii of Figure 1(b) can also be considered the isosteres of a series of compounds recently reported by our group ( Figure 1(b) , iv and v ) 41 . These inhibitors, even if devoid of any zinc binding group (ZBG), resulted active selectively against hCA IX in the µM range, prompting us to consider that the replacement of -CH 2 by -NH could improve the activity against hCAs.…”

5‐[2‐(N‐(Substituted phenyl)acetamide)]amino‐1,3,4‐thiadiazole‐2‐sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects

“…CAs is widespread in organisms, varying with respect to tissue distribution and subcellular localization . Fifteen α‐isozymes (CA I–XV) have been isolated and characterized so far, but only 12 of them are catalytically active . CA II is the most widely expressed isoform and is identified in the anterior chamber of the eye, and that is also responsible for the production of bicarbonate and the main constituent of the aqueous humour .…”

“…[8,9] Fifteen αisozymes (CA I-XV) have been isolated and characterized so far, but only 12 of them are catalytically active. [10][11][12] CA II is the most widely expressed isoform and is identified in the anterior chamber of the eye, and that is also responsible for the production of bicarbonate and the main constituent of the aqueous humour. [13] CAI and II are ubiquitous CA isoforms, and both exist in the cytoplasm.…”

A class of carbonic anhydrase IX/XII – selective carboxylate inhibitors

“…The 15 human (h) CA isoforms are in fact involved in a multitude of diseases, and mainly their inhibitors have pharmacologic applications for the treatment of a range of diseases including glaucoma and other ophthalmologic problems, oedema, epilepsy, obesity, tumours, arthritis, etc [17][18][19][20][21][22][23][24][25] . Only sulphonamides and sulphamate CA inhibitors (CAIs) are in clinical use at this moment [1][2][3]5,[23][24][25] , although many other different chemotypes were discovered in the last period to exert such an action, among which coumarins and sulphocoumarins [26][27][28][29][30][31] , phenols 20,22 , mono-/ dithiocarbamates 32 , and carboxylates [33][34][35][36][37][38] . What is notable for these new chemotypes is the fact that they possess rather different inhibition mechanisms from the sulphonamides, which coordinate in deprotonated form to the metal ion from the CA active site [1][2][3][4][5] .…”