Fluorinated pyrrolidines and piperidines incorporating tertiary benzenesulfonamide moieties are selective carbonic anhydrase II inhibitors

How many carbonic anhydrase inhibition mechanisms exist?

“…By using superacid chemistry Thibaudeau's group reported a wide range of halogenated secondary/tertiary derivatives (e.g. [71][72][73], some of which showed selective inhibitory action against the tumor-associated isoforms hCA IX/ XII, without significant inhibition of hCA I and II [145][146][147][148] . By using saccharin 11 as lead 46 , Carradori's group reported a range of N-substituted saccharins, among which 74-77 (and some of their congeners) showed CA XII selective inhibitory action 149 .…”

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date. Thus, the sulfonamides reported here incorporate in their molecule the urea fragment found in SLC-0111 and the secondary sulfonamide moiety present in sulfa drugs and several recently investigated CAIs [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] .…”

“…In addition, a range of secondary and tertiary sulfonamides has been investigated as CAIs recently, some of them showing effective and selective inhibition of several important isoforms [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date.…”

Synthesis and carbonic anhydrase I, II, IV and XII inhibitory properties of N-protected amino acid – sulfonamide conjugates

“…The metal ion may be in a tetrahedral or trigonal bipyramidal geometries, with the sulfonamides and their isosteres (sulfamides, sulfamates, etc. ), most anions, dithiocarbamates and their isosteres, carboxylates and hydroxamates binding in this way [1][2][3]5,13 ; (ii) the inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion, represented by the phenols, some carboxylates, the polyamines, 2-thioxocoumarins, and sulfocoumarins [1][2][3]13,14 ; (iii) the inhibitors which occlude the entrance to the active site cavity (coumarins and their isosteres), this binding site coinciding with that where CA activators bind [13][14][15][16][17][18][19][20] ; (iv) the compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner) 21 , and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples 13,[22][23][24][25][26] . The sulfonamides however remain the main class of CAIs with many clinically used drugs as antiglaucoma agents [27][28][29] , diuretics 30 , antiobesity drugs [31][32][33] , antiepilpetics 34 , and more recently agents for the management of hypoxic tumors [35][36][37][38] , neuropathic pain 39 and ischaemia …”