Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

Abstract

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

Keywords: carbonic anhydrase; inhibitors; metalloenzymes; pyrazole derivatives.

Figure 1

Structure of drugs bearing the pyrazole moiety.

Figure 2

Structure of acetazolamide (AAZ).

Scheme 1

Synthesis of 3-(2-hydroxyaryl)-1H-pyrazole derivatives.

Scheme 2

Synthesis of 1-aryl-4-oxo-1,4-dihydropyridazine derivatives.

Scheme 3

Synthesis of 6,7-dimethoxy-1-methyl-1,4-dihydroindeno[1,2-c]pyrazole derivatives.

Figure 3

Structure–activity relationship summary of tested compounds.

Figure 4

(A) Superposition of compound 15 bound to hCA I (green) in comparison to hCA II (magenta), with specific residues labeled. (B) 2D interaction diagram of compound 15 docking pose interactions with the key amino acids in hCA I, (C) in hCA II. Active site zinc shown as blue sphere; red dotted arrows indicate H-bond, and yellow spheres hydrophobic interactions. Orange double-headed arrow indicates the direction of conformational change of the compound bound to hCA I in comparison to hCA II enzyme.

Figure 5

(A) 2D interaction diagram of compound 5d docking pose interactions with the key amino acids in hCA II, (B) in hCA XII. (C) Superposition of compound 5d bound to hCA II (magenta) in comparison to hCA XII (blue), with specific residues labeled. (D) 3D diagram of compound 5d bound to hCA XII. Active site zinc shown as blue sphere, red dotted and green arrows indicate H-bond and yellow spheres hydrophobic interactions.

Figure 6

(A) Superposition of compound 10d bound to hCA I (orange) in comparison to AAZ (yellow) in hCA I. (B) 2D interaction diagram of compound 10d docking pose interactions with the key amino acids in hCA I. Active site zinc shown as blue sphere, red dotted arrows indicate H-bond, and yellow spheres indicate hydrophobic interactions.