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

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.

Antibacterial properties and carbonic anhydrase inhibition profiles of azido sulfonyl carbamate derivatives

Aim: The aim of this study was to identify inhibition of carbonic anhydrase I and II (CA I and II) isozymes by azido sulfonyl carbamates through both in vitro and in silico approaches and also to determine the drug-likeness properties and antibacterial activities of azido sulfonyl carbamates. Methods & Results: In vitro inhibition and molecular docking studies of azido sulfonyl carbamate derivatives (1–4) on isozymes were performed. Except for derivative 4, all derivatives inhibited human CA I and II. Almost all compounds had antibacterial effects. The docking results showed that compound 3 had the best results, with binding energy of -8.20 kcal/mol for human CA I and -8.24 kcal/mol for human CA II. Conclusion: Molecule 4 inhibited only CA I. Its usage as a potential chemotherapeutic agent specific to the CA I isozyme may be considered.

Carbonic Anhydrase Inhibition Improves Pulmonary Artery Reactivity and Nitric Oxide-Mediated Relaxation in Sugen-Hypoxia Model of Pulmonary Hypertension

Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen5416 (20mg/kg, sc) and subjected to hypoxia (9%O2) (Su+Hx), or Su+Hx treated with acetazolamide (ACTZ, 100mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su+Hx and reduced in Su+Hx+ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su+Hx and improved in Su+Hx+ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su+Hx and improved in Su+Hx+ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su+Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su+Hx that was ameliorated in Su+Hx+ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation, and may enhance responsiveness to vasodilator therapies in PH.