Investigation on Hydrazonobenzenesulfonamides as Human Carbonic Anhydrase I, II, IX and XII Inhibitors

Abstract

A small series of hydrazonobenzenesulfonamides was designed, synthesized and studied for their human carbonic anhydrase (hCA) inhibitory activity. The synthesized compounds were evaluated against hCA I, II, IX and XII isoforms using acetazolamide (AAZ) as the standard inhibitor. Various hydrazonosulfonamide derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The most potent and selective hydrazones 8, 9, 10, 11, 19 and 24 were docked into isoforms I, II, IX and XII to better understand their activity and selectivity for the different CA isoforms.

Imidazole‐hydrazone derivatives: Synthesis, characterization, X‐ray structures and evaluation of anticancer and carbonic anhydrase I–II inhibition properties

“…Carbonic anhydrases (CAs), which are enzymes that catalyze the interconversion of CO 2 and HCO 3−, are present in several organisms [2] . There are now 15 distinct isoforms known, each with a unique molecular structure, catalytic capabilities, organ and tissue distribution, subcellular localization, and capacity to interact with various inhibitor types [3] . There are various cytosolic forms (CA I, II, III, and IV) seen in mammals.…”

Celecoxib Derivatives Containing Pyrazole Linked‐Sulfonamide Moiety: Carbonic Anhydrase I–II and Acetylcholinesterase Inhibition Profiles, Molecular Docking Studies

“…The inhibitory effect of celecoxib‐derived compounds on the CA II isozyme, which has recently been found to be associated with neurodegeneration and aging processes, which is generally associated with people suffering from diseases such as osteoporosis, glaucoma, and renal tubular acidosis, was investigated [12] . hCA II is effectively inhibited by many of the pyrazole compounds reported here.…”

“…According to their cell distribution, these isoforms are grouped membrane‐bound (CA IV, CA IX, CA XII, CA XIV, and CA XV), cytosolic (CA I, CA II, CA III, CA VII, and CA XIII), mitochondrial (CA VA and VB), and secretory (CA VI) [11] . Of the cytosolic isoforms, hCA I and hCA II are widely expressed in erythrocytes, gastrointestinal tract, eyes, and kidney cells, and these isoforms are considered off‐target for tumor‐associated, transmembrane hCA IX and XII [12] . hCAs have become drug targets to treat conditions associated with pathologies such as glaucoma diuretics, Alzheimer's, hemolytic anemia, osteoporosis, epilepsy, and the importance of these isoenzyme inhibitors is emphasized in scientific studies [13] .…”

“…[11] Of the cytosolic isoforms, hCA I and hCA II are widely expressed in erythrocytes, gastrointestinal tract, eyes, and kidney cells, and these isoforms are considered off-target for tumor-associated, transmembrane hCA IX and XII. [12] hCAs have become drug targets to treat conditions associated with pathologies such as glaucoma diuretics, Alzheimer's, hemolytic anemia, osteoporosis, epilepsy, and the importance of these isoenzyme inhibitors is emphasized in scientific studies. [13] In addition, sulfonamides are the most important and leading CA inhibitor [14] group besides many biological activities such as anticancer, [15] antiinflammatory, [16] and antibacterial.…”

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

“…The inhibitory activities on hCAs of benzene­sulfon­amides 5 – 13 (Table ) and 14 – 24 (Table ) have been explored by stopped-flow CO 2 hydrase assay, using acetazol­amide (AAZ) as reference compound. The cytosolic hCA I isoform has been taken as an off-target isoform, while both cytosolic hCA II and transmembrane hCA IX are outstanding targets for the treatment of glaucoma due to their role in maintaining intraocular pressure.…”