Non-Classical Inhibition of Carbonic Anhydrase

Abstract

Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives.

Aspirin: A Suicide Inhibitor of Carbonic Anhydrase II

“…Many of these sulfonamide-based molecules are used clinically, such as dorzolamide, for the treatment of glaucoma [13,14]. In addition to sulfonamides, a variety of other chemical motifs have been identified to inhibit CA, such as carboxylic acids [15]. Nicotinic and ferulic acid have recently been identified as inhibitors of CAII [16].…”

Discovery of potent carbonic anhydrase, acetylcholinesterase, and butyrylcholinesterase enzymes inhibitors: The new amides and thiazolidine-4-ones synthesized on an acetophenone base

“…The CA I isoform is available in cerebral and retinal illness, and we pursued the supposition that proteins of the CA I isoform could demonstrate treatment purposes for inhibiting CA I‐induced vascular permeance . The HCA I isoform is significantly expressed in the human body, and it is available in great concentrations in the gastrointestinal tract and blood .…”

“…4.2.1.1), as isoforms I and II, are extremely available in the gastrointestinal tract and in red blood cells of vertebrates, arriving at concentrations as high as 0.2 mM and having a significant role in blood pH homeostasis as well as in carrying carbon dioxide (CO 2 ) to the lungs. [ Both of these cytosolic isoenzymes are the predominant ones among the 16 CAs recorded throughout history in the tissues of vertebrates/different cells . Twelve of them are described by a common Zn 2+ ion at the active site, while they differ in tissue and organ expression, molecular features, catalytic activity cellular localization, and how they respond to various groups of inhibitors …”

Computational Evaluation of Pharmacokinetics and Potential Protein Targets of Ginger (Zingiber officinale)

“…For example, ACE and CA are zinc metalloenzymes that could cause hypertension but they differ in location and reaction. All the CA targets of ginger in table 2 belonged to the cytoplasmic CA isozymes [22,23], and not membrane bound.…”