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

Abstract

N-protected amino acids (Gly, Ala and Phe protected with Boc and Z groups) were reacted with sulfonamide derivatives, leading to the corresponding N-protected amino acid-sulfonamide conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV and hCA XII. Among them, hCA II, IV and XII are antiglaucoma drug targets, being involved in aqueous humor secretion within the eye. Low nanomolar inhibition was measured against all four isoforms with the 20 reported sulfonamides, but no selective inhibitory profiles, except for some CA XII-selective derivatives, were observed. hCA I, II and XII were generally better inhibited by sulfonamides incorporating longer scaffolds and Gly/Ala, whereas the best hCA IV inhibitors were homosulfanilamide derivatives, incorporating Phe moieties. The amino acid-sulfonamide conjugates show good water solubility and effective hCA II, IV and XII inhibition, and may be considered as interesting candidates for antiglaucoma studies.

Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6-pentasubstituted-4-hydroxy-cyclohexanes

“…CA II and CA I are the two main CA isoforms available at high concentrations in the cytosol of erythrocytes of several vertebrates, and the tumor‐associated, transmembrane isoforms CA IX and also CA II are together the most active of all CAs . Indeed, the design of potent, new, and isoenzyme‐selective inhibitors of different CAs can be applied for treating several diseases . hCAs, of which at least 15 isoenzymes actually belong to the α‐CA genetic family, are used as drugs for treating antiglaucoma, diuretics, antiepileptics, agents, antitumor, and antiobesity .…”

“…[73][74][75] Indeed, the design of potent, new, and isoenzyme-selective inhibitors of different CAs can be applied for treating several diseases. [76][77][78] hCAs, of which at least 15 isoenzymes actually belong to the -CA genetic family, are used as drugs for treating antiglaucoma, diuretics, antiepileptics, agents, antitumor, and antiobesity. [79,80] Recently, the cloning of genomes of multitude microorganisms, such as fungi, pathogenic bacteria, and protozoa, has advanced enormously.…”

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

“…In addition, in humans, CA isoforms exist in a wide variety of tissues including the reproductive tract, gastrointestinal tract, kidneys, lungs, CNS, eyes, and skin . Thus far, seven types of CA families have been recorded: the α‐, β‐, γ‐, δ ‐, ζ‐, n‐, and θ‐CAs . All of the human CAs (hCAs) belongs to the α‐CA family.…”

“…[24][25][26][27] Thus far, seven types of CA families have been recorded: the -, -, -, -, -, n-, and -CAs. [28][29][30] All of the human CAs (hCAs) belongs to the -CA family. hCA II has an important role in bicarbonate (HCO 3 − ) production in the eye, and it hence has a validated purpose for the treatment of glaucoma.…”

The synthesis of some β-lactams and investigation of their metal-chelating activity, carbonic anhydrase and acetylcholinesterase inhibition profiles

“…So far, five different CA inhibition mechanisms were reported: (i) the zinc ion (Zn 2+ ) binders are the inhibitors which coordinate to the catalytically crucial Zn 2+ from the enzyme active site. In this inhibition type, Zn 2+ may be in a tetrahedral or trigonal bipyramidal geometries, with the sulfonamides and sulfamides, sulfamates, most anions, dithiocarbamates, carboxylates, and hydroxamates binding in this way 97 ; (ii) the inhibitors that anchor to the Zn 2+ -coordinated water molecule (H 2 O)/hydroxide ion (-OH), represented by the phenols, some carboxylates, the polyamines, 2-thioxocoumarins, and sulfocoumarins 96,98 ; (iii) the inhibitors-like coumarins and their isosteres which occlude the entrance to the active site cavity, this binding site coinciding with that where CA activators bind 99 ; (iv) the compounds which bind out of the active site cavity, and (v) compounds for which the inhibition mechanism is not known, among which the secondary or tertiary sulfonamides are the most investigated examples 100 . The hCA I and II isoenzyme inhibitory activity of the imines (10)(11)(12)(13)(14) and b-lactam analogs (15)(16)(17)(18)(19) was shown in Table 3.…”