Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors

Abstract

Carbonic anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life, classified into seven genetically different families (α–θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3−) and protons (H+). Fifteen isoforms of human CA (hCA I–XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) have been used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.

Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid–sulphonamide conjugates

“…Most of the compounds exhibited inhibition constants K I values ranging from 0.5 to 8.9 nM against hCA II, being more effective inhibitors than the standard sulphonamide acteazolamide AZA. In parallel to the results in hCA I, 4-(2-aminoethyl)benzenesulphonamide derivatives (1-12) showed better inhibition than the corresponding homosulphonamide derivatives (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Compounds 1 and 3 also showed a better inhibition against hCA VA compared to AAZ, while compounds 2, 4-6 showed a comparable inhibition to that of AAZ.…”

“…The starting materials and reagents used in the reactions were supplied commercially by Aldrich, Acros, Merck, AFG Bioscience, Bachem, Alfa Aesar, or Fluorochem (all from Milan, Italy). Nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR) spectra were recorded using a Bruker Advance III 400 or 300 MHz spectrometers in DMSO-d 6 . Chemical shifts are reported in parts per million (ppm) and the coupling constants (J) are expressed in Hertz (Hz).…”

“…HCl reagent. All compounds were fully characterised by 1 H, 13 C NMR, MS, and FTIR (ATR) spectroscopy and elemental analyses. The analytical and spectral data of all the synthesised compounds were in full agreement with the proposed structures.…”

“…Therefore, synthesis of new sulphonamide derivatives is an active research topic for organic and pharmaceutical chemists 8, 9 . Both sulphonamides [10][11][12] and amino acids [13][14][15] have been reported to have various biological activities, but there are few reports of their successful combination in one molecule as a hybrid drug candidate [16][17][18] . Due to their antimicrobial and CA inhibitory properties, both primary and secondary sulphonamide derivatives are under investigation to determine compounds possessing the highest activity with possibly few side-effects 19,20 .…”

A Facile and Eco-Friendly Method for the Synthesis of Sulfonamide and Sulfonate Carboxylic Acid Derivatives—X-ray Structure, Hirshfeld Analysis and Spectroscopic Characterizations

“…Since the commercialization of Prontosil [1] as a drug in 1935, intense surveys have been made and a huge number of sulfonamide derivatives and their biological applications have been reported [2][3][4][5][6][7][8][9][10][11]. Several methods for the synthesis of sulfonamide from different substrates have been reported, for example, using sulfonyl chloride and amines [12,13] using a chlorinating agent with the corresponding sulfurated starting materials [14][15][16][17] or using non-conventional methods such as transition metals [18] or Grignard reagents [19].…”