Therapeutic potential of sulfamides as enzyme inhibitors

Abstract

Sulfamide, a quite simple molecule incorporating the sulfonamide functionality, widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications, may give rise to at least five types of derivatives, by substituting one to four hydrogen atoms present in it, which show specific biological activities. Recently, some of these compounds started to be exploited for the design of many types of therapeutic agents. Among the enzymes for which sulfamide-based inhibitors were designed, are the carbonic anhydrases (CAs), a large number of proteases belonging to the aspartic protease (HIV-1 protease, gamma-secretase), serine protease (elastase, chymase, tryptase, and thrombin among others), and metalloprotease (carboxypeptidase A (CPA) and matrix metalloproteinases (MMP)) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays important roles for the binding of the inhibitor to the active site cavity, either by directly coordinating to a metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors, interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN-SO2-NH motif, which substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-chemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized moiety when attached to an organic scaffold. This interesting motif is thus of great value for the design of pharmacological agents with a lot of applications.

One Pot Synthesis of Some Novel Sulfonamide Derivatives Containing -NH2 Group: Spectral Characterization and Biological Evaluation

“…So sulfonamides and their derivatives are used as antibiotics medicines [2]. Apart from this application as an antibacterial agent, various sulfonamide derivatives are known to inhibit many enzymes such as Serine protease [3][4][5], cyclooxygenase [6], matrix metalloproteinase [7] and carbonic anhydrase [8][9][10][11]. Moreover their widespread potential values have led to discovery of various therapeutic applications in cancer chemotherapy, hypoglycemia, diuretics [12] and anti-impotence agent Viagra [13].…”

Identification of Potent and Selective Human Carbonic Anhydrase VII (hCA VII) Inhibitors

“…[16] Moreover, we prepared and tested a new class of sulfonamides 11-14, which we designed on the basis of previously published findings that the ArSO 2 NH 2 fragment is a crucial structural requirement of CAIs. [17,18] Scheme 1 shows the synthetic pathway to obtain the benzenesulfonamides 11-14. (14).…”

Carbonic anhydrase inhibitors: X-ray crystallographic studies for the binding of 5-amino-1,3,4-thiadiazole-2-sulfonamide and 5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide to human isoform II

“…[1][2][3][4][5][6] Inhibitors of these zinc-containing enzymes show a multitude of applications as diuretic, antiglaucoma, antiobesity or antitumor drugs, being also used as diagnostic tools. [1][2][3][4][5][6] Various CA isoforms are responsible for specific physiological functions, and drugs with such a diversity of actions target different isozymes of the 15 presently known in humans.…”

“…[1][2][3][4][5][6] Inhibitors of these zinc-containing enzymes show a multitude of applications as diuretic, antiglaucoma, antiobesity or antitumor drugs, being also used as diagnostic tools. [1][2][3][4][5][6] Various CA isoforms are responsible for specific physiological functions, and drugs with such a diversity of actions target different isozymes of the 15 presently known in humans. [2][3][4][5][6] In all of them, the inhibitor is bound as anion to the catalytically critical Zn 2+ ion, also participating in extensive hydrogen bond networks and van der Waals interactions with amino acid residues both in the hydrophobic and hydrophilic halves of the enzyme active site, as shown by X-ray crystallographic studies of such enzyme-inhibitor complexes.…”

“…[1][2][3][4][5][6] Various CA isoforms are responsible for specific physiological functions, and drugs with such a diversity of actions target different isozymes of the 15 presently known in humans. [2][3][4][5][6] In all of them, the inhibitor is bound as anion to the catalytically critical Zn 2+ ion, also participating in extensive hydrogen bond networks and van der Waals interactions with amino acid residues both in the hydrophobic and hydrophilic halves of the enzyme active site, as shown by X-ray crystallographic studies of such enzyme-inhibitor complexes. [7][8][9][10][11][12][13][14] Among the three main classes of potent CA inhibitors (CAIs) described up to now, the sulfonamides, the sulfamates, and the sulfamides, the first one is the most investigated, since classical, clinically used drugs such as acetazolamide 1, methazolamide 2, ethoxzolamide 3, dichlorophenamide 4, dorzolamide 5, and brinzolamide 6 all belong to it.…”