Inhibition of serine proteases by functionalized sulfonamides coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold

Groutas, William C.; He, Shu; Kuang, Rongze; Ruan, Sumei; Tu, Juan; Chan, Ho-Kit

doi:10.1016/s0968-0896(01)00037-2

Cited by 34 publications

(12 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lack of inhibitory activity toward PR 3 is not intuitively obvious and may be due to unproductive binding arising from the way the substituted thioether and ester moieties are projecting into the S’ subsites. We have previously observed that inhibitory potency is dependent on the pK a of the conjugate acid of the leaving group (ArS − ), as well as its inherent structure, and that the latter can be modulated to enhance binding affinity through favorable interactions with the S’ subsites 29. With the exception of compound 16 , the rest of the compounds showed little variation in their inhibitory prowess toward the enzyme.…”

Section: Resultsmentioning

confidence: 99%

Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding

Li¹,

Dou²,

He³

et al. 2009

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

A series of mechanism-based inhibitors designed to interact with the S’ subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S’ subsites. The best inhibitor (compound 16) had a kinact/KI value of 4580 M−1 s−1.

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding

Li¹,

Dou²,

He³

et al. 2009

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…44 Functionalized sulfonamides coupled with 1,2,5-thiadizolidin-3-one 1,1-dioxide scaffolds of type 60 were also recently shown to act as potent inhibitors of several serine proteases, including the enzyme of interest in this section. 49 It is not clear what the role of the sulfonamide moieties in the HNE inhibitors discussed here is, since no X-ray crystal structures of such adducts are available, but presumably these highly polar moieties enhance water solubility of these drugs, and also favor molecular interactions with critical amino acid residues present in the binding site of the enzyme.…”

Section: H U M a N N E U T R O P H Y L E L A S T A S E S U L F O N mentioning

confidence: 98%

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Supuran

Casini

Scozzafava

2003

Medicinal Research Reviews

398

153

View full text Add to dashboard Cite

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

show abstract

“…3). [70][71][72][73][74][75][76][77][78][79] A general heterocyclic scaffold have been designed by Groutas et al [70][71][72][73][74][75][76][77][78][79] based on the interaction with both the S and S 0 subsite of the target enzyme (Fig. 3).…”

Section: Human Elastasesmentioning

confidence: 99%

“…Among them, some compounds were found to be more selective for one of the three enzymes, but with moderate inhibitory activity. [70][71][72][73][74][75][76][77][78][79] Even if no compounds presenting such structures are currently in clinical trials, the cyclic or heterocyclic sulfamide represent a powerful design scaffold with considerable flexibility for obtaining large libraries of selective and sometimes potent inhibitors.…”

Section: Human Elastasesmentioning

confidence: 99%

Therapeutic potential of sulfamides as enzyme inhibitors

Winum¹,

Scozzafava²,

Montéro³

et al. 2006

Med. Res. Rev.

178

107

View full text Add to dashboard Cite

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.

show abstract

Inhibition of serine proteases by functionalized sulfonamides coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold

Cited by 34 publications

References 30 publications

Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding

Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Therapeutic potential of sulfamides as enzyme inhibitors

Contact Info

Product

Resources

About