New non-peptidic Inhibitors of Papain Derived from Etacrynic Acid

Kaeppler, Ulrich; Schirmeister, Tanja

doi:10.2174/1573406054368701

Cited by 8 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…89 Among the isolated compounds, biflavone amentoflavone (86) was recognized as a potent noncompetitive inhibitor, exhibiting an IC 50 value of 8.3 μM. An SAR study demonstrated the three authentic flavones, apigenin (90), luteolin (82), and quercetin (83), showed inhibitory activities (IC 50 ) of 280.8, 20.2, and 23.8 μM, respectively. The activity of amentoflavone (86) was consistent with the binding interactions (docking studies of 86 with PDB ID 2Z3E, see SI, Figure S6), with Val186 and Gln192 as one of the key binding modes with the target site.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

View full text Add to dashboard Cite

Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CL(pro), has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CL(pro) chemotherapies discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CL(pro). Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

show abstract

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

View full text Add to dashboard Cite

show abstract

“…[11]), its norethyl derivative (12, for synthesis, see the Supporting Information), trans-(1-phenyl)but-2-en-1-one (9, Sigma-Aldrich), 3-methylenechroman-4-one (10, synthesized according to ref. [38]), and 6-chloro-4H-chromen-4-one (11,Maybridge). The structures of these compounds are shown in Figure 3.…”

Section: Chemoassaysmentioning

confidence: 99%

“…Another approach starts from substituted etacrynic acid, [10,11] which possesses an a,b-unsaturated ketone moiety as an electrophilic building block ( Figure 1). While the vinylogous esters lead to irreversible inhibition, the etacrynic acid derivatives show only reversible inhibition of proteases.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

Paasche¹,

Schiller²,

Schirmeister³

et al. 2010

ChemMedChem

View full text Add to dashboard Cite

We investigated the reactions between substituted alpha,beta-unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS-CoV M(pro)) by etacrynic acid derivatives as well as for the excess toxicity of substituted alpha,beta-unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4-addition followed by a ketonization step, and underscores the importance of a base-catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron-pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the s-cis conformation leads to higher reactivity than the s-trans conformation. The computed data explain the trends in measured inhibition potencies of substituted alpha,beta-unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.

show abstract

“…In terms of inhibition mechanism, ethacrynic acid derivatives are a new interesting class of inhibitors [166,167]. The compounds are derived from the well known diuretic drug [168].…”

Section: Inhibitors Containing An Activated Double Bond: Methylene Kementioning

confidence: 99%

“…These interesting properties of ethacrynic acid led to the development of derivatives thereof as potential non-peptidic cysteine protease inhibitors [166][167]. To investigate which structural features are necessary for inhibition, the prototype compound was modified on several positions and tested on various proteases (Fig.…”

Section: Inhibitors Containing An Activated Double Bond: Methylene Kementioning

confidence: 99%

Inhibitors of Cysteine Proteases

Vičík¹,

Busemann²,

Baumann³

et al. 2006

CTMC

View full text Add to dashboard Cite

The roles of cysteine proteases (CP) as protein degrading and protein processing enzymes both in physiological and pathological processes of mammals are well known. Furthermore, the key roles of CP;s in the life cycles of infectious agents like protozoa and viruses turn them into new important targets for anti-infective drugs. Thus, the effective inhibition of pathologically relevant cysteine proteases has raised increasing interest in drug development. One strategy to create CP inhibitors is the use of electrophilic moieties, which covalently bind to the cysteine residue of the active site of the target protease. In a previous approach we have selected the aziridine-2,3-dicarboxylic acid as weak electrophilic inhibitor fragment. In order to achieve effective enzyme inhibition this electrophile was incorporated into peptidic or peptidomimetic sequences addressing the substrate binding sites of the protease. High selectivity could be obtained with compounds, which bind into both the primed and non-primed substrate binding pockets. In a second approach the alpha,beta-unsaturated ketone of the well-known diuretic drug ethacrynic acid was found to be another appropriate electrophilic moiety. Derivatives thereof turned out to be new non-peptidic CP inhibitors. Results of inhibition assays obtained with these two inhibitor series on various proteases of human, protozoan, and viral origin, theoretical studies to investigate binding modes and inhibition mechanisms, and structure-activity relationships are presented. Furthermore, the results of in vitro assays on respective pathogens as well as the results of first toxicity studies are summarized.

show abstract

New non-peptidic Inhibitors of Papain Derived from Etacrynic Acid

Cited by 8 publications

References 0 publications

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

Inhibitors of Cysteine Proteases

Contact Info

Product

Resources

About