Ewgenij Proschak

Goethe-Universität Frankfurt am Main · Institut für Pharmazeutische Chemie

Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial sid...

A novel oxadiazolone‐based method for the synthesis of 3‐aminobenzisoxazoles by N−O bond formation and of 2‐aminobenzoxazoles through a Tiemann‐type rearrangement has been developed. The synthesis of these two pharmaceutically relevant heterocycles was realized by an unexplored retrosynthetic disconnection using a cyclic nitrenoid precursor‐based s...

Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple path...

Focused compound libraries are well-established tools for hit identification in drug discovery and chemical probe development. We present the compilation and application of a focused screening library of fatty acid mimetics (FAMs), which are compounds designed to bind the orthosteric site proteins that endogenously accommodate natural fatty acids a...

Soluble epoxide hydrolase (sEH) is a promising target for a number of inflammation-related diseases. In addition, inhibition of sEH has been shown to reduce neuroinflammation, which plays a critical role in the development of central nervous system (CNS) diseases such as Alzheimer's disease. In this study, we present the rational design of a small...

The Front Cover shows a scaffold hop from amodiaquine to a new agonist of the neuroprotective transcription factor Nurr1 through library synthesis from rationally and computationally selected building blocks. The first library served to replace the diethylaminomethylphenol residue before the second set varied the chloroquinoline motif. The analogue...

Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult to cure. Metallo-β-lactamases (MBLs) are a diverse set of zinc-containing enzymes that catalyze the hydrolysis of β-lactam drugs, including carbapenems, which are considered as the last resort to fight severe infections. To restore...

3-Aminoindazoles are privileged scaffolds for bioactive drug-like molecules. In this study, a microwave-assisted cascade reaction for the synthesis of N-1 substituted 3-aminoindazoles with yields up to 81% has been developed. Starting from 3-(2-bromoaryl)-1,2,4-oxadiazol-5(4H)-ones, the reaction exhibits a broad substrate scope including anilines,...

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT1A, 5-HT2A, 5-HT7 receptor, and dopamine D2 recep...

Several lines of evidence suggest the ligand‐sensing transcription factor Nurr1 as a promising target to treat neurodegenerative diseases. Nurr1 modulators to validate and exploit this therapeutic potential are rare, however. To identify novel Nurr1 agonist chemotypes, we have employed the Nurr1 activator amodiaquine as template for microscale anal...

The transcription factor hypoxia-inducible factor 1 (HIF1) is an important driver of cancer and is therefore an attractive drug target. Acriflavine (ACF) was suggested to inhibit HIF1 but its mechanism of action is unknown. Here, we investigated the interaction of ACF with DNA and lncRNAs and its function in human endothelial cells. ACF promoted ap...

The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), which has been proposed as a promising therapeutic target for diabetic wound healing and gastrointestinal lesions. In this study, the rational design of a fluorescent probe based on the synthetic BLT2 agonist CA...

The Cover Feature shows the general mode of action of thiol‐based metallo‐beta‐lactamase inhibitors. The hero in the desert represents a person administering such an inhibitor. The whip in his hands (with the thiol group at the end) represents the monothiol metallo‐beta‐lactamase inhibitor which deprives the bacteria from using their metallo‐beta‐l...

Carbapenemases such as metallo-β-lactamases (MBLs) are spreading among Gram-negative bacterial pathogens. Infections due to these multidrug-resistant bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase producing bacteria include β-lactamase inhibitor combinations. Nitroxoline is a broad-spectrum antibio...

Dimerization of Taspase1 activates an intrinsic serine protease function that leads to the catalytic Thr234 residue which allows to catalyze the consensus sequence Q⁻³X⁻²D⁻¹•G¹X²D³D⁴, present in Trithorax family members and TFIIA. Noteworthy, Taspase1 performs only a single hydrolytic step on substrate proteins which makes it impossible to screen f...

Kidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past 10 years...

Increasing antimicrobial resistance is evolving to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches aim to target bacterial virulence instead of growth. Another strategy is to restore the activity of antibiotics already in clinical use. This can be ac...

Leuktriene B4 receptor 2 (BLT2) is a G-protein coupled receptor modulation of which is discussed to be a therapeutic option for healing of intestinal lesions. In this work, new BLT2 agonists were identified by a virtual screening of a repurposing library and in vitro assay of the most promising compounds. Irbesartan, an approved type-1 angiotensin...

Non-alcoholic steatohepatitis (NASH) presents as an epidemic chronic liver disease that is closely associated with metabolic disorders and involves hepatic steatosis, inflammation, and fibrosis as key factors. Despite the enormous global prevalence of NASH, effective pharmacological interventions are lacking. Based on the hypothesis that the multif...

Diversity‐oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS‐compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)‐catalyzed coupling of dithiols to diazo building blocks. The synthetizes library was probed against metallo‐β‐l...

Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30–100 µM and 5–20-fold p...

Nuclear receptors (NRs) activate transcription of target genes in response to binding of ligands to their ligand binding domains (LBDs). Typically, in vitro assays use either gene expression or the recruitment of coactivators to the isolated LBD of the NR of interest to measure NR activation. However, this approach ignores that NRs function as homo...

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exc...

Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi‐factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such approach appears particularly suitable in non‐alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pat...

Nonalcoholic fatty liver disease (NAFLD) is an epidemic chronic liver disease and may progress over nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma. The multiple metabolic, environmental, and genetic factors that are involved in NAFLD/NASH pathogenesis and progression suggest a need for multimechanistic intervent...

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human...

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus targeting this protein domain may offer a therapeutic strategy to combat current and future virus pandemics. To assist...

The nsP3 macrodomain is a conserved protein interaction module that plays essential regula-tory roles in host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus, targeting this protein domain may offer a therapeutic strategy to combat the current and future virus pandemics. To assi...

The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARγ agonists are highly effective oral antidiabetics with great potential in MetS, which pro...

Spirocyclic scaffolds are incorporated in variousapproved drugs and drug candidates. The increasing interest inless planar bioactive compounds has given rise to the developmentof synthetic methodologies for the preparation of spirocyclicscaffolds. In this Perspective, we summarize the diverse syntheticroutes to obtain spirocyclic systems. The impac...

Designed multi-target ligands are a popular approach to generate efficient and safe drugs and fragment-based strategies have been postulated as a versatile avenue to discover multi-target ligand leads. To systematically probe the potential of fragment-based multiple ligand discovery, we have employed a large fragment library for comprehensive scree...

Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidaemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and bad patient adherence...

Objectives This study analysed the novel carbapenem-hydrolysing class D β-lactamase OXA-822 identified in the clinical Acinetobacter calcoaceticus isolate AC_2117. Methods WGS was employed for identification of β-lactamases. Micro-broth dilution was used for evaluation of antibiotic susceptibility of AC_2117 and transformants containing blaOXA-822...

The first potent Leukotriene B4 (LTB4) receptor type 2 (BLT2) agonists, endogenous 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and synthetic CAY10583 (CAY) have been recently described to accelerate wound healing by enhanced keratinocyte migration and indirect stimulation of fibroblast activity in diabetic rats. CAY represents a very va...

Renal fibrosis is a contributor to chronic kidney disease and an important predictor of long-term prognosis. We developed a dual soluble epoxide hydrolase inhibitor-PPAR-γ agonist (sEHi/PPAR-γ), RB394, and investigated its ability to attenuate renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. RB394 efficacy was compared to an s...

Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The...

Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hor-mone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and non-classical THs as another molecular activi-ty o...

Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vasc...

Multitarget ligands are interesting candidates for drug discovery and development due to improved safety and efficacy. However, rational design and optimization of multitarget ligands is tedious because affinity optimization for two or more targets has to be performed simultaneously. In this study, we demonstrate that, given a molecular fragment, w...

The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here we report the discovery and profiling of a new PPARγ modulator chemot...

Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibito...

Multi-target anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with sub-micromolar activity towards both targets has been designed and synthetized. Preliminary structure-activity relationship studies...

In the present article we describe the creation of a small carboranylcarboxamide compound library followed by a screening campaign at the soluble epoxide hydrolase (sEH). We identified meta-carboranyl alkylamides, -anilides, and -benzylamides as potent sEH inhibitors. Furthermore, we optimized the scaffolds and we derived structure-activity relatio...

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activ...

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities, which are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity located in the N-terminal domai...

Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and although they have shown immunomodulatory effects, there is still no therapeutically useful PPARγ a...

Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a com-puter-aided approach was used to de-orphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure anal...

Generic in‐capillary as well as offline capillary electrophoresis‐based enzyme assays were developed for serine‐β‐lactamases and metallo‐β‐lactamases. The hydrolysis of benzylpenicillin to benzylpenicilloic acid was analyzed using 100 mM sodium phosphate solution, pH 6.0, as background electrolyte. In‐capillary assays employed an uncoated as well a...

Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) act...

Objectives: The aim of this study was to characterize the Acinetobacter calcoaceticus clinical isolate AC_2117 with the novel carbapenem-hydrolysing class D β-lactamase (CHDL) OXA-679. Methods: Identification of the species and β-lactamases was verified by genome sequencing (PacBio) and phylogenetic analyses. Antibiotic susceptibility of AC_2117...

The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator- activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist...

The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among inn...

As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation and metabolic homeostasis, and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydropho...

Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to...

Aims/hypothesis: The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes. Methods: We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) in...

Chronic inflammation and pain is a major global health problem, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most frequently prescribed drugs and common option for the treatment of inflammatory pain. However, they have the potential to cause serious complications, such as gastrointestinal (GI) lesions, bleeding and cardiovascular (C...

Gout is the most common arthritic disease in human but was long neglected and therapeutic options are not satisfying. However, with the recent approval of the urate transporter inhibitor lesinurad, gout treatment has experienced a major innovation. Here we show that lesinurad possesses considerable modulatory potency on peroxisome proliferator-acti...

Multi-targeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects...

Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) s...

Multi-target design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist z...

The prediction of protein–ligand interactions and their corresponding binding free energy is a challenging task in structure-based drug design and related applications. Docking and scoring is broadly used to propose the binding mode and underlying interactions as well as to provide a measure for ligand affinity or differentiate between active and i...

The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class a...

Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of 4 selected compoun...

The interaction of fibroblast growth factors (FGFs) with their fibroblast growth factor receptors (FGFRs) are important in the signaling network of cell growth and development. SSR128129E (SSR)[1,2], a ligand of small molecular weight with potential anti‐cancer properties, acts allosterically on the extracellular domains of FGFRs. Up to now, the st...

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Ps...