Synthesis, Biological Evaluation, and Docking Studies of Open-Chain Carbohydrate Amides as Acetylcholinesterase Inhibitors.

Introduction: Alzheimer's disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors.

Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.

Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-β-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors.

3-Oxo-β-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling.

3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits.

Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential.

Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer's disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman's assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined.

Dipeptidyl Vinyl Sulfone as a Novel Chemical Tool to Inhibit HMGB1/NLRP3-Inflammasome and Inflamma-miRs in Aβ-Mediated Microglial Inflammation.

Rapid microglial activation and associated inflammatory pathways contribute to immune-defense and tissue repair in the central nervous system (CNS). However, persistent activation of these cells will ultimately result in vast production of pro-inflammatory mediators and other neurotoxic factors, which may induce neuronal damage and contribute to chronic neurodegenerative diseases, as Alzheimer's disease (AD). Therefore, small molecules with immunomodulatory effects on microglia may be considered as potential tools to counteract their proinflammatory phenotype and neuroimmune dysregulation in such disorders.

Clickable 4-Oxo-β-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes.

Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-β-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety.

Wittig Reaction: Domino Olefination and Stereoselectivity DFT Study. Synthesis of the Miharamycins' Bicyclic Sugar Moiety.

2-O-Acyl protected-d-ribo-3-uloses reacted with [(ethoxycarbonyl)methylene]triphenylphosphorane in acetonitrile to afford regio- and stereoselectively 2-(Z)-alkenes in 10-60 min under microwave irradiation. This domino reaction is proposed to proceed via tautomerization of 3-ulose to enol, acyl migration, tautomerization to the 3-O-acyl-2-ulose, and Wittig reaction. Alternatively, in chloroform, regioselective 3-olefination of 2-O-pivaloyl-3-uloses gave (E)-alkenes, key precursors for the miharamycins' bicyclic sugar moiety.

Converting maslinic acid into an effective inhibitor of acylcholinesterases.

During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical.

Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties.

Cytotoxic bile acids, such as deoxycholic acid (DCA), are responsible for hepatocyte cell death during intrahepatic cholestasis. The mechanisms responsible for this effect are unclear, and recent studies conflict, pointing to either a modulation of plasma membrane structure or mitochondrial-mediated toxicity through perturbation of mitochondrial outer membrane (MOM) properties. We conducted a comprehensive comparative study of the impact of cytotoxic and cytoprotective bile acids on the membrane structure of different cellular compartments.

The bile acid-sensitive ion channel (BASIC) is activated by alterations of its membrane environment.

The bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC family of ion channels. Channels of this family are characterized by a common structure, their physiological functions and modes of activation, however, are diverse. Rat BASIC is expressed in brain, liver and intestinal tract and activated by bile acids.

Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II.

Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay.

Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.

The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients.

Optimization of O3-acyl kojic acid derivatives as potent and selective human neutrophil elastase inhibitors.

Human neutrophil elastase (HNE) is an attractive target for treating chronic and acute inflammatory lung diseases. An optimization campaign of the kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be the most potent inhibitors with IC5o values down to 80 nM.

Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations.

Submillimolar concentrations of cytotoxic bile acids (BAs) induce cell death via apoptosis. On the other hand, several cytoprotective BAs were shown to prevent apoptosis in the same concentration range. Still, the mechanisms by which BAs trigger these opposite signaling effects remain unclear.

Discovery of new heterocycles with activity against human neutrophile elastase based on a boron promoted one-pot assembly reaction.

Herein we demonstrate for the first time that a boron promoted one-pot assembly reaction may be used to discover novel enzyme inhibitors. Inhibitors for HNE were simply assembled in excellent yields, high diastereoselectivities and IC50 up to 1.10 μM, based on components like salicylaldehyde, aryl boronic acids and amino acids.

N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases.

The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation.

Targeting COPD: advances on low-molecular-weight inhibitors of human neutrophil elastase.

Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease.

Zeolites and other silicon-based promoters in carbohydrate chemistry.

Silicon-based materials, namely zeolites, clays, and silica gel have been widely used in organic synthesis, allowing mild reaction conditions and environmentally friendly methodologies. These heterogeneous catalysts are easy to handle, possess nontoxic and noncorrosive character and offer the possibility of recovery and reuse, thus contributing to clean and sustainable organic transformations. Moreover, they present shape-selective properties and provide stereo- and regiocontrol in chemical reactions.