Synthesis, in vitro and in vivo biological evaluation of novel dual compounds targeting both acetylcholinesterase and serotonergic 5-HT receptors with potential interest in the treatment of Alzheimer's disease.

In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride.

Disruption of PHF6 Peptide Aggregation from Tau Protein: Mechanisms of Palmatine Chloride in Preventing Early PHF6 Aggregation.

The formation of neurofibrillary tangles (NFTs), composed of tau protein aggregates, is a hallmark of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). NFTs consist of paired helical filaments (PHFs) of tau protein with a dominant β-sheet secondary structure. Within these PHFs, the PHF6 hexapeptide (Val-Gln-Ile-Val-Tyr-Lys) has been commonly highlighted as a key site for tau protein nucleation.

Discovery of a pocket network on the domain 5 of the TrkB receptor - A potential new target in the quest for the new ligands.

The important role that the neurotrophin tyrosine kinase receptor - TrkB has in the pathogenesis of several neurodegenerative conditions such are Alzheimer's disease, Parkinson's disease, Huntington's disease, has been well described. This shouldn't be a surprise, since in the physiological conditions, once activated by brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), the TrkB receptor promotes neuronal survival, differentiation and synaptic function. Considering that the natural ligands for TrkB receptor are large proteins, it is a challenge to discover small molecule capable to mimic their effects.

Design, synthesis and preliminary biological evaluation of rivastigmine-INDY hybrids as multitarget ligands against Alzheimer's disease by targeting butyrylcholinesterase and DYRK1A/CLK1 kinases.

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of BuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with DYRK1A/CLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the -appendage of the benzothiazole core led to potent and selective BuChE inhibitors with IC up to 27 nM and potent DYRK1A and CLK1 inhibitors with IC up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of BuChE and DYRK1A/CLK1 kinases (IC = 68 nM and IC = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action.

Gold(I)-Mediated Radioiododecarboxylation of Arenes.

A novel radioiodination method is developed using carboxylic acids as radiolabeling precursors. This method involves decarboxylation and organogold(I) intermediate formation, enabling efficient radioiodination of (hetero)arenes and cinnamic and phenylpropiolic acids. Additionally, we demonstrated the prolonged stability of crude gold(I) organometallic compounds, showcasing their enduring radiolabeling capabilities.

Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands.

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain.

Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core.

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases.

On the Tracks of the Aggregation Mechanism of the PHF6 Peptide from Tau Protein: Molecular Dynamics, Energy, and Interaction Network Investigations.

The formation of neurofibrillary tangles (NFTs), composed of tau protein aggregates, is a hallmark of some neurodegenerative diseases called tauopathies. NFTs are composed of paired helical filaments (PHFs) of tau protein with a dominant β-sheet secondary structuration. The NFT formation mechanism is not known yet.

Synthesis and Physicochemical Properties of Cryptophazane-A Soluble and Functionalizable C -Symmetrical Cryptophane.

The first example of a cryptophazane, a cryptophane functionalized with a nitrogen atom replacing one of the methylene bridges, is obtained with a 28 % overall yield over 8 steps, through the preparation of a C -symmetrical aza-cyclotriveratrylene (aza-CTV). Herein, we demonstrate that the introduction of a nitrogen atom on this part of the cryptophane core enhances the solubility in organic media of both the cryptophane and the synthetic intermediates, while presenting the same conformation as known cryptophanes. Cryptophazane was prepared on a multigram scale and easily functionalized.

Tau protein aggregation: Key features to improve drug discovery screening.

Tauopathies are neurodegenerative disorders associated with the accumulation of abnormal tubulin associated unit (tau) protein in the brain. Tau pathologies include a broad spectrum of diseases, with Alzheimer's disease (AD) being the most common tauopathy. The pathophysiological mechanisms of AD are still only partially understood.

Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1.

Introduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1.

Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1.

Cryptic Pockets Repository through Pocket Dynamics Tracking and Metadynamics on Essential Dynamics Space: Applications to Mcl-1.

Detection of cryptic pockets (hidden protein pockets) is a hot topic in structure-based drug discovery, especially for drugging the yet undruggable proteome. The experimental detection of cryptic pockets is still considered an expensive endeavor. Thus, computational methods, such as atomistic simulations, are used instead.

Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on Protein and Stability, and Review of the Literature.

The role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in () associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis.

Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer's Disease Treatment through Rigidification Strategy.

The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT receptor agonist.

First Synthesis of Racemic Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ).

Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT receptor antagonist with therapeutic interest in Alzheimer's disease.

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors.

Insights into Mcl-1 Conformational States and Allosteric Inhibition Mechanism from Molecular Dynamics Simulations, Enhanced Sampling, and Pocket Crosstalk Analysis.

In this study, we explored the structural dynamics of Mcl-1, an anti-apoptotic protein. On the basis of structural ensembles, the essential dynamics was extracted and showed two major axes of variability: a breathing motion at the binding interface and a correlated motion through the internal loops. A free energy surface characterizing the breathing motion at the binding interface was generated and suggested an equilibrium between a closed conformation and a "ready to bind" conformation as the predominant states of Mcl-1 in solution.

Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT receptors activities for the treatment of Alzheimer's disease.

A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HTR agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo.

Synthesis of Pyridoclax Analogues: Insight into Their Druggability by Investigating Their Physicochemical Properties and Interactions with Membranes.

Pyridoclax is considered a promising anticancer drug, acting as a protein-protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug-membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air-water interface.

Hot-Spots of Mcl-1 Protein.

Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments.

In silico chemical library screening and experimental validation of novel compounds with potential varroacide activities.

The mite Varroa destructor is an ectoparasite and has been identified as a major cause of worldwide honey bee colony losses. The use of yearly treatments for the control of varroosis is the most common answer to prevent collapses of honey bee colonies due to the mite. However, the number of effective acaricides is small and the mite tends to become resistant to these few active molecules.

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD.

Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy.

Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy.