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.

A Biomimetic Multiparametric Assay to Characterise Anti-Amyloid Drugs.

Alzheimer's disease (AD) is the most widespread form of senile dementia worldwide and represents a leading socioeconomic problem in healthcare. Although it is widely debated, the aggregation of the amyloid β peptide (Aβ) is linked to the onset and progression of this neurodegenerative disease. Molecules capable of interfering with specific steps in the fibrillation process remain of pharmacological interest.

Novel thienopyrimidones targeting hepatic and erythrocytic stages of Plasmodium parasites with increased microsomal stability.

Based on the structure of a previously identified hit, Gamhepathiopine 1, which showed promising antiplasmodial activity, but poor microsomal stability, several strategies were investigated to improve the metabolic stability of the compounds. This included the introduction of fluorine or deuterium atoms, as well as carbocyclic groups. Among the new compounds, the 2-aminocyclobutyl derivative 5g demonstrated enhanced microsomal stability compared to compound 1, while retaining antiplasmodial activity against erythrocytic and hepatic stages of Plasmodium, without significant cytotoxicity against primary hepatocytes.

UHPLC-MS/MS method for the quantification of ultra-traces of irinotecan and its metabolites in red blood cells and plasma to detect caregivers' contamination.

The occupational exposure of caregivers to antineoplastic agents has been demonstrated since 1979. Since the early 1990s, numerous studies from several countries have demonstrated the contamination of care facilities by antineoplastic drugs. As it is easier to sample, most contamination measurements in workers are carried out in urine sample.

Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor.

Numerous studies have been published about the implication of the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis and motor neuron disease. BDNF activates the TrkB receptor with high potency and specificity, promoting neuronal survival, differentiation and synaptic plasticity. Based on the main structural characteristics of LM22A-4, a previously published small molecule that acts as activator of the TrkB receptor, we have designed and synthesized a small data set of compounds.

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L.

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy.

Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series.

β-Amyloid peptide interactions with biomimetic membranes: A multiparametric characterization.

Alzheimer's disease is the most common form of senile dementia in the world, and amyloid β peptide1-42 (Aβ) is one of its two principal biological hallmarks. While interactome concept was getting forward the scientific community, we proposed that the study of the molecular interactions of amyloid β peptide with the biological membranes will allow to highlight underlying mechanisms responsive of AD. We have developed two simple liposomal formulations (phosphatidylcholine, cholesterol, phosphatidylglycerol) mimicking neuronal cell membrane (composition, charge, curvature radius).

Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones.

Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from -alkylated--carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF.

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.

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series.

A functional m A-RNA methylation pathway in the oyster Crassostrea gigas assumes epitranscriptomic regulation of lophotrochozoan development.

N -methyladenosine (m A) is a prevalent epitranscriptomic mark in eukaryotic RNA, with crucial roles for mammalian and ecdysozoan development. Indeed, m A-RNA and the related protein machinery are important for splicing, translation, maternal-to-zygotic transition and cell differentiation. However, to date, the presence of an m A-RNA pathway remains unknown in more distant animals, questioning the evolution and significance of the epitranscriptomic regulation.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs.

Antipsychotic lurasidone: Behavioural and pharmacokinetic data in C57BL/6 mice.

Lurasidone is an atypical antipsychotic that has been shown to be effective in reversing schizophrenia-related cognitive impairment. The development of new preclinical models of schizophrenia is a key for improving treatments of cognitive symptoms. This study investigated the effects of chronic lurasidone treatment in C57BL/6 male mice via intraperitoneal injection (1 mg/kg daily at 5 p.

New 8-Nitroquinolinone Derivative Displaying Submicromolar Activities against Both and .

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated against , , and , in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative was revealed, presenting EC values of 12 and 500 nM on trypomastigotes and amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC ≤ 13 μM).

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer's Disease Treatment.

Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease.

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.

Novel multi target-directed ligands targeting 5-HT receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease.

Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells.

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.

Microplate assay for lipophilicity determination using intrinsic fluorescence of drugs: Application to a promising anticancer lead, pyridoclax.

Lipophilicity must be necessarily determined in drug discovery since this physicochemical property will directly influence the pharmacokinetics of a drug as its pharmacodynamics profile. Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant cancers. The partition coefficient (Kp) of this anticancer drug was determined by microplate assays, well adapted in drug discovery, since being rapid, and requiring only poor drug amounts.

Nongenotoxic 3-Nitroimidazo[1,2-]pyridines Are NTR1 Substrates That Display Potent Antileishmanial Activity.

Twenty nine original 3-nitroimidazo[1,2-]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. evaluation highlighted compound as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC > 100 μM) alongside good antileishmanial activities (IC = 1-2.1 μM) against , , and ; and good antitrypanosomal activities (IC = 1.