The treatment of Alzheimer's disease should undoubtedly be multifactorial and require a polypharmacological approach to be effective. Pleiotropic prodrugs can release, upon inhibition of a primary target, a drug that targets a second protein of therapeutic interest. Here, we describe the design of prodrugs that release a potent serotonin reuptake inhibitor, 7-hydroxysertraline, upon the inhibition of butyrylcholinesterase. Indeed, 7-hydroxysertraline is not only a ligand of the serotonin transporter but also possesses the structural requirements to yield carbamates, able to bind to the catalytic site of butyrylcholinesterase and undergo its carbamylation. This behavior could result in a pseudo-irreversible inhibition of butyrylcholinesterase, followed by release of the serotonin reuptake inhibitor. Several carbamates of 7-hydroxysertraline were synthesized and evaluated in vitro for their acetyl- and butyrylcholinesterase inhibitory activities and their affinity for the serotonin transporter. Structure-activity relationships were then established based on a molecular modelling study. Investigations into cholinesterase inhibition kinetics have been conducted, resulting in the selection of two prodrugs for in vivo evaluation in an Alzheimer's disease mouse model. One of these, compound 8e, provided complete protection against short- and long-term memory deficits induced by intracerebroventricular administration of β-amyloid oligomers. This makes compound 8e a promising candidate for preclinical development as a possible treatment for Alzheimer's disease.

Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.

The multifactorial origin of Alzheimer's disease (AD) is currently being addressed with the development of combination therapy or multitarget directed ligands. If the conventional approach of targeting acetylcholinesterase (AChE) for AD treatment has limitations, it could offer opportunities for a polypharmacological approach by designing covalent pseudoirreversible prodrugs inspired by rivastigmine's mechanism of action. This study focuses on introducing aminated drugs to the rivastigmine carbamate moiety, namely, fluoxetine and memantine, which have shown synergy with cholinesterase inhibition. These innovative carbamates target sustained drug release through covalent pseudoirreversible cholinesterase inhibition, strategically balancing inhibitory potency, selectivity, mechanism, and reactivation kinetics. This comprehensive approach demonstrates the potential of targeting ChE via a covalent mechanism and provides valuable insights into the structure-activity relationships of these derivatives. Interestingly, this study provides a useful biochemical toolbox for characterizing pseudoirreversible cholinesterase carbamate-type inhibitors. The most promising compound was evaluated in in cellulo and in vivo AD models, highlighting the potential of polypharmacological interventions as innovative and multifaceted anti-AD drugs.

Tegaserod is a serotonin receptor agonist with potential neuroprotective properties for Alzheimer's disease. Due to its low druggability profile and to avoid detrimental side effects, a brain-targeted formulation is required. Nanocarriers targeting the blood-brain barrier (BBB) with a shuttle peptide, such as peptide-22, or enabling direct nose-to-brain delivery were considered as valuable approaches. This study aimed to compare two types of lipid-based nanocarriers and determine the best formulation for intravenous (IV) or intranasal (IN) administration. Tegaserod-loaded nanoemulsions and liposomes were successfully developed, improving the solubilization of tegaserod in injectable formulations. Their properties were optimized for the IV route, and the two formulations were compared in terms of granulometric properties, stability, stealth properties, and transport across a human model of the human BBB. Based on these evaluations, peptide-22-decorated tegaserod-loaded nanoemulsions were the most promising for IV administration. In addition, tegaserod-loaded nanoemulsions or liposomes were incorporated in a gelling formulation with properties optimized for the IN route, focusing on gelation temperature, osmolarity, and pH. Due to its rheological profile and behavior at room temperature, gel-embedded liposomes emerged as the most suitable formulation for the IN route. The successful development of these nanocarriers will facilitate further preclinical evaluation of tegaserod in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which the current treatments remain largely symptomatic. Pleiotropic prodrug strategies offer a promising approach to address this complexity, combining complementary pharmacological mechanisms within a single molecular entity. In this study, we report the design, synthesis, and biological evaluation of novel carbamate-based pleiotropic prodrugs that combine butyrylcholinesterase (BuChE) inhibition and β2-adrenergic receptor (β2-AR) agonism. Seven salmeterol-derived carbamates were synthesized and evaluated for their cholinesterase inhibitory activity, β2-AR activity, and neuroprotective potential. Several derivatives exhibited potent and selective inhibition of human BuChE in the nanomolar range, revealing a clear structure-activity relationship driven by carbamate substitution and amine protection. Kinetics and LC-MS analyses demonstrated a pseudo-irreversible covalent inhibition mechanism associated with rapid enzyme reactivation, thereby enabling controlled salmeterol release. While carbamates behaved as inactive prodrugs at the β2-AR level, selected compounds displayed significant neuroprotective effects in a cellular model of amyloid-β-induced toxicity. Collectively, these findings validate salmeterol-derivated carbamates as innovative pleiotropic prodrugs and support the potential of combining BuChE inhibition and β2-AR agonism as a disease-modifying strategy for Alzheimer's disease.

Aqueous solubility is a critical parameter in drug design. Common methods to measure solubility are often too slow or too inaccurate to be routinely used. Measuring very low solubilities (10-6 M and below) represents additional challenges. In this paper, we first describe a fast and reliable method to measure aqueous solubility of drug-like molecules in a 96-well plate format using only conventional laboratory equipment and a UV absorbance plate reader. The method was validated against the gold-standard saturation shake-flask on a set of 31 drug molecules and represents a practical improvement over already described high-throughput solubility determination methods. We then use this method to explore the solubility of six poorly soluble molecules in water-organic solvent mixtures. We discuss the relationship between solvent fraction and logarithmic solubility (logS), conditions to make this relationship linear, and how to use it to extrapolate solubility to 0 % cosolvent. We demonstrate that the MDM mixture (1:1:1 methanol, acetonitrile and dioxane) provides linear logS - cosolvent relationship for all tested compounds, and excellent extrapolation abilities. Our method opens the way to the systematic determination of very low solubilities at the very first stages of drug design programs, a valuable input for structure-property relationship studies.

Evasion of apoptosis is a hallmark of tumor progression, often driven by the overexpression of anti-apoptotic proteins from the Bcl-2 family, including Mcl-1. Mcl-1 has emerged as a critical therapeutic target, particularly in chemoresistant cancers such as ovarian cancers. This anti-apoptotic protein has been involved not only in the resistance to various conventional chemotherapeutic agents, but also in the resistance to BH3-mimetic molecules targeting Bcl-2 and/or Bcl-xL proteins, leading in some cases to therapeutic failures of these innovative molecules. However, conventional Mcl-1 inhibitors are hindered by off-target effects and toxicity, especially cardiac toxicity. To address these limitations, we have designed a PROTAC targeting Mcl-1, derived from the repositioning of an oligopyridine-based inhibitor. Its efficacy was evaluated in the IGROV1-R10 ovarian cancer cell line, a chemoresistant model. Our results demonstrate 80-90% Mcl-1 degradation after 48 h at 10 nM, as confirmed by Western blot analysis. Furthermore, a comprehensive study of its physicochemical properties and pharmacokinetic parameters allowed us to characterize its entire cellular journey, from membrane permeability to ternary complex formation with the CRBN E3 ligase. This integrated approach highlights the challenges associated with PROTACs and proposes new optimization strategies to enhance their efficacy and selectivity. This work contributes to the development of targeted degradation strategies to overcome chemoresistance and paves the way for innovative anticancer therapies.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive onset of symptoms, including memory loss, accompanied by other neurological impairments. This progression is attributed to the deterioration of neuronal connections and a decrease in neurotransmission. Although this phenomenon has been extensively studied in the cholinergic system, it also affects other neurobiological pathways, particularly adrenergic transmission. In this context, the use of agonists, in particular, β2-adrenergic receptor (β2AR) agonists, may represent a promising therapeutic approach. After reviewing the main pharmacological aspects related to these receptors, we will first present the different existing modulators and their peripheral effects. We will then analyze the results of studies investigating their use in disease models. Finally, we will discuss the conditions and prospects for the development of a new treatment for Alzheimer's disease using a β2AR agonist.

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 beta-sheet secondary structure. Within these PHFs, the PHF6 hexapeptide (Val(306)-Gln-Ile-Val-Tyr-Lys(311)) has been commonly highlighted as a key site for tau protein nucleation. Palmatine chloride (PC) has been identified as an inhibitor of PHF6 aggregation, capable of reducing aggregation propensity at submicromolar concentrations. In pursuit of novel anti-AD drugs targeting early tau aggregation stages, we conducted an in silico study to elucidate PC's mechanism of action during PHF6 aggregation. Our observations suggest that while PHF6 can still initiate self-aggregation in the presence of PC, PC molecules subtly influence PHF6 aggregation dynamics, favoring smaller aggregates over larger complexes. The study underlined the key roles of aromatic rings in PC binding to different PHF6 aggregates by interacting through pi-pi stacking with the PHF6 Tyr310 side chain. The presence of aromatic rings in compounds to be able to inhibit the earlier complexation phase seems to be essential. These in silico findings lay a foundation for the design of compounds that could intervene in resolving the neurotoxicity of protein aggregates in AD.

INTRODUCTION:Molecular Glue Degraders (MGDs) is a concept that refers to a class of compounds that facilitate the interaction between two proteins or molecules within a cell. These compounds act as bridge that enhances specific Protein-Protein Interactions (PPIs). Over the past decade, this technology has gained attention as a potential strategy to target proteins that were traditionally considered undruggable using small molecules. AREAS COVERED:This review presents the concept of cellular homeostasis and the balance between protein synthesis and protein degradation. The concept of protein degradation is concerned with molecular glues, which form part of the broader field of Targeted Protein Degradation (TPD). Next, pharmacochemical strategies for the rational design of MGDs are detailed and illustrated by examples of Ligand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design (FBDD). EXPERT OPINION:Expanding the scope of what can be effectively targeted in the development of treatments for diseases that are incurable or resistant to conventional therapies offers new therapeutic options. The treatment of microbial infections and neurodegenerative diseases is a major societal challenge, and the discovery of MGDs appears to be a promising avenue. Combining different approaches to discover and exploit a variety of innovative therapeutic agents will create opportunities to treat diseases that are still incurable.

In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT4 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. In this respect, the replacement of the methoxy group of the latter with a deuterated one led to deudonecopride. On the other hand, the replacement of the chlorine atom of donecopride by various halogen atoms was of particular interest, among which fluorine led to a potent analog, we called flucopride. The latter exhibited promising in vitro activities associated to excellent drugability parameters. Flucopride was consequently involved in in vivo studies such as a scopolamine-induced deficit model of working memory and in a novel object recognition test. Through these evaluations, flucopride demonstrated both its antiamnesiant and promnesiant capacities, which could make it a potential preclinical drug candidate for the treatment of Alzheimer's disease.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20 c. The ability of compound 20 c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

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.

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. To identify such compounds, we have set up a small molecule screening process combining multiple experimental methods (UV and florescence spectrometry, ITC, and ATR-FTIR) to identify and characterise potential modulators of Aβ1-42 fibrillation through the description of the biochemical interactions (molecule–membrane Aβ peptide). Three known modulators, namely bexarotene, Chicago sky blue and indomethacin, have been evaluated through this process, and their modulation mechanism in the presence of a biomembrane has been described. Such a well-adapted physico-chemical approach to drug discovery proves to be an undeniable asset for the rapid characterisation of compounds of therapeutic interest for Alzheimer’s disease. This strategy could be adapted and transposed to search for modulators of other amyloids such as tau protein.

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. The distribution and elimination half-lives of irinotecan suggest that blood can be considered as better than urine for the biomonitoring of a potential contamination of healthcare workers. We describe here the development and the validation of a UHPLC-MS/MS method to simultaneously quantify irinotecan, and two of its main metabolites, APC and SN-38, at ultra-trace levels in plasma and red blood cells (RBC). This method has been applied to blood samples collected from several healthcare services in a French comprehensive cancer center. The results demonstrate that the method is sensitive enough to identify a contamination of healthcare workers by irinotecan and SN-38 at very low concentrations. Moreover, the results show that analysis of RBC is of great interest and complementary to that of serum.

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. The lead idea for the design of the new compounds was to modify the third position of the LM22A-4, by introducing different substitutions in order to obtain compounds which will have not only better physicochemical properties but selective activity as well. ADME and toxicity profiles of molecules have been evaluated as well as their biological properties through the TrkB receptor and affinity to promote neurite differentiation.

We developed new macromolecular engineering approaches enabling the preparation of star-like polypeptoids by ring-opening polymerization. Parallely to the evaluation of their cytotoxicity of the HepG2 human cell line, their screening toward a wide variety of Gram-positive and Gram-negative bacteria higlighted several compounds showing not only good but also selective antimicrobial activity.

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. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues' biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay.

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. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.