First Synthesis of Racemic Trans 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). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 uM) and (h)MAO-B (IC50 = 6.4 uM)

An Alternative Synthesis of 3′,4′-Diaminoflavones to Evaluate Their Antioxidant Ability and Cell Apoptosis of Zebrafish Larvae

[[abstract]]We described herein a concise synthesis of 3′,4′-diaminoflavone 10. This new, three-step synthetic approach is more efficient than the conventional seven-step synthetic method. The route is shortened significantly by introducing the amino moieties early and eliminating the need for nitro group reduction. The other two analogues, 5,7-dihydroxy-3′,4′-diaminoflavone 11 and 5,7-dimethoxy-3′,4′-diaminoflavone 12, were also synthesized similarly. The above three compounds, along with flavone, were evaluated for their antioxidant and UVB-protection abilities on zebrafish larvae. The data showed that compound 10 exhibited the best result, with −102.3% of ROS-scavenging rate.[[journaltype]]國外[[incitationindex]]SCI[[ispeerreviewed]]Y[[booktype]]電子版[[booktype]]紙本[[countrycodes]]CH

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.

International audienceTo 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. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Buchwald–Hartwig Reactions of Monohaloflavones

The article describes the amination of different monobromoor monochloroflavones with primary and secondary alkylamines and aniline derivatives by Buchwald–Hartwig reaction. The influence of the phosphine ligands used is described. The use of amino acid derivatives as a nitrogen source is also demonstrated. This latter reaction allows the synthesis of unique flavone–amino-acid conjugates

Différentiation sociale et sa régulation au sein d'un clone : cas de la fourmi parthénogénétique Cerapachys biroi

Le succès écologique remarquable des insectes sociaux est le fruit d une coopération basée notamment sur une division du travail dans laquelle les individus de la société sont répartis en (sous-)castes. Les mécanismes pré-imaginaux et imaginaux de différenciation sociale, à l origine respectivement d une spécialisation morphologique et comportementale, ont été étudiés chez la fourmi Cerapachys biroi. Les colonies de C. biroi présentent la particularité de ne posséder ni reines ni mâles. Une reproduction asexuée, par parthénogenèse thélytoque, est alors distribuée entre les ouvrières (à fertilité réduite) et les quelques intercastes (spécialisées dans la ponte) qui composent ces colonies. L étude des mécanismes de différenciation indique que les sociétés de C. biroi procèdent à une régulation adaptative du ratio intercastes/ouvrières: globalement, les colonies stériles favorisent la production d intercastes tandis que les colonies fertiles contraignent les larves à se développer en ouvrières. Chez cette espèce où la reproduction est essentiellement assurée par des ouvrières à fertilité limitée, un tel mécanisme autorégulé restaure la fertilité coloniale ou favorise le développement de la société. Grâce à ses caractéristiques particulières, la fourmi C. biroi a permis de montrer que l expérience individuelle pouvait, à elle seule, générer une division du travail durable entre des ouvrières identiques. L analyse des profils cuticulaires a révélé que les sociétés de C. biroi, ainsi que les différentes (sous-)castes qu elles contiennent, présentent des signatures chimiques différentes. Sur la base du concept de super-organisme, une comparaison des mécanismes de différenciation en jeu chez les cellules immunitaires et les insectes sociaux est finalement présentée. Cette démarche novatrice, qui conduit à l élaboration d un nouveau modèle de différenciation en immunologie, démontre tout l intérêt heuristique potentiel d une telle approche en biologie.The striking ecological success of social insects results from an extreme cooperation notably based on a division of labour. This labour division is achieved either by morphological specialization or by behavioural task specialization of colony members. The preimaginal and imaginal mechanisms leading to these (sub)caste differentiations have been investigated in the ant Cerapachys biroi. In this species, there are neither queens nor males. Within a colony, reproduction is evenly distributed among all workers and intercastes through thelytokous parthenogenesis. Workers reproduce in their youth, before ceasing as they become foragers, while intercastes display higher and lasting laying capacities. The study of caste differentiation showed that, faced with colonial sterility, societies of C. biroi alter caste ratios by considerably increasing the production of intercastes. In fertile conditions, larval development is constrained to worker fate by a contact pheromone probably applied during brood care. In this species in which reproduction mainly relies on young workers with finite fertility, an adaptive self-regulated mechanism of caste regulation thus allows to restore colonial fertility or to enhance colony growth. Furthermore, the singular traits exhibited by C. biroi ants have allowed to show that individual experience alone can generate a lasting labour division among similar workers. Moreover, the cuticular profile analyses revealed that C. biroi colonies present different chemical signature. This also turned to be true for the different (sub)castes of this species. Finally, according to the superorganism paradigm, the differentiation mechanisms in T cells and in social insects are compared. This unprecedented analysis gives rise to a new model for T cell differentiation and thus points out the heuristic significance for such a cross-disciplinary approach in biology.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Fonctionnalisation sélective de la diosmétine pour la synthèse de nouvelles flavones à visée anticancéreuse

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present)

International audienceIntroduction: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.Areas covered: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.Expert opinion: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development