Synthesis and biological evaluation of benzochromenopyrimidinones as cholinesterase inhibitors and potent antioxidant, non-hepatotoxic agents for Alzheimer’s disease

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.JMC thanks Government of Spain for support (SAF2016-65586-R), JJ and OS thank MH CZ- DRO (UHHK 00179906).We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

An integrated case-based reasoning approach for personalized itinerary search in multimodal transportation systems

Suggesting personalized itinerary search for travelers in a multimodal transportation system is a challenging problem. This is due to the increased complexity and diversity of transportation means, the intricacy and multitude of destinations along with the amount of rapidly changing information available to the traveler. Providing the transportation user with the relevant information that only meets his needs, preferences and personal profile is of foremost importance in efficiently supporting passenger mobility requirements in a large urban agglomeration. In this paper, we propose a multi-criteria approach for suggesting personalized itinerary to transportation users based on their preferences and needs. The proposed approach integrates case-based reasoning with Choquet integral to suggest the itinerary that best matches the user’s preferences. Further, the proposed method predicts the user’s behavior by comparing his preferences to those of other users with the same preferences for a given context. This will help the user to adopt the best action when facing a new situation in his itinerary search. This will help the user adopt the best action facing a new situation. Personalized information retrieval is processed based on criteria which weights are determined using the two-additive Choquet integral. The performance of the proposed algorithm was assessed by solving a real-life itinerary planning problem defined in the Tunisian urban public transit network. A comparison study involving both qualitative and quantitative assessment of the proposed approach as compared to two other methods was also carried out. Based on the performance analysis, as well as the comparison study, our new approach provides the best solutions for applications requiring personalization based user’s preferences in a multi-criteria setting

Electric Vehicle Powertrain Analysis: Comparison Between PMSM and HESM

International audienc

PMSM cogging torque reduction: Comparison between different shapes of magnet

International audienceIn most of the industrial applications, such as vehicular traction, when a Permanent Magnet Synchronous Motor (PMSM) can be used, a low cogging torque is required. The air gap variation, the magnet shapes and stator slots forms are the origins of cogging torque. In this work which aims at reducing cogging torque, we focus on the rotor magnet shapes optimizations. From intensive Finite Elements (FE) simulations of a Surface-mounted Permanent Magnet Synchronous Motor (SPMSM), 3-phases, 2-pairs of pole and 36 stator slots (3-circuits by pole and phase), a cogging torque reduction can be reached. The effect of different magnet shapes on cogging torque is studied in order to identify the optimal design for each one

Synthesis and biological assessment of racemic benzochromenopyrimidinetriones as promising agents for Alzheimer's disease therapy

International audienceAim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. Results: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a–6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6′,7′]chromeno[2′,3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b–6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 μmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power. Conclusion: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease

Isoxazolotacrines as non-toxic and selective butyrylcholinesterase inhibitors for Alzheimer's disease

Background: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease. Results: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 ± 1.12 μM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity analysis. Conclusion: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease.Peer Reviewe

Synthesis, Biological Assessment and Molecular Modeling of Racemic QuinoPyranoTacrines for Alzheimer's Disease Therapy

In this report we describe the synthesis, biological evaluation and molecular modeling of new tacrine analogues such as QuinoPyranTacrines (QPTs), designed by juxtaposition of 1,4- naphthoquinone and tacrine. From these results we have identified QPT16 as a permeable, selective human acetylcholinesterase inhibitor [IC50= 1.1 0.15 mM], 3.5-fold less-hepatotoxic than tacrine at 1000 mM concentration, and consequently, a potential new hit-compound for further investigation targeted to find a new agent for AD therapy.LI thanks the Regional Council of Franche-Comte (2016YC-04540 and 04560) for financial support. OS thanks Faculty of Military Health Sciences, University of Defence, MH CZ – DRO (UHHK, 00179906) and by Long Term Development Plan – 1011 for support. JMC thank MINECO (Spain) for grant SAF2015-65586-R, and EU (COST Action CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process”) for support.Peer Reviewe