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)

Investigations on (C6H9N2)2[MIIBr4] halogenometallate complexes with MII = Co, Cu and Zn: Crystal structure, thermal behavior and magnetic properties

International audienceThree complexes with the general formula (C6H9N2)2[MIIBr4] with MII = Cu (1), Co (2) and Zn (3) have been grown by the slow evaporation method at room temperature. These compounds were subjected to the following characterization techniques: single crystal X-ray diffraction, thermal analysis (ATG-TD), In situ X-ray powder diffraction and temperature dependent magnetic susceptibility measurements. The crystals of (C6H9N2)2[CuBr4] belong to the triclinic P1¯ space group, whereas (C6H9N2)2[CoBr4] and (C6H9N2)2[ZnBr4] crystallize in the orthorhombic system with the Pbcn space group. Molecular structures of the three coordination compounds consist of [MBr4]2- anions and 2-amino-6-methylpyridinium cations linked together via non-covalent interactions including hydrogen bonding, π···π stacking and halogen···halogen interactions which lead to three-dimensional supramolecular architecture. The thermal decomposition of the copper compound reveals the slow crystallization of CuBr at 130 °C. Both compounds 1 and 2 exhibit weak antiferromagnetic interactions. © 2017 Elsevier B.V

Polymorphism in the metal–organic hybrid (PhCH2NEt3)2[CoBr4]: Synthesis, crystal structures and physico-chemical characterizations

Two polymorphs of the new complex (C13H22N)2[CoBr4] have been prepared. The crystal structures of the polymorphs were determined by X-ray crystallography. Polymorph I belongs to the triclinic system, space group P-1 (No 2), while polymorph II adopts the monoclinic space group P21/c (No 14). The crystal packing is guided by Csingle bondH···Br hydrogen bonds; these interactions contribute to the overall stabilization of the structures as they connect anions and cations together into a three-dimensional network. The polymorphs present different structure-properties relationships. Hirshfeld surfaces analysis contributes to the identification of the primary intermolecular contacts that guide the packing diagram. The thermal decomposition was studied by DSC, VT-PXRD, TDA and TGA techniques. The optical band gap energy suggests the semiconductor nature of the polymorphs. Temperature dependent magnetic susceptibility measurements in the temperature range of 1.8–310 K reveal that the polymorphs exhibit very weak antiferromagnetic interactions or contributions from single ion anisotropy

Design, theoretical study, druggability, pharmacokinetics and properties evolution of a new organo-bromocadmate compound as prospective anticancer agent

International audienceCrystals of the organic-inorganic hybrid complex [H3NCH2(C5H4NH)]2CdBr6·2H2O ([H3NCH2(C5H4NH)] = diprotonated 3-picolylamine or 3-ampH2), were grown successfully by slow evaporation solution growth method at room temperature and characterized by single-crystal X-ray diffraction, infrared absorption, optical absorption and thermal analysis. The title compound belongs to the triclinic space group P1 ̅, with a crystal structure consisting of inorganic layers built up from hexabromocadmate anions [CdBr6]4- and free water molecules, linked together by O-H···Br hydrogen bonds and halogen···halogen interactions, along the b axis. The organic cations, 3-ampH2, are intercalated between the mineral layers via N-H···Br hydrogen bonds. The optimized molecular structure and the vibrational spectra were calculated thanks to the Density Functional Theory (DFT) method resorting to the B3LYP function with the LanL2DZ basis set. Infrared spectrum was used to gain more information of the title compound, with the assignment of the observed vibration modes. Good agreement has been found between the calculated results and the experimental data. Subsequently, the optical properties were diagnosed throughout optical absorption explaining the possible charge transfer interactions that happen within the molecules. The thermal behavior was studied by TG/DT analyses. In silico analyses showed that the synthesized compound bound several anticancer receptors (TNF-α, COX-2, VEGF...) with high affinities, which together with molecular interactions, druggability and pharmacokinetics satisfactory explain the anticancer potential of the compound

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

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

Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer’s disease therapy

In view of the multifactorial nature of Alzheimer’s disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer’s disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1–40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration

Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy

International audienc