Bernard Refouvelet

Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified (E)‐3‐(hydroxy‐3‐methoxyphenyl)‐N‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐N‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50=68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA‐BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1–40, Aβ1–42, H2O2, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease.

Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease.

Alzheimers disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimers disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimers disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimers disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.

Substituted benzopyranobenzothiazinones. Synthesis and estrogenic activity on MCF-7 breast carcinoma cells

In the search for new agents with estrogenic activity mediated by estrogen receptors (ER), six 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones 3a-f were synthesized. These compounds were readily prepared by the addition of 2-aminothiophenol 2 to substituted 4-hydroxycoumarin derivatives 1a-e. The estrogenic effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells and the specificity of described compounds was evaluated by the inhibition of their effect by ICI 182,780, an antiestrogenic compound. Among the compounds tested, 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one 3e and 6,12-dihydro-3-hydroxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one 3f exhibited an ER-dependent proliferation and a high binding affinity to ER, but a moderate capacity to activate the transcription of a reporter gene. Their pharmacological profiles are defined by their binding properties and their mechanism of action by computational modelling studies.

Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease.

Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established.

A novel cyclic hexapeptide as chiral selector: Application for HPLC separation of a series of dansyl amino and arylalkanoic acids.

In this paper, the synthesis of a cyclic hexapeptide molecule was presented and evaluated for the enantiomer separation of a series of dansyl amino and arylalkanoic acids using high performance liquid chromatography (HPLC). It was clearly vizualized that this chiral selector allowed the separation of a great number of enantiomer pairs. The influences of the size and the hydrogen bonding donor (HBD) parameter of the organic modifier (OM) (THF (HBD=0.00), propan-2-ol (HBD=0.33), methanol (HBD=0.43)) added in the mobile phase were also investigated on both the enantiomer-chiral selector association and enantioseparation.

Synthesis, regioselectivity, and DFT analysis of new antioxidant pyrazolo[4,3-c]quinoline-3,4-diones

Abstract The condensation of hydrazine, N-methylhydrazine, and N-phenylhydrazine with ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate derivatives has been investigated. As a result, 12 new antioxidant pyrazolo[4,3-c]quinolin-3,4-diones were obtained with good to high yields. When two cross-products could be possible, only one isomer bearing the methyl or the phenyl group at the N1 position is isolated and unequivocally characterized using 1D and 2D NMR techniques, FT-IR, and combustion analyses. DFT analysis of the reaction mechanism was carried out in the Pearson’s hard soft acid base framework, confirming the assigned structure to the observed pyrazolo[4,3-c]quinolin-3,4-diones. These calculations indicate a favored kinetic control for the synthesized pyrazolo[4,3-c]quinolin-3,4-diones compared to its possible regioisomer. Graphical abstract

Pharmacophore Modelling and Synthesis of Quinoline-3-Carbohydrazide as Antioxidants

From well-known antioxidants agents, we developed a first pharmacophore model containing four common chemical features: one aromatic ring and three hydrogen bond acceptors. This model served as a template in virtual screening of Maybridge and NCI databases that resulted in selection of sixteen compounds. The selected compounds showed a good antioxidant activity measured by three chemical tests: DPPH radical, OH° radical, and superoxide radical scavenging. New synthetic compounds with a good correlation with the model were prepared, and some of them presented a good antioxidant activity.

An efficient two-step synthesis of 4-methyl-1,2,3,5,6,10b-hexahydropyrimido〔5,4-c〕quinoline-2,5-diones via biginelli reaction

An efficient two-step synthesis of 4-methyl-l,2,3,5,6,10b-hexahydropyrimido[5,4-c]quinoline-2,5-diones is presented. It consists of the reactions of appropriate aldehyde, urea and ethyl acetoacetate according to Biginelli reaction, followed by cyclisation with ammonia.

Structure elucidation of benzopyran-2-ol in solution and in solid state following the reduction of coumarin by DIBAL-H

Lactols are compounds of increasing interest in the synthesis of active pharmaceutical derivatives. Nevertheless, the product obtained by the reduction of the carbonyl group of coumarin has been described only twice, and without definition of its precise chemical structure. Since these studies, doubts have been raised about the existence of a monomeric or dimeric form. Our study has led us to conclude definitely that the single dimeric form exists and to precisely define the spectral properties of the two diastereoisomers.