Synthesis, antioxidant and Aß anti-aggregation properties of new ferulic, caffeic and lipoic acid derivatives obtained by the Ugi four-component reaction.

We report herein the synthesis antioxidant and Aß anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1-12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aß1-40 self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer's disease.

Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer's disease therapy.

We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC50 = 11.90 ± 0.05 nM), moderate hAChE (IC50 = 1.73 ± 0.34 µM), hMAO A (IC50 = 2.78 ± 0.12 µM), and MAO B (IC50 = 21.29 ± 3.85 µM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure.

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.

Package-Less Liquid Phase Sensing Using Surface Acoustic Waves on Lithium Tantalate Oxide.

Surface acoustic wave (SAW) transducers propagating shear waves are compatible with sensing chemical compounds in a liquid phase. However, if the liquid surrounding the sensor possesses a higher permittivity than the piezoelectric substrate, then the interdigitated electrodes for converting the incoming electromagnetic wave to acoustic waves are susceptible to capacitive short-circuiting, leading to excessive insertion losses. By using high-permittivity lithium tantalate oxide (LTO), we demonstrate chemical sensing in water without the need for dedicated microfluidic packaging. Nevertheless, the gravimetric sensitivity of these package-less transmission Love-mode delay lines remains comparable to that of low-permittivity quartz when appropriately tuning the guiding layer of thin film to confine energy to the surface in a Love mode. We extend the transmission line gravimetric sensitivity measurement to a reflective delay line geometry for passive transducers that can be wirelessly probed. For instance, ground-penetrating radar (GPR) can be used for subsurface sensing, here targeting water pollution detection, operating in the 100-500-MHz range. This center frequency was selected as a tradeoff between penetration depth (lower frequency) and antenna size (smaller at higher frequency). Nonspecific binding of proteins detection is shown in the context of biosensing applications.

A Kinetic Approach to Synergize Bactericidal Efficacy and Biocompatibility in Silver-Based Sol-Gel Coatings.

Silver ions are antimicrobial agents with powerful action against bacteria. Applications in surface treatments, as Ag+-functionalized sol-gel coatings, are expected in the biomedical field to prevent contaminations and infections. The potential cytotoxicity of Ag+ cations toward human cells is well known though. However, few studies consider both the bactericidal activity and the biocompatibility of the Ag+-functionalized sol-gels. Here, we demonstrate that the cytotoxicity of Ag+ cations is circumvented, thanks to the ability of Ag+ cations to kill Escherichia coli (E. coli) much faster than normal human dermal fibroblasts (NHDFs). This phenomenon was investigated in the case of two silver nitrate-loaded sol-gel coatings: one with 0.5 w/w% Ag+ cations and the second with 2.5 w/w%. The maximal amount of released Ag+ ions over time (0.25 mg/L) was ten times lower than the minimal inhibition (MIC) and minimal bactericidal (MBC) concentrations (respectively, 2.5 and 16 mg/L) for E. coli and twice lower to the minimal cytotoxic concentration (0.5 mg/L) observed in NHDFs. E. coli were killed 8-18 times, respectively, faster than NHDFs by silver-loaded sol-gel coatings. This original approach, based on the kinetic control of the biological activity of Ag+ cations instead of a concentration effect, ensures the bactericidal protection while maintaining the biocompatibility of the Ag+ cation-functionalized sol-gels. This opens promising applications of silver-loaded sol-gel coatings for biomedical tools in short-term or indirect contacts with the skin.

Toward conformational identification of molecules in 2D and 3D self-assemblies on surfaces.

The design of supramolecular networks based on organic molecules deposited on surfaces, is highly attractive for various applications. One of the remaining challenges is the expansion of monolayers to well-ordered multilayers in order to enhance the functionality and complexity of self-assemblies. In this study, we present an assessment of molecular conformation from 2D to 3D supramolecular networks adsorbed onto a HOPG surface under ambient conditions utilizing a combination of scanning probe microscopies and atomic force microscopy- infrared (AFM-IR). We have observed that the infrared (IR) spectra of the designed molecules vary from layer to layer due to the modifications in the dihedral angle between the C=O group and the neighboring phenyl ring, especially in the case of a 3D supramolecular network consisting of multiple layers of molecules.

Reversible single molecular switch operating at 300 K on a surface.

A single 4-pyridylazobenzene molecule is observed at room temperature on a Si(111)-B surface by using scanning tunnel microscopy. The reversible conformational switching of this molecule is induced by tunneling electrons and observed at room temperature. This process is based on an intramolecular rotation of a single phenyl group without isomerization of the N=N double bond.

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

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 µM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.

Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aß1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy.

Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and ß-amyloid (Aß1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) µm], has strong antioxidant activity (3.61 µmol Trolox equivalents), and moderate Aß1-42 antiaggregating power (40.3 %).

Donepezil-ferulic acid hybrids as anti-Alzheimer drugs.

BACKGROUND: Due to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget drugs. RESULTS: Donepezil-ferulic acid hybrids (DFAHs) were prepared by the one-pot Ugi-4CR in low-to-moderate yields. DFAHs are potent antioxidant agents, showing oxygen radical absorbance capacity values in the range 4.80-8.71 trolox equivalents, quite higher compared with those recorded for ferulic acid and melatonin. From the ChEs inhibition studies, we conclude that DFAH 8, bearing an ethylene linker, and DFAH 12, bearing a propylene linker, both substituted with a melatonin motif, are the most potent inhibitors, in the nanomolar range. CONCLUSION: We have identified DFAH 8 as a very potent antioxidant, and totally selective equineButyrylCholinEsterase (eqBuChE) inhibitor.

Novel aminotetrazole derivatives as selective STAT3 non-peptide inhibitors.

The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.

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 ß-amyloid (Aß) 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 Aß1-40 , Aß1-42 , H2 O2 , 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.

Self-assembly of a halogenated molecule on oxide-passivated Cu(110).

The supramolecular self-assembly of brominated molecules was investigated and compared on Cu(110) and Cu(110)-O(2×1) surfaces under ultrahigh vacuum. By using scanning tunnelling microscopy, we show that brominated molecules form a disordered structure on Cu(110), whereas a well-ordered supramolecular network is observed on the Cu(110)-O(2×1) surface. The different adsorption behaviors of these two surfaces are described in terms of weakened molecule-substrate interactions on Cu(110)-O(2×1) as opposed to bare Cu(110). The effect of oxygen-passivation is to suppress debromination and it can be a convenient approach for investigating other self-assembly processes on copper-based substrates.

Noncovalent bicomponent self-assemblies on a silicon surface.

Two-dimensional supramolecular multicomponent networks on surfaces are of major interest for the building of highly ordered functional materials with nanometer-sized features especially designed for applications in nanoelectronics, energy storage, sensors, etc. If such molecular edifices have been previously built on noble metals or HOPG surfaces, we have successfully realized a 2D open supramolecular framework on a silicon adatom-based surface under ultrahigh vacuum with thermal stability up to 400 K by combining molecule-molecule and molecule-silicon substrate interactions. One of these robust open networks was further used to control both the growth and the periodicity of the first bicomponent arrays without forming any covalent bond with a silicon surface. Our strategy allows the formation of a well-controlled long-range periodic array of single fullerenes by site-specificity inclusion into a bicomponent supramolecular network.

Dipole-driven self-organization of zwitterionic molecules on alkali halide surfaces.

We investigated the adsorption of 4-methoxy-4'-(3-sulfonatopropyl)stilbazolium (MSPS) on different ionic (001) crystal surfaces by means of noncontact atomic force microscopy. MSPS is a zwitterionic molecule with a strong electric dipole moment. When deposited onto the substrates at room temperature, MSPS diffuses to step edges and defect sites and forms disordered assemblies of molecules. Subsequent annealing induces two different processes: First, at high coverage, the molecules assemble into a well-organized quadratic lattice, which is perfectly aligned with the <110> directions of the substrate surface (i.e., rows of equal charges) and which produces a Moiré pattern due to coincidences with the substrate lattice constant. Second, at low coverage, we observe step edges decorated with MSPS molecules that run along the <110> direction. These polar steps most probably minimize the surface energy as they counterbalance the molecular dipole by presenting oppositely charged ions on the rearranged step edge.