Synthesis,Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS^•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC₅₀ 36.9 and 37.1 μM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC₅₀ 11.4, 4.1, and 8.7 μM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. In silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 μΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60–97%) values.     

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC₅₀ 3.4 μΜ and 2.8 μΜ), several times more potent than the reference Trolox (IC₅₀ 25 μΜ). Most of the compounds decreased carrageenan-induced rat paw edema (37–67% at 150 μmol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC₅₀ 13 μΜ). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 μmol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.     

Oligo(ethylene imine)-grafted glycidyl methacrylate linear and star homopolymers: Odd–even correlated transfection efficiency

The present study aims to investigate an odd–even effect of the number of ethylene imine units in the side-groups of totally abiotic synthetic polymers on their efficiency in DNA transfection. A library of fifteen polymers was fabricated. Two star homopolymers and one linear homopolymer based on glycidyl methacrylate were synthesized and used as precursors to which five linear oligo(ethylene imine)s (OEI) were grafted. The number of ethylene imine groups of the OEIs was varied. Specifically, ethylene diamine, diethylene triamine, triethylene tetramine, tetraethylene pentamine, and pentaethylene hexamine were used. Each of these fifteen OEI-grafted polymers was evaluated in terms of their efficiency to transfer plasmid DNA encoding firefly luciferase in C2C12 mouse myoblast cells. The transfection efficiency displayed an odd-even pattern, with all OEI-grafted polymers with an odd number of ethylene imine repeating units exhibiting higher transfection efficiency compared with those possessing an even number of ethylene imine repeating units. The odd–even effect was more pronounced for the star polymers with longer arms (degree of polymerization, DP = 100), while in case of the linear polymers, the odd–even effect was only observed for the lowest polymer loading. The cytotoxicity of the OEI-grafted polymers also followed an odd–even pattern, with the OEI-grafted star polymers with an arm DP of 100 and the linear polymers clearly presenting an odd-even effect, while the cytotoxicity of the OEI-grafted star polymers with an arm DP of 20 slightly increased with the number of ethylene imine repeating units.     

Reduction of pentafluorophenyl esters to the corresponding primary alcohols using sodium borohydride

Primary alcohols and chiral N-protected 2-amino alcohols can be obtained in high yields from the reaction of pentafluorophenyl esters of the corresponding carboxylic acids with sodium borohydride in THF under mild conditions. This reductive method is rapid and compatible with various functional groups as well as with the most common N-protective groups Z, Boc and Fmoc.     

Compatibilisation effect of PP-g-MA copolymer on iPP/SiO2 nanocomposites prepared by melt mixing

In the present study, a series of iPP/SiO₂ nanocomposites, containing 1, 2.5, 5, 7.5, 10 and 15 wt% SiO₂ nanoparticles, were prepared by melt mixing in a twin screw co-rotating extruder. Poly(propylene-g-maleic anhydride) copolymer (PP-g-MA) containing 0.6 wt% maleic anhydride content was added to all nanocomposites at three different concentrations, 1, 2.5 and 5 wt%, based on silica content. Mechanical properties such as tensile strength at break and Young’s modulus were found to increase and to be mainly affected by the content of silica nanoparticles as well as by the copolymer content. For the tensile strength at break as well as for yield point, a maximum was observed, corresponding to the samples containing 2.5-5 wt% SiO₂. At higher concentrations, large nanosilica agglomerates are formed that have as a result a decrease in tensile strength. Young’s modulus increases almost linearly on the addition of SiO₂, and takes values up to 60% higher than that of neat iPP. Higher concentrations of PP-g-MA resulted in a further enhancement of mechanical properties due to silica agglomerate reduction. This finding was verified from SEM and TEM micrographs. Evidently the surface silica hydroxyl groups of SiO₂ nanoparticles react with maleic anhydride groups of PP-g-MA and lead to a finer dispersion of individual SiO₂ nanoparticles in the iPP matrix. The enhanced adhesion in the interface of the two materials, as a result of the mentioned reaction, has been studied and proved by using several equations. The increased Vicat point of all nanocomposites, by increasing the PP-g-MA content, can also be mentioned as a positive effect.     

Novel Co5 and Ni4 Metal Complexes and Ferromagnets by the Combination of 2-Pyridyl Oximes with Polycarboxylic Ligands

The use of 2-pyridyl oximes in metal complexes chemistry has been extensively investigated in the last few decades as a fruitful source of species with interesting magnetic properties. In this work, the initial combination of pyridine-2-amidoxime (pyaoxH₂) and 2-methyl pyridyl ketoxime (mpkoH) with isonicotinic acid (HINA) and 3,5-pyrazole dicarboxylic acid (H₃pdc) has provided access to three new compounds, [Ni₄(INA)₂(pyaox)₂(pyaoxH)₂(DMF)₂] (1), [Co₅(mpko)₆(mpkoH)₂(OMe)₂(H₂O)](ClO₄)₆ (2), and [Co₅(OH)(Hpdc)₅(H₂pdc)] (3). 1 displays a square-planar metal topology, being the first example that bears simultaneously HINA and pyaoxH₂ in their neutral or ionic form. The neighbouring Ni₄ units in 1 are held together through strong intermolecular hydrogen bonding interactions, forming a three-dimensional supramolecular framework. 2 and 3 are mixed-valent Co₄^IIICo^II and Co₂^IIICo^II₃ compounds with a bowtie and trigonal bipyramidal metal topology, accordingly. Direct current and alternate current magnetic susceptibility studies revealed that the exchange interactions between the Ni^II ions in 1 are ferromagnetic (J = 1.79(4) cm⁻¹), while 2 exhibits weak AC signals in the presence of a magnetic field. The syntheses, crystal structures, and magnetic properties of 1–3 are discussed in detail.     

Conformational Properties and Putative Bioactive Targets for Novel Thiosemicarbazone Derivatives

The structure assignment and conformational analysis of the thiosemicarbazones, DKI21 and DKI24, were performed through homonuclear and heteronuclear 2D Nuclear Magnetic Resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-ROESY, 2D-HSQC, and 2D-HMBC) and quantum mechanics (QM) calculations, using Functional Density Theory (DFT). In addition, utilizing a combination of 2D-NOESY and 2D-ROESY spectra an exo structure was established for both of the analogs. This experimental results were confirmed by theoretical mechanistic studies, as the lowest minima conformations derived through DFT calculations were compatible with the spatial correlations observed in the 2D-NOESY and 2D-ROESY spectra. Finally, molecular binding experiments were performed to detect the potential targets for DKI21 and DKI24, derived from SwissAdme. In silico molecular binding experiments showed favorable binding energy values for the most of the enzymes studied. The ADMET calculations, using the preADMET and pKCSm software, showed that the two molecules appear as possible drug leads.     

Analysis of the heterogeneous dynamics of imidazolium-based [Tf2N−] ionic liquids using molecular simulation

The complex dynamic behaviour of the imidazolium-based ionic liquids [C_nmim⁺][Tf₂N^?], n = 4, 8, 12 is examined at various temperatures and at atmospheric pressure using molecular dynamics simulation. An existing all-atom force field is further optimised in order to attain reasonable agreement with experimental data for transport properties, such as self-diffusivities and viscosities. Dynamical heterogeneity phenomena are quantified through the calculation of the non-Gaussian parameter and the deviation of the self-part of the van Hove correlation function from the expected normal distribution. From this analysis, ions that move faster or slower than expected are detected in the system. These subsets of ‘fast’ and ‘slow’ ions form individual clusters consisting of either mobile or immobile ions. Detailed analysis of the ions’ diffusion reveals preferential motion along the direction of the alkyl tail for the cation and along the vector that connects the two sulphur atoms for the anion. For the longest alkyl tails, the heterogeneity in the dynamics becomes more pronounced and is preserved for several nanoseconds, especially at low temperatures.     

Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action

Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with Aβ (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aβ amyloid self-assembly. However, the molecular mechanism of their function is not well understood. Using solution-state and solid-state NMR spectroscopy in combination with ensemble-averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3-GI is highly dynamic, can adopt a β-like structure, and oligomerizes into colloid-like assemblies in a process that is reminiscent of liquid–liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with Aβ40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.