Exploring the interactions of irbesartan and irbesartan–2-hydroxypropyl-β-cyclodextrin complex with model membranes

The interactions of irbesartan (IRB) and irbesartan–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex with Dipalmitoyl Phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from Differential Scanning Calorimetry (DSC), Small angle X-ray Scattering (SAXS), ESI Mass-Spectrometry (ESI-MS) and solid state Nuclear Magnetic Resonance (ssNMR). Molecular Dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-β-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1 nm from the membrane centre

A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

Model Mono-, Di-, and Tri-ω-Functionalized Three-Arm Star Polybutadienes. Synthesis and Association in Dilute Solutions by Membrane Osmometry and Static Light Scattering

Three-arm polybutadienes with one, two, and three functional end groups were prepared by anionic polymerization using [3-(dimethylamino)propyl]lithium and sec-butyllithium as initiators and methyltrichlorosilane as linking agent. Characterization carried out on the dimethylamine-capped polymers by size exclusion chromatography (SEC), in THF, low-angle laser light scattering (LALLS) in THF, and membrane osmometry (MO) in toluene indicates a high degree of molecular and structural homogeneity. The 1,2 content, determined by NMR spectroscopy, of the arms having the functional groups was higher (12-32%) than that of the arms without the functional groups (7-10%), owing to the tertiary amine group of the initiator. The dimethylamine end groups were transformed to the highly polar sulfozwitterionic ones by reaction with cyclopropanesultone. Association of the different ω-functionalized star polybutadienes was studied in dilute solutions of cyclohexane by MO and LALLS. It was found that although the dimethylamine-capped polybutadienes do not associate, the corresponding zwitterionic species associate strongly in this solvent. At fixed molecular weight of the arms, the degree of association increases with decreasing number of functional groups and, for the same number of functional groups, with decreasing molecular weight of the arms. The trifunctional species form gels at concentrations needed for MO experiments. Comparison with linear ω-zwitterionic polybutadienes in cyclohexane shows that the stars associate less strongly, maybe due to the sterically hindered star structure (monofunctional species) and to intramolecular interactions (di- and trifunctional species). © 1995, American Chemical Society. All rights reserved

Statistical copolymers of N-vinylpyrrolidone and benzyl methacrylate via RAFT: Monomer reactivity ratios, thermal properties and kinetics of thermal decomposition

Statistical copolymers of N-vinylpyrrolidone (NVP) with benzyl methacrylate (BzMA) were prepared by Reversible Addition-Fragmentation chain Transfer Polymerization (RAFT), employing three different xanthates as RAFT agents: [(O-ethylxanthyl)methyl]benzene, [1-(O-ethylxanthyl)ethyl]benzene and O-ethyl S-(phthalimidylmethyl) xanthate. The reactivity ratios were estimated using the Fineman-Ross, inverted Fineman-Ross, Kelen-Tüdos and extended Kelen-Tüdos linear graphical methods, as well as the computer program COPOINT. Structural parameters of the copolymers were obtained by calculating the dyad sequence fractions and the mean sequence length. All the methods are in agreement that the probability for the incorporation of BzMA units is much greater than for that of NVP units. The glass-transition temperature (Tg) values of the copolymers were measured by Differential Scanning Calorimetry and examined by means of several theoretical equations, allowing for the prediction of these Tg values. Subsequently, a systematic and detailed investigation of the thermal degradation of these copolymers compared with that of the respective homopolymers, was carried out by Thermogravimetric Analysis, within the framework of the Ozawa-Flynn-Wall and Kissinger methodologies. As expected, the thermal stability of the copolymers is influenced by the structure of the substituents of the thiocarbonylthio end groups due to the RAFT agents. © 2018 Taylor & Francis Group, LLC

Block copolymers based on 2-methyl- and 2-phenyl-oxazoline by metallocene-mediated cationic ring-opening polymerization: Synthesis and characterization

Previous studies have shown that the cationic polymerization of oxazolines, lactones and vinyl ethers can be efficiently promoted by metallocene complexes activated by floroaryl borates. Taking this into account, different series of block copolymers, i.e. PPhOx-b-PMeOx, Pϵ-CL-b-PMeOx, Pϵ-CL-b-PPhOx, PEVE-b-PPhOx, along with the triblock terpolymers, Pϵ-CL-b-PMeOx-b-PEVE and Pϵ-CL-b-PPhOx-b-PEVE, were prepared by sequential addition of monomers. The synthesis was monitored by SEC and NMR spectroscopy, showing that well-defined products are obtained in most cases. The microphase separation of the samples was studied by DSC and their thermal stability by TGA measurements. © The Royal Society of Chemistry 2016

Supramolecular triblock copolymers through the formation of hydrogen bonds: Synthesis, characterization, association effects in solvents of different polarity

Anionic polymerization techniques were employed for the synthesis of linear polystyrene (PS) and block copolymer of PS and polyisoprene (PI) PS-b-PI bearing end hydroxyl groups. Following suitable organic chemistry transformation, the -OH end groups were converted to moieties able to form complementary hydrogen bonds including 2,6-diaminopurine, Dap, thymine, Thy, and the so-called Hamilton receptor, Ham. The formation of hydrogen bonds was examined between the polymers PS-Dap and PS-b-PI-Thy, along with the polymers PS-Ham and PS-b-PI-Thy. The conditions under which supramolecular triblock copolymers are formed and the possibility to form aggregates were examined both in solution and in the solid state using a variety of techniques such as 1H-NMR spectroscopy, size exclusion chromatography (SEC), dilute solution viscometry, dynamic light scattering (DLS), thermogravimetric analysis (TGA), differential thermogravimetry (DTG), and differential scanning calorimetry (DSC). © 2020 by the authors

Synthesis and characterization of chiral poly(alkyl isocyanates) by coordination polymerization using a chiral half-titanocene complex

A new chiral half-titanocene complex, [CpTiCl2(O-(S)-2-Bu)], is synthesized and characterized by 1H and 13C NMR spectroscopy. This complex is employed for the coordination polymerization of n-butyl and n-hexyl- isocyanate leading to chiral polymers, as revealed by their CD spectra. Only the left-handed helix is produced, due to the chiral (S)-2-butoxy group, which is bound to the polymer chain end. The polymerization of 3-(triethoxysilyl)propyl isocyanate produces less soluble polymers. On the other hand, phenyl isocyanate reacts slowly with the complex leading quantitatively and selectively to triphenyl isocyanurate. 2-Ethylhexyl isocyanate is slowly and selectively cyclotrimerized in the presence of the half-titanocene complex. However, a statistical copolymer of 2-ethylhexyl isocyanate and hexyl isocyanate is produced. The reaction of benzyl isocyanate with the complex leads to a mixture of low molecular weight polymer and cyclotrimer. The polymers are characterized using SEC, NMR, and CD spectroscopy and their thermal properties are investigated by TGA/DSC analysis. © 2015 Wiley Periodicals, Inc

End-functionalized polymers with zwitterionic end-groups

The synthesis, dilute solution and bulk properties of well-defined polymers with different architectures (linear homopolymers, di- and tri-block copolymers and star homopolymers) having dimethylamine and sulfobetaine end-groups are reviewed. The end functionalized polymers were prepared by means of anionic polymerization using high vacuum techniques. 3-Dimethylaminopropylithium was used as a functional initiator for the introduction of dimethylamine end-groups. This group was switched to a sulfozwitterionic one by reaction with cyclopropanesultone. The high molecular and compositional homogeneity of these model materials was confirmed by extensive molecular characterization data. Their aggregation behavior in dilute solutions having different polarities was studied by osmometry, viscometry and static and dynamic light scattering and was compared to predictions derived from theoretical models. The end-functionalized polystyrenes and the block copolymers of styrene possess lower degrees of association than the homopolydienes, probably due to the polarizability of the phenyl groups. The bulk properties of the functionalized homopolymers and diblock copolymers, studied by SAXS, rheology and dielectric spectroscopy, revealed new features of self-organization at this low ionic content and extraordinary phase stability at higher temperatures. The adsorption behavior of linear and star homopolydienes was investigated by ellipsometry and by using a surface-force apparatus