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Relevant academic research and scientific papers

Sustainable Micellar Gold Catalysis - Poly(2-oxazolines) as Versatile Amphiphiles

The application of five polymer amphiphiles in the gold-catalyzed allene cycloisomerizations under aqueous micellar conditions is described. The polymers were prepared by ring-opening cationic polymerization based on poly(2-methyl-2-oxazoline) as hydrophilic segment and different hydrocarbon- or fluorocarbon-based hydrophobic segments. The catalytic activity in the gold-catalyzed allene cyclization is strongly dependent on the type of gold precursor, the salt concentration in the bulk aqueous medium, and the concentration of the polymeric amphiphile. Best results were obtained with 2 mol% of gold(III) bromide, 1 mM of amphiphile and 5 M sodium chloride, affording over 80% yield for different heterocyclic products. The catalyst system is also suitable for the dehydrative cyclization of acetylenic diols to furans. Moreover, successful catalyst recycling was demonstrated in three consecutive runs when using optimized extraction conditions.

Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic loga ?P values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity-reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one-and two-fluorine a deletions' within perfluoroalkyl groups. Quantum chemical loga ?P calculations (SMD-MN15) based on solvent-dependent three-dimensional (3D) conformational analysis gave excellent correlations with experimental values, superior to Cloga ?P predictions based on 2D structural motifs. The availability of a systematic collection of data based on a small number of parent molecules illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.

3-(1H-PYRAZOL-4-YL)PYRIDINE ALLOSTERIC MODULATORS OF M4 MUSCARINIC ACETYLCHOLINE RECEPTOR

Provided are cinnolinyl and quinolinyl pyrazol-4-yl-pyridine compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor, compositions comprising said compounds, and uses of said compounds in the treatment or prevention of diseases in which M4 muscarinic acetylcholine receptors are involved, especially neurological and psychiatric disorders and diseases.

Exploring physicochemical space: Via a bioisostere of the trifluoromethyl and ethyl groups (BITE): Attenuating lipophilicity in fluorinated analogues of Gilenya for multiple sclerosis

The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (logD) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).

METHOD FOR PREPARING IMIDAZOLE DERIVATIVE AND INTERMEDIATE THEREOF AND CRYSTAL FORM

Disclosed are a method for preparing an imidazole derivative and crystal form A and crystal form B thereof, and also disclosed is a method for preparing a compound of formula (I) and an intermediate thereof.

Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors

Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their Ki values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a Ki against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a Ki value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a Ki value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.

NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS

Disclosed herein are cannabinoid receptor ligands of formula (I) wherein A1, A5, Rx, X4, and z are as defined in the specification. Compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

Efficient incorporation of unsaturated methionine analogues into proteins in vivo

A set of eight methionine analogues was assayed for translational activity in Escherichia coli. Norvaline and norleucine, which are commercially available, were assayed along with 2-amino-5-hexenoic acid (2), 2-amino-5-hexynoic acid (3), cis-2-amino-4-hexenoic acid (4), trans-2-amino-4-hexenoic acid (5), 6,6,6-trifluoro-2-aminohexanoic acid (6), and 2-aminoheptanoic acid (7), each of which was prepared by alkylation of diethyl acetamidomalonate with the appropriate tosylate, followed by hydrolysis. The E. coli methionine auxotroph CAG18491, transformed with plasmids pREP4 and pQE15, was used as the expression host, and translational activity was assayed by determination of the capacity of the analogue to support synthesis of the test protein dihydrofolate reductase (DHFR) in the absence of added methionine. The importance of amino acid side chain length was illustrated by the fact that neither norvaline (8) nor 7 showed translational activity, in contrast to norleucine (9), which does support protein synthesis under the assay conditions. The internal alkene functions of 4 and 5 prevented incorporation of these analogues into test protein, and the fluorinated analogue 6 yielded no evidence of translational activity. The terminally unsaturated compounds 2 and 3, however, proved to be excellent methionine surrogates: 1H NMR spectroscopy, amino acid analysis, and N-terminal sequencing indicated ～85% substitution of methionine by 2, while 3 showed 90-100% replacement. Both analogues also function efficiently in the initiation step of protein synthesis, as shown by their near-quantitative occupancy of the N-terminal amino acid site in DHFR. Enzyme kinetics assays were conducted to determine the rate of activation of each of the methionine analogues by methionyl tRNA synthetase (MetRS); results of the in vitro assays corroborate the in vivo incorporation results, suggesting that success or failure of analogue incorporation in vivo is controlled by MetRS.

Deamination Reactions, 43 - The Effect of Trifluoromethyl Groups on the Reactivity of Aliphatic Diazonium Ions and Carbocations

Various trifluoroalkanamines (9, 26, 35, 38, 45, 56, and 67) have been prepared and diazotized (water, pH 3.5) to probe the effect of trifluoromethyl groups on the reactivity of aliphatic diazonium ions.The product distributions reveal that α-CF3 groups enhance inverting displacement and enforce rearrangement (hydride shifts) separating the positive charge from CF3.Migrations of the positive charge from the β- to the γ-position are less strongly promoted than those from α to β.Enhancement factors of ca. 15 (α -> β) and 4 (β -> γ) may be derived by comparison with analogous alkanediazonium ions.The positive charge does not migrate in the reverse direction (β -> α) except for minor amounts of a pinacolic rearrangement (68 -> 7).A migration of the positive charge from γ to β has been detected with 36 but a tenfold decrease as compared to the analogous butanediazonium ion 37 is indicated.All observations are reasonably explained in terms of the relative stabilities of the intermediate trifluoroalkyl cations.