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A safe and efficient method for the in-situ preparation of (diazomethyl)dimethylphosphine oxide - a hereto unexplored diazoalkane reagent - is developed. The method is based on the diazotization of the corresponding P(O)Me2-substituted amine (readily available in multigram quantities) in non-aqueous media. The protocol provides the target product as ca. 1.5â M CHCl3 solution which is stable at -18 °C. The utility of the synthesized diazoalkane is illustrated by its [3+2] cycloaddition with electron-poor alkynes and alkenes providing the corresponding P(O)Me2-substituted pyrazoles and pyrazolines with moderate to good efficiency. In this view, the title compound represents and an important extension of medicinally relevant phosphine oxide reagents.
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Numerous studies reported an association between GABAA R subunit genes and epilepsy, eating disorders, autism spectrum disorders, neurodevelopmental disorders, and bipolar disorders. This study was aimed to find some potential positive allosteric modulators and was performed by combining the inâ silico approach with further inâ vitro evaluation of its real activity. We started from the GABAA R-diazepam complexes and assembled a lipid embedded protein ensemble to refine it via molecular dynamics (MD) simulation. Then we focused on the interaction of α1ß2γ2 with some Z-drugs (non-benzodiazepine compounds) using an Induced Fit Docking (IFD) into the relaxed binding site to generate a pharmacophore model. The pharmacophore model was validated with a reference set and applied to decrease the pre-filtered Enamine database before the main docking procedure. Finally, we succeeded in identifying a set of compounds, which met all features of the docking model. The aqueous solubility and stability of these compounds in mouse plasma were assessed. Then they were tested for the biological activity using the rat Purkinje neurons and CHO cells with heterologously expressed human α1ß2γ2 GABAA receptors. Whole-cell patch clamp recordings were used to reveal the GABA induced currents. Our study represents a convenient and tunable model for the discovery of novel positive allosteric modulators of GABAA receptors. A High-throughput virtual screening of the largest available database of chemical compounds resulted in the selection of 23 compounds. Further electrophysiological tests allowed us to determine a set of 3 the most outstanding active compounds. Considering the structural features of leader compounds, the study can develop into the MedChem project soon.
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Receptores de GABA-A , Ácido gama-Aminobutírico , Animais , Ratos , Camundongos , Humanos , Cricetinae , Cricetulus , Fluxo de Trabalho , Regulação Alostérica , Receptores de GABA-A/química , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
A comprehensive study of physicochemical properties (pKa , LogP, and intrinsic microsomal clearance) within the series of mono- and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both pKa and LogP values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of "Janus face" (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis-3,5-difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3-difluoroazetidine derivative). According to pKa - LogP plots, the title compounds provide a valuable extension of the fluorine-containing (e. g., fluoroalkyl-substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.
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Aminas , Flúor , Flúor/química , Aminas/química , Fenômenos Químicos , Conformação Molecular , Descoberta de DrogasRESUMO
Catalytic activity in arylzinc compound formation was studied for eight Co complexes with phosphines along with their redox properties for implementing the idea of rational design. It was found that Co(XantPhos)Cl2 and Co(N-XantPhos)Cl2 demonstrated distinct reversible CoII/CoI redox processes and acted as efficient catalysts of arylzinc compound formation. Meanwhile, for Co(DPEphos)Cl2, Co(dppf)Cl2, Co(dppb)Cl2, Co(PPh3)2Cl2, and Co(XantPhos)(Piv)2 (the latter one without the addition of LiCl), reversible redox processes were not observed. These catalysts did not act efficiently for the model process of organozinc compound formation. Co4(dppe)5Cl8 was the only exception, explained by a completely different structure (CoP4Cl and CoPCl3) of donor sets instead of CoP2X2 (X = Cl or O). The stability of complexes in tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) solutions was studied by UV-vis spectroscopy. Previously unknown X-ray structures for Co(XantPhos)(Piv)2, Co(N-XantPhos)Cl2, and {Co(DMF)6}{(CoCl3)2(dppb)} were determined. The use of pivalate counterions instead of chloride for Co(XantPhos)2+ led to a significant (ca. 20 times) increase of the kinetic solubility in THF compared to Co(XantPhos)Cl2, preserving high catalytic productivity upon the addition of LiCl. This allowed the latter to be efficiently used in combination with LiCl as the catalyst for arylzinc compound formation on a 2 g scale. The data obtained in this work can be regarded as experimental confirmation of the first and last stages of the plausible reaction pathway of arylzinc compound formation, involving CoII â CoI and CoI â CoII transformations, which could be a significant framework for further mechanistic investigations.
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Catalytic borylations of sp3 C-H bonds occur with high selectivities for primary C-H bonds or secondary C-H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C-H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C-H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C-H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C-B bond.
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An efficient chlorotrimethylsilane-promoted synthetic protocol for the preparation of functionalized fused ß-trifluoromethyl pyridines by cyclization of electron-rich aminoheterocycles or substituted anilines with a trifluoromethyl vinamidinium salt was developed. The efficient and scalable approach for producing represented trifluoromethyl vinamidinium salt demonstrated huge prospects for further use. The structure specificities of the trifluoromethyl vinamidinium salt and their impact on the reaction progress were determined. The procedure's scope and alternative ways of the reaction were investigated. The possibility of increasing the reaction scale up to 50 g and further modification of obtained products was shown. A minilibrary of potential fragments for 19F NMR-based fragment-based drug discovery (FBDD) was synthesized.
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An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH2/NHBoc, OH, SH, or SO2F groups attached to the carbocycle either directly or via a CH2 unit) relying on the divergent strategy is described. This class of compounds provides sp3-enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis- and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer-Pople puckering parameters and exit vector (EVP) plots.
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A series of seven palladium-containing composites, i.e., four Pd/C and three Pd(OH)2/C (Pearlman's catalysts), was prepared using modified common approaches to deposition of Pd or hydrated PdO on charcoal. All the composites were tested in the catalytic hydrogenation of diene carboxylates with the isolated-ring scaffold, e.g., 5,6-dihydropyridine-1(2H)-carboxylates with 2-(alkoxycarbonyl)cyclopent-1-en-1-yl and hex-1-en-1-yl substituents at the C(4)-position. The performance of the composites was also studied via the hydrogenation of quinoline as a model reaction. The composites were characterized by transmission and scanning electron microscopy (TEM and SEM), powder X-ray diffraction, and low-temperature N2 adsorption. It was found that the composites containing Pd nanoparticles (NPs) of 5-40 nm size were the most efficient catalysts for the hydrogenation of dienes, providing the reduced products with up to 90% yields at p(H2) = 100 atm, T = 30 °C for 24 h. The method of Pd NPs formation had more effect on the catalyst performance than the size of the NPs. The catalytic performance of Pearlman's catalysts (Pd(OH)2/C) in the hydrogenation of dienes was comparable to or lower than the performance of the Pd/C systems, though the Pearlman's catalysts were more efficient in the hydrogenation of quinoline.
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Alternating current (AC) electrolysis is receiving increased interest as a versatile tool for mild and selective electrochemical transformations. This work demonstrates that AC can enable the concept of a stirring-free electrochemical reactor where the periodic switch of electrode polarity, inherent to AC, provides uniform electrolysis across the whole volume of the reactor. Such design implies a straightforward approach for scaling up electrosynthesis. This was demonstrated on the range of electrochemical transformations performed in three different RVC-packed reactors on up to a 50-mmol scale. Redox-neutral, oxidative, and reductive processes were successfully implemented using the suggested design and the applicable frequency ranges were further investigated for different types of reactions. The advantages of the AC-enabled design - such as the absence of stirring and a maximized surface area of the electrodes - provide the possibility for its universal application both for small-scale screening experimentation and large-scale preparative electrosynthesis without significant optimization needed in between.
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In this research, the oxidation of a series of benzoins, R-C(=O)-CH(OH)-R, where R = phenyl, 4-methoxyphenyl, 4-bromophenyl, and 2-naphthyl, by hydrogen peroxide in the presence of nanostructured HKUST-1 (suspension in acetonitrile/water mixture) was studied. The respective benzoic acids were the only products of the reactions. The initial average reaction rates were experimentally determined at different concentrations of benzoin, H2O2 and an effective concentration of HKUST-1. The sorption of the isotherms of benzoin, dimethoxybenzoin and benzoic acid on HKUST-1, as well as their sorption kinetic curves, were measured. The increase in H2O2 concentration expectedly led to an acceleration of the reaction. The dependencies of the benzoin oxidation rates on the concentrations of both benzoin and HKUST-1 passed through the maxima. This finding could be explained by a counterplay between the increasing reaction rate and increasing benzoin sorption on the catalyst with the increase in the concentration. The electronic effect of the substituent in benzoin had a significant influence on the reaction rate, while no relation between the size of the substrate molecule and the rate of its oxidation was found. It was confirmed by DFT modeling that the reaction could pass through the Baeyer-Villiger mechanism, involving an attack by the HOO- anion on the C atom of the activated C=O group.
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Peróxido de Hidrogênio , Estruturas Metalorgânicas , Peróxido de Hidrogênio/química , Benzoína/química , Oxirredução , CatáliseRESUMO
The reaction of trimethyl(trifluoromethyl)silane-tetrabutylammonium difluorotriphenylsilicate (CF3SiMe3-TBAT) with a series of imidazoles gives products of the formal difluorocarbene insertion into the C-H bond at the C-2 position (i.e., C-difluoromethylation). According to NMR spectra, the corresponding 2-(trimethylsilyl)difluoromethyl-substituted derivatives are likely formed as the intermediates in the reaction, and then, they slowly convert to 2-difluoromethyl-substituted imidazoles. Quantum chemical calculations of two plausible reaction mechanisms indicate that it proceeds through the intermediate imidazolide anion stabilized through the interaction with solvent molecules and counterions. In the first proposed mechanism, the anion reacts with difluorocarbene without an activation barrier, and then, the CF2 moiety of the adduct attacks the CF3SiMe3 molecule. After the elimination of the CF3 anion, 2-(trimethylsilyl)difluromethyl-substituted imidazole is formed. Another possible reaction pathway includes silylation of imidazolide anion at the N-3 atom, followed by the barrierless addition of difluorocarbene at the C-2 atom and then by 1,3-shift of the SiMe3 group from N-3 to the carbon atom of the CF2 moiety. Both proposed mechanisms do not include steps with high activation barriers.
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New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened according to the above models, in order to find possible ACE2-chemical probes, useful for the study of SARS-CoV2-induced neurological disorders. An enzymology inhibition assay for ACE2 was optimized, and the combined diversified set of predicted selective ACE2-binding molecules from QSAR modeling, docking, and ultrafast docking was screened in vitro. The in vitro hits included two novel chemotypes suitable for further optimization.
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Enzima de Conversão de Angiotensina 2 , COVID-19 , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/metabolismo , RNA Viral , SARS-CoV-2RESUMO
Here, neuromodulatory effects of selective angiotensin-converting enzyme 2 (ACE2) inhibitors were investigated. Two different types of small molecule ligands for ACE2 inhibition were selected using chemical genetic approach, they were synthesized using developed chemical method and tested using presynaptic rat brain nerve terminals (synaptosomes). EBC-36032 (1 µM) increased in a dose-dependent manner spontaneous and stimulated ROS generation in nerve terminals that was of non-mitochondrial origin. Another inhibitor EBC-36033 (MLN-4760) was inert regarding modulation of ROS generation. EBC-36032 and EBC-36033 (100 µM) did not modulate the exocytotic release of L-[14C]glutamate, whereas both inhibitors decreased the initial rate of uptake, but not accumulation (10 min) of L-[14C]glutamate by nerve terminals. EBC-36032 (100 µM) decreased the exocytotic release as well as the initial rate and accumulation of [3H]GABA by nerve terminals. EBC-36032 and EBC-36033 did not change the extracellular levels and transporter-mediated release of [3H]GABA and L-[14C]glutamate, and tonic leakage of [3H]GABA from nerve terminals. Therefore, synthesized selective ACE2 inhibitors decreased uptake of glutamate and GABA as well as exocytosis of GABA at the presynaptic level. The initial rate of glutamate uptake was the only parameter that was mitigated by both ACE2 inhibitors despite stereochemistry issues. In terms of ACE2-targeted antiviral/anti-SARS-CoV-2 and other therapies, novel ACE2 inhibitors should be checked on the subject of possible renin-angiotensin system (RAS)-independent neurological side effects.
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Enzima de Conversão de Angiotensina 2 , Neurotransmissores , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Animais , Ácido Glutâmico , Imidazóis/farmacologia , Leucina/análogos & derivados , Leucina/farmacologia , Neurotransmissores/farmacologia , Terminações Pré-Sinápticas , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Sinaptossomos , Ácido gama-Aminobutírico , Tratamento Farmacológico da COVID-19RESUMO
A practical divergent synthetic approach is reported for the library of regio- and stereoisomers of glutamic acid analogs built on the spiro[3.3]heptane scaffold. Formation of the spirocyclic scaffold was achieved starting from a common precursor - an O-silylated 2-(hydroxymethyl)cyclobutanone derivative. Its olefination required using the titanium-based Tebbe protocol since the standard Wittig reaction did not work with this particular substrate. The construction of the second cyclobutane ring of the spirocyclic system was achieved through either subsequent dichloroketene addition or Meinwald oxirane rearrangement as the key synthetic steps, depending on the substitution patterns in the target compounds (1,6- or 1,5-, respectively). Further modified Strecker reaction of the resulting racemic spirocyclic ketones with the Ellman's sulfinamide as a chiral auxiliary had low to moderate diastereoselectivity; nevertheless, all stereoisomers were isolated in pure form via chromatographic separation, and their absolute configuration was confirmed by X-ray crystallography. Members of the library were tested for the inhibitory activity against H. pylori glutamate racemase.
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Ácido Glutâmico , Compostos de Espiro , Cristalografia por Raios X , Cetonas/química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , EstereoisomerismoRESUMO
Physico-chemical properties important to drug discovery (pKa , LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem-difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.
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Química Farmacêutica , Cicloparafinas , Flúor/química , Halogenação , SolubilidadeRESUMO
DNA-Encoded Library (DEL) technology has emerged as an alternative method for bioactive molecules discovery in medicinal chemistry. It enables the simple synthesis and screening of compound libraries of enormous size. Even though it gains more and more popularity each day, there are almost no reports of chemoinformatics analysis of DEL chemical space. Therefore, in this project, we aimed to generate and analyze the ultra-large chemical space of DEL. Around 2500 DELs were designed using commercially available building blocks resulting in 2,5B DEL compounds that were compared to biologically relevant compounds from ChEMBL using Generative Topographic Mapping. This allowed to choose several optimal DELs covering the chemical space of ChEMBL to the highest extent and thus containing the maximum possible percentage of biologically relevant chemotypes. Different combinations of DELs were also analyzed to identify a set of mutually complementary libraries allowing to attain even higher coverage of ChEMBL than it is possible with one single DEL.
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Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Quimioinformática , Química Farmacêutica , DNA/química , Descoberta de Drogas/métodos , Bibliotecas de Moléculas Pequenas/químicaRESUMO
The ability to efficiently synthesize desired compounds can be a limiting factor for chemical space exploration in drug discovery. This ability is conditioned not only by the existence of well-studied synthetic protocols but also by the availability of corresponding reagents, so-called building blocks (BBs). In this work, we present a detailed analysis of the chemical space of 400â¯000 purchasable BBs. The chemical space was defined by corresponding synthonsâfragments contributed to the final molecules upon reaction. They allow an analysis of BB physicochemical properties and diversity, unbiased by the leaving and protective groups in actual reagents. The main classes of BBs were analyzed in terms of their availability, rule-of-two-defined quality, and diversity. Available BBs were eventually compared to a reference set of biologically relevant synthons derived from ChEMBL fragmentation, in order to illustrate how well they cover the actual medicinal chemistry needs. This was performed on a newly constructed universal generative topographic map of synthon chemical space that enables visualization of both libraries and analysis of their overlapped and library-specific regions.
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Química Farmacêutica , Descoberta de Drogas , Descoberta de Drogas/métodos , Indicadores e ReagentesRESUMO
An efficient synthesis (up to a 200 g scale) of 3-hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5-carboxylates. The catalytic hydrogenolysis of the isoxazoline N-O bond was optimal upon using H2 (1 atm) at rt, with the following order of the catalyst activity: Pd-C > Pd(OH)2-C > Pt-C. The reactions with Pt-C were more selective for the synthesis of pyrrolidones, while Pd-C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 (cis- and trans-isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6- or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF3 (but not CHF2 or CH2Cl), ester, and most N-Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.
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Aminas , Lactamas , Catálise , Reação de Cicloadição , EstereoisomerismoRESUMO
Most of the existing computational tools for de novo library design are focused on the generation, rational selection, and combination of promising structural motifs to form members of the new library. However, the absence of a direct link between the chemical space of the retrosynthetically generated fragments and the pool of available reagents makes such approaches appear as rather theoretical and reality-disconnected. In this context, here we present Synthons Interpreter (SynthI), a new open-source toolkit for de novo library design that allows merging those two chemical spaces into a single synthons space. Here synthons are defined as actual fragments with valid valences and special labels, specifying the position and the nature of reactive centers. They can be issued from either the "breakup" of reference compounds according to 38 retrosynthetic rules or real reagents, after leaving group withdrawal or transformation. Such an approach not only enables the design of synthetically accessible libraries and analog generation but also facilitates reagents (building blocks) analysis in the medicinal chemistry context. SynthI code is publicly available at https://github.com/Laboratoire-de-Chemoinformatique/SynthI.
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Indicadores e ReagentesRESUMO
We elaborate new models for ACE and ACE2 receptors with an excellent prediction power compared to previous models. We propose promising workflows for working with huge compound collections, thereby enabling us to discover optimized protocols for virtual screening management. The efficacy of elaborated roadmaps is demonstrated through the cost-effective molecular docking of 1.4 billion compounds. Savings of up to 10-fold in CPU time are demonstrated. These developments allowed us to evaluate ACE2/ACE selectivity in silico, which is a crucial checkpoint for developing chemical probes for ACE2.