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  • Open access
  • 99 Reads
Asymmetric aza-Henry reaction of hydrazones

In this work, the enantioselective organocatalyzed addition of nitroalkanes to N-benzoyl hydrazones has been developed for the first time. In order to find a chiral organocatalyst suitable to promote the reaction under high stereo-control and reaction rates, the catalytic activity of several cinchone-derived Brønsted bases was evaluated. As a result of the study, simple quinine alkaloid was able to catalyze, in the optimal reaction conditions, the synthesis of alkyl substituted betha-nitroalkylhydrazides with good yields (up to 91%) and enantiomeric excesses (up to 77%), while quinidine alkaloid was used to obtain the opposite enantiomer with similar catalytic results. Moreover, the further recrystallization of the corresponding enantio-enriched mixtures led to the obtainment of each enantiomer with ee up to 94%. The scope of the catalytic method was explored (14 examples), and the effect of substitutients present in the substrates was evaluated in terms of activity and selectivity. Additionally, the catalyzed reaction pathway was study ab initio in order to understand the successful chiral induction by the catalyst. Hence, in the transition state of the rate limiting step (RLS), quinine is acting as bifunctional catalyst activating both substrates simultaneously. This step involves the protonation of the hydrazone and the attack of the nitronate anion to the sp2 prochiral center in a concerted process. Experimental kinetic studies support this reaction mechanism.

  • Open access
  • 67 Reads

The pyridone derivatives are heterocyclic compounds with vital substructures of many naturally compounds [1] and medicines having a wide range of biological applications, such as antimalarial, antiasthma, vasodilatory, antiepilepsy, antimicrobial, antidiabetic, antiviral, and antioxidant activity, etc. [2]. Over the past decades, much attention has been focused on the synthesis of N-substituted pyridines [3]. The synthesis of N-alkyl-2(1H)-pyridones is feasible by the alkylation of 2-pyridones. In this case, selectively witching the reaction course is required to induce the N- or O-alkylation. In general, N-alkylation is performed via the sodium salt and O-alkylation via the silver salt, but a mixture of N- and O-alkylation was obtained in almost all cases [4-6]. However, there is still a need for more efficient approaches allowing the selective N-alkylation of 2-pyridones, as known procedures generally suffer from competition between N- and O-alkylation and/or low yields [7].

This work describes the synthesis of a series of N-alkylated 2-pyridone derivatives obtained from alkylation with different alkylating agents (Figure 1). The methodology developed is elaborated into the one-pot synthesis under the microwave, the compounds will be presented and discussed.

  • Open access
  • 61 Reads
Synthesis of functionalized thiopyrano [2,3-b]quinolines via a cascade reactions catalyzed by magnetic arginine/alginate biocomposite

An effective synthesis of functionalized thiopyrano[2,3-b]quinolines has been described via cascade reactions using superparamagnetic iron oxide nanoparticles (SPIONs) coated with L-arginine (Arg) grafted alginate (Alg) called Fe3O4@Alg@CPTMS@Arg. The reaction was performed between commercially available CH acids compounds such as dimedone or malononitrile, and 2-mercapto-quinoline-3-carbaldehydes under green conditions. This efficient method provides a new route for the formation of functionalized three or four fused rings.

  • Open access
  • 81 Reads
Glucose-Based Molecular Rotors as Fluorescent Inhibitors and Probes of Glycogen Phosphorylase Function

Glycogen phosphorylase (GP) is an enzyme with a key role in glucose homeostasis. Dysregulation of GP is involved in a number of pathological states such as Type 2 diabetes and cancer, while recent findings connect GP to Alzheimer’s disease and a number of other neurological disorders. The ubiquitous presence of GP has ascended the design and synthesis of GP activity-modulating agents into an exciting field in chemical research. Our team has been working on the synthesis and study of potential GP inhibitors, with the main aim to create new agents against Type 2 diabetes.

Herein, the synthesis and photochemical study of a (β-D-glucopyranosyl)julolidine analogue (GPJ), a fluorescent inhibitor of glycogen phosphorylase with properties of a molecular rotor, are reported. A straightforward synthesis involved the condensation of the corresponding acryloyl chloride with peracetylated β-D-glucopyranosylamine followed by deprotection. Fluorescence measurements in mixtures of ethylene glycol:glycerol solutions of increasing viscosity determined that the fluorescence intensity increases with the viscosity of the medium, indicating that GPJ exhibits the characteristics of a molecular rotor. GPJ does not fluoresce in aqueous buffer solution but, in the presence of increasing amounts of GP, we observed an increase of fluorescence intensity, attributed to the GP:RotA complex. It is expected that this new molecular rotor will find in vitro and in vivo applications as a molecular probe of its interaction with GP, in a cellular environment.

  • Open access
  • 63 Reads
Study of Organic Radicals Generated by Naphthoquinone-Hydantoins Interaction in Basic Aqueous Solution

Thiohydantoin’s characteristic thiourea core provides important biologic activity to the molecule that has been explored for pharmaceutic industry in nervous system treatment. Quinones are a family of compounds with a series of interesting properties characterized by a strong redox character due to the presence of an α,β-unsaturated system in the highly conjugated system of the ring, these properties give quinones affinity to such biological process that involves polar elements.

In the present work we study the synthesis of thiohydantoins from L-amino acids and isothiocyanates with a high purity method based on Edman cycle, these molecules where completely characterized for the next synthesis steps. Reactivity of naphthoquinones through Michael addition was studied to obtain the thiohydantoin-naphthoquinone hybrid with potential biological properties. Preliminary studies with thiohydantoin analogs like commercial hydantoin and thiohydantoin with 1,4-naphthoquinone and 2,3-dichloro-1,4-naphthoquinone were made in different conditions, including microwave assisted synthesis. Interesting results were obtained in all cases, color change was observed without structural changes. The impossibility to obtain the NMR spectra properly joined to the presence of redox properties give the clues to the presence of radicals in the final molecules. EPR spectroscopy analysis give positive results to all the hydantoin-naphthoquinone hybrids. Radicals obtained showed stability in different conditions despite de absence of transition metals in their structure like common radical molecules.

  • Open access
  • 86 Reads
Rational design, synthesis, and in-silico evaluation of homologous local anesthetic compounds as TASK-1 channel blockers

Advances in different technological and scientific fields have led to the development of tools that allow the design of drugs in a rational way, using defined therapeutic targets, through simulations that offer a molecular view of the ligand-receptor interactions, giving precise information for the design and synthesis of new compounds. Ion channels are of great relevance as therapeutic targets since they play roles in different pathologies. Several ion channels are expressed in the atria and constitute a therapeutic target for the treatment of atrial fibrillation (AF), the most common type of arrhythmia and an important risk factor for an increase in cerebrovascular accidents. The action potential (AP) of a cardiomyocyte is initiated by depolarization of the membrane through the inflow of sodium (Na+). The repolarization currents are carried out by different potassium (K+) channels. Background shows that TASK-1 channels can contribute to PA. TASK-1 channel blockers could become innovative strategies against FA, the compounds used in this study will be based on local anesthetic (LA) -type compounds that have been shown to be TASK-1 channel blockers such as lidocaine, ropivacaine and bupivacaine, and have antiarrhythmic capacity, becoming potentially effective drugs for the treatment of AF.

The main objective of this study is, based on the common characteristics of LAs, to propose the synthesis of analogues of LAs and evaluate them in-silico as TASK-1 channel blockers.

  • Open access
  • 73 Reads
Searching for new biologically active compounds derived from isoquinoline alkaloids

Many isoquinoline alkaloids are biologically active compounds and are successfully used as pharmaceuticals. Compounds belonging to isochinolines can be used as anesthetics, e.g. Quinisocaine (INN), antihypertensive drugs, e.g. Quinapril, Debrisoquine, antiviral agents – Saquinavir (SQV) used in the treatment and prevention of HIV / AIDS, and vasodilators, e.g. commonly used papaverine. In addition, tetrahydroisoquinolines (TIQs) derivatives constitute a wide group of compounds of pharmaceutical importance. These endogenous amines are present in the brain of mammals and are involved in the pathogenesis of Parkinson's disease. Currently, studies on the synthesis and pharmacological properties of TIQ derivatives is conducted on a large scale.

In the presented studies, the search for new compounds and synthesis of isoquinoline alkaloid derivatives was undertaken. A number of syntheses were carried out to obtain racemic products. Asymmetric reduction of 3,4-dihydroisoquinolines was conducted with borane in the presence of chiral terpene spiroboranes.

  • Open access
  • 78 Reads
The reaction of malononitrile dimer with 4-methyl-2,6-dichloronicotinonitrile

The reaction of 4-methyl-2,6-dichloronicotinonitrile with malononitrile dimer (2-amino-1,1,3-tricyanopropene) in the presence of triethylamine leads to regioselective nucleophilic substitution of the chlorine atom at position 6 and the formation of triethylammonium 2-amino-3-(4-methyl-6-chloro-5-cyanopyridin-2-yl)-1,1,3-tricyanoprop-2-en-1-ide. The structure of the product was confirmed by X-ray studies.

  • Open access
  • 78 Reads
Study of 1,2,4-triazole-3(5)-thiol behavior in reactions with 1-phenyl-1H-pyrrole-2,5-dione derivatives and 3-bromodihydrofuran-2(3H)-one and antimicrobial activity of products

The thiazolo[3,2-b][1,2,4]triazole-6-one represent a bicyclic heteroatom-rich scaffold which recently, has considerably attracted the attention of medicinal chemists due to their diverse biological activities. The [2+3]-cyclocondensation reaction of substituted 1,2,4-triazole-3(5)-thiols with equivalents of electrophilic synthon [C2]2+ is key synthetic approach for 5-substituted thiazolo[3,2-b][1,2,4]triazole-6-ones. The chloroacetic acid as [C2]2+ synton is studied well (mostly in multicomponent reaction with aromatic/heteroaromatic aldehydes) in this reaction type meanwhile data about other ones are limited. In present work we report our studies of the interaction of 1-phenyl-1H-pyrrole-2,5-dione derivatives (N-arylmaleimides) and 3-bromodihydrofuran-2(3H)-one (α-bromo-γ-butyrolactone) as possible [C2]2+ synthons with 1,2,4-triazole-3(5)-thiole targeting on synthesis of novel 5-substituted thiazolo[3,2-b][1,2,4]triazole-6-ones. According to obtained results was establish that in the above-mentioned interactions (conditions: classic heating, a wide range of solvents and reaction time) the thiol-ene click process (with N-arylmaleimides) and nucleophilic substitution (with α-bromo-γ-butyrolactone) take place, but not [2+3]-cyclocondensation reaction as could be expected. The structure of compounds was studied and confirmed using 1H, 13C NMR spectroscopy, LC-MS spectrometry, and X-ray diffraction analysis. The screening of antimicrobial activity (MIC determination) for synthesized compounds was performed against Gram-positive and Gram-negative bacteria, as well as yeasts. The synthesized 1-(4-R-phenyl)-3-(2H-[1,2,4]triazol-3-ylsulfanyl)-pyrrolidine-2,5-diones were found highly active against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains of Staphylococcus aureus, as well as Candida albicans strains. The obtained results suggest to coming design and synthesis of new 1,2,4-triazole/pyrrolidine-2,5-dione hybrids as potential molecules with promising antimicrobial properties.

  • Open access
  • 68 Reads

Introduction: The goal of the present work was to evaluate the chemical reactivity of amino acids with polar uncharged sidechains (Setine, Threonine, Asparagine and Glutamine) using density functional theory (DFT) and thermodynamics modeling by calculating a series of molecular descriptors and properties of their optimized geometries.

Experimental and/or Modelling: The predictive calculations were achieved with Spartan software from Wavefunction, Inc. Irvine CA USA [1], hybrid algorithm B3LYP (the Becke’s 3-term functional; Lee, Yang, Parr exchange Hybrid) [2, 3] and polarization basis set 6-31G (d, p) for equilibrium geometry at ground state in vacuum and in water, after minimization energy and geometry optimization.

Thermodynamic properties (zero-point energy, enthalpy, constant volume heat capacity, entropy and Gibbs energy) for these derivatives have been calculated and related to ligands electrochemical behavior. Reduction and oxidation potentials have been correlated to their calculated energy levels for LUMO and HOMO orbitals.

The results of this work were compared with those obtained for other amino acids, with different functional groups.