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A new tetrahydroacridine derivative (CHDA) with acetylcholinesterase inhibitory properties was synthesized. Using a range of physicochemical techniques, it was shown that the compound strongly adsorbs onto the surface of planar...

Synthetic chemistry and drug design through different software is becoming more and more important nowadays. In this modern era each person is suffering from many diseases due to various factors such as financial, environmental, food etc. Proposed thiocarbamates of various diamines were synthesized hypothetically and they were docked with AChE (Acetylcholine esterase) and BChE (Butyrylcholine esterase) using MOE (Molecular Operating Environment). From results of MOE, most active (KR-25 and KR-26) were synthesized using reported methods and their structures were confirmed with Fourier-transform infrared spectroscopy, mass spectrometry and XRD (X-ray powder diffraction). Later on in-vitro enzyme inhibition studies against both targeted enzymes were screened out which also supported the docking results. The DFT (Density Functional Theory) studies were carried out for all proposed structures in the form of optimization and HOMO-LUMO calculation. ADMET (absorption, distribution, metabolism, excretion and toxicity) studies were applied on compounds in order to check their different parameters. It was concluded from docking, in-vitro enzyme inhibition and ADMET that KR-25 and KR-26 are more potent for AChE and BChE.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using “clickable” fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.

The new complex of N,N-Dimethylglycine (DMG) with chloranilic acid (CLA) was synthesized and examined for thermal, structural, and dynamical properties. The structure of the reaction product between DMG and CLA was investigated in a deuterated dimethyl sulfoxide (DMSO-d6) solution and in the solid state by Nuclear Magnetic Resonance (NMR) (Cross Polarization Magic Angle Spinning-CPMAS NMR). The formation of the 1:1 complex of CLA and DMG in the DMSO solution was also confirmed by diffusion measurement. X-ray single crystal diffraction results revealed that the N,N-dimethylglycine–chloranilic acid (DMG+–CLA−) complex crystallizes in the centrosymmetric triclinic P-1 space group. The X-ray diffraction and NMR spectroscopy show the presence of the protonated form of N,N-dimethylglycine and the deprotonated form of chloranilic acid molecules. The vibrational properties of the co-crystal were investigated by the use of neutron (INS), infrared (IR), and Raman (RS) spectroscopies, as well as the density functional theory (DFT) with periodic boundary conditions. From the band shape analysis of the N–CH3 bending vibration, we can conclude that the CH3 groups perform fast (τR ≈ 10−11 to 10‒13 s) reorientational motions down to a temperature of 140 K, with activation energy at ca. 6.7 kJ mol−1. X-ray diffraction and IR investigations confirm the presence of a strong N+–H···O− hydrogen bond in the studied co-crystal.

The Suzuki–Miyaura cross-coupling reactions between 2,3,5-tribromo-4,6-dimethylpyridine and ortho-methoxyphenyl or ortho-chlorophenyl boronic acids were studied. The use of limited amount of the boronic acid resulted in the regioselective formation of biarylated products. In the case of ortho-methoxy- and ortho-chloro substituted series, the complete arylation furnished stable at room temperature atropisomers of different stereochemistry. This result may be attributed to the presence of additional transition state stabilisation caused by the complexation of the palladium atom with ortho-methoxy group and this observation may be helpful in the stereoselective synthesis of analogous compounds. The structure of all obtained pyridine derivatives was unambiguously determined by NMR spectroscopy, as well as the single-crystal X-ray analysis. All compounds described are chiral entities and the presence of individual enantiomers were visualized by the NMR spectra with chiral solvating agent.

In the present paper the structural and dynamical properties of crystalline 2,6–dimethylpyrazine - picric acid cocrystal are described. The title cocrystal crystallizes in centrosymmetric monoclinic P21/c space group. The X-ray diffraction and NMR spectroscopy show the presence of protonated form of 2,6-dimethypyrazine and deprotonated form of picric acid molecules. The Hirshfeld surface analysis for determine of intermolecular contacts was performed. Low temperature phase transition was observed and described by temperature dependent investigations: X-ray diffraction, different scanning calorimetry (DSC) and IR spectroscopy. The vibrational properties of cocrystal were investigated by use of IR and Raman spectroscopies, as well as density functional theory (DFT) with periodic boundary conditions. Activation energy for reorientational motion of CH3 group was determined from the band shape analysis of C CH3 bending vibration.

The Stobbe condensation between 3′,4′,5′-trimethoxyacetophenone and a benzylidenesuccinate derived from piperonal gave the Z,E-2,3-bisbenzylidenesuccinate as the only product. Such regioselectivity was explained by considering the Newman’s projections of the transition states of this reaction. Introducing L-prolinol as a chiral auxiliary, macrolactonization and subsequent photocyclization of the atropoisomeric cyclic amide ester led to new cyclolignan analogue. By comparing the regioselectivity observed in this study with our previous results, some general rules regarding the photocyclization of chiral 2,3-bisbenzylidenesuccinates could be established.

The synthesis of new chiral N-monotosylated-1,2-diamines based on the (-)-menthol skeleton is presented. The elimination of HCl from neomenthyl chloride obtained from an Appel reaction led to p-menth-3-ene in excellent yield. Further functionalization of the double bond in p-menth-3-ene with chloramine-T gave the corresponding N-tosylaziridines, which upon reaction with sodium azide and subsequent reduction of the azide functional group, formed the 1,2-diamine system. The synthesized chiral ligands proved effective in the asymmetric transfer hydrogenation of aromatic ketones and an endocyclic imine.

During the attempted photochemical cyclization of 2,3-bisbenzylidene-γ-hydroxybutyric acid cyclic amide ester, it was observed that a γ-butyrolactone ring was formed, which was concurrent with the release of the amine fragment from the amide. The process occurs with high yield giving rise to the formation of β-apopicropodophyllin and its regioisomer. Additional experiments confirmed the photochemical nature of this transformation, and that it is independent from the photocyclization of the benzylidene groups – a typical reactivity for the members of the fulgide family. In contrast to the latter UV-driven cyclization, the photochemical cleavage of the amide was proven to proceed under irradiation with visible light.

Racemic ketoprofen (KP) and β-cyclodextrin (β-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of β-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of β-CD and KP. NMR results indicated that KP/β-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M−1, showing that KP is quite strongly associated with β-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/β-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the preparation of the KP/β-CD complex, only method 3 is suitable.

New molecular complexes of l -leucine and d -leucine with chloranilic acid have been synthesized. Crystal structures of these crystals have been solved; they crystallize in non-centrosymmetric monoclinic P21 space group. In the crystal, leucine molecules exist in protonated form (C6NO2H14+) and chloranilic acid molecules in deprotonated form (C6HCl2O4−). Electronic (UV–Vis) and vibrational absorption (VA) spectra for both materials were collected. Circular dichroism methods such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) were used to determine the absolute configuration of new complexes. In both methods a characteristic (−,+) Cotton patterns are observed. In ECD spectra absorption bands are observed at 212 nm for acetonitrile solution and at 202 nm for aqueous solution. VCD spectra (in DMSO-d6 solution) show (−,+) Cotton pattern with strong peaks at 1323 cm−1 (CH rocking mode). Differential scanning calorimetry (DSC) and thermogravimetric (TG) investigations were performed to explore thermal properties of new materials. In DSC curve the decomposition and combustion processes are observed in 220–227 °C. The decomposition process was described by use of TG method and quadruple mass spectrometer (QMS). NMR spectra of pure l -leucine and chloranilic acid as well as l -leucine – chloranilic acid complex in solutions (D2O and DMSO) and in solid state confirm the geometry of molecules in complex both in solution and in solid state.

Natural (−)-menthol was applied to construction of mono-N-tosylated-1,2-diamine derivatives. The O-tosylation and elimination of the tosylate of the menthol intermediate led to trans-p-menth-2-ene. The unsaturated menth-2-ene was next transformed into a mixture of N-tosylaziridines, which upon reaction with sodium azide gave four isomeric azides. The reduction of the formed tosylazides on Pd/C gave new chiral mono-N-tosylated-1,2-diamines, which were used as ligands in the asymmetric transfer hydrogenation protocol on aromatic ketones and endocyclic imine.

The first synthesis of sterically demanding, stable at room temperature atropisomeric derivatives of penta-(ortho-substituted phenyl)pyridines is described. The Suzuki-Miyaura cross-coupling reaction of pentabromopyridine and selected meta- and ortho-tolylboronic acids afforded a series of pentaarylpyridine derivatives. The structures of two room temperature stable atropisomeric derivatives of penta-(o-tolyl)pyridines were confirmed by single-crystal X-ray analysis. Racemic atropisomers were examined by 1H NMR spectroscopy with a chiral solvating agent in order to visualize the presence of individual enantiomers.

The Suzuki–Miyaura cross-coupling reaction of 3,5-dibromo-2,4,6-collidine and bromo derivatives of 2,6- and 2,4-lutidine with several ortho-substituted boronic acids produced a library of arylated pyridines. The reaction conditions were carefully optimized to allow high yield of the desired products. In several cases the presence of stable atropisomers were detected, even at elevated temperature during GC–MS analysis. Some of the diastereomers were isolated and characterized by spectroscopic methods and X-ray crystallography. Racemic forms of selected samples were tested by 1H NMR spectroscopy in the presence of chiral solvating agents in order to visualize the presence of individual enantiomers.

The present study was designed to check enzyme (esterase and α-glucosidase) inhibition potential of newly synthesized thiazolidinones. Two precursors from ethylene diamine were prepared and further condensed with different aromatic aldehydes yielded fourteen different compounds. The synthesized compound ‘a’ was characterized with single crystal X-Ray diffraction (SC-XRD) technique, while the structures of all others were determined with FTIR and NMR (1H and 13C) spectroscopy. The compounds were further theoretically optimized through Gaussian 9 software and calculated their different parameters and energy gap between HOMO and LUMO. In-vitro enzyme inhibition studies were carried out spectrophotometrically which depicted that these molecules may be good therapeutic for targeted enzymes and their related diseases. Docking results of the synthetic thiazolidinone also advocated experimental out comes of the under studied compounds.

The Suzuki–Miyaura reaction of 4-amino-3,5-dibromo-2,6-lutidine with various ortho-substituted phenylboronic acids resulted in the formation of a series of mono- and diarylated lutidines in the form of atropisomers. The absolute stereochemistry of the chiral compounds was established, in some cases, by X-ray crystal structure analysis and HPLC-ECD (ECD = electronic circular dichroism) in combination with time-dependent density functional theory (TDDFT) calculations.

A series of new N-substituted benzimidazole derivatives was synthesized and their antifungal activity against Candida albicans was evaluated. The chemical step included synthesis of appropriate ketones containing benzimidazole ring, reduction of ketones to the racemic alcohols, and acetylation of alcohols to the esters. All benzimidazole derivatives were obtained with satisfactory yields and in relatively short times. All synthesized compounds exhibit significant antifungal activity against Candida albicans 900028 ATCC (% cell inhibition at 0.25 μg concentration > 98%). Additionally, racemic mixtures of alcohols were separated by lipase-catalyzed kinetic resolution. In the enzymatic step a transesterification reaction was applied and the influence of a lipase type and solvent on the enantioselectivity of the reaction was studied. The most selective enzymes were Novozyme SP 435 and lipase Amano AK from Pseudomonas fluorescens (E > 100). Chirality 00:000–000, 2016. © 2016 Wiley Periodicals, Inc.

We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and l-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin.

A novel domino reaction featuring a Michael addition/[1,2]-Stevens rearrangement reaction of pyrrolidinium ylides with electrophilic alkenes is described. Ylides generated under mild conditions from 2-aryl- N-cyanomethyl- N-methylpyrrolidinium salts entered the Michael addition, followed by a [1,3]-hydrogen shift and finally the [1,2]-Stevens rearrangement to give 3-aryl-2-cyano-2-(2-EWG-ethyl)-1-methylpiperidines.

Inelastic neutron scattering (INS) and infra-red (IR) spectroscopy methods were used for determination of dynamic structure of l -leucine – chloranilic acid complex. A theoretical dynamic pattern calculated by the density functional theory (DFT) method for periodic boundary conditions accompanied the experimental ones. Normal modes in the vibrational spectra were defined and described. The characteristic presence of the Hadži's trio enriched by numerous submaxima is observed in the wavenumber range 3200–800 cm−1. Bands assigned to CH3 torsion vibrations in the leucine cation were observed at 231 cm−1 and 258 cm−1 in the INS spectrum. Temperature-dependent far-infrared spectra in the temperature range 9 K–290 K were obtained. Vibrational bands were analyzed as a function of temperature. Activation energies for reorientational motion of CH3 and CH2 groups were determined by means of the band shape analysis performed for torsional and twisting vibrations of these groups. The estimated energy is equal to Ea = 2.7 ± 0.2 kJ/mol and Ea = 2.17 ± 0.12 kJ/mol for CH3 and CH2 groups, respectively. A phase transition at about 130 K in the l -leucine – chloranilic acid complex was observed.

The crystal structure of 1,4-di(2-phenyl-1H-imidazol-4-yl)benzene (DPI4B) is determined by X-ray diffraction with a final R-factor of 6.42% at room temperature. It crystallizes with a space group P21/c, Z = 4, a = 5.01790(10), b = 28.8971(6), and c = 12.9362(3) A; β = 98.757(2)°. Two 4-phenyl-1H-imidazole (4PI) fragments are related by inversion symmetry and each makes a dihedral angle of 0° with the benzene rings. Despite the presence of a total number of five homo- and heterocyclic rings in the DPI4B molecule, similarly to 2-phenyl-1H-imidazole (2PI) but in contrast to 1,4-di(1H-imidazol-4-yl)benzene (DI4B) and 4-phenyl-1H-imidazole (4PI), it is almost planar. Each plane containing a terminal phenyl ring makes a small dihedral angle of about 3° with the central benzene ring plane. The average twisting angle of the whole molecule is equal to 7°. The ordering of compounds studied according to the decreasing twisting angle is 4PI > DI4B > DPI4B > 2PI and is the same as that according to hydrogen bond lengt...

A simple enantioselective synthetic procedure for the preparation of mianserin and epinastine in optically pure form is described. The key step in the synthetic pathway is the asymmetric reduction of the cyclic imine using asymmetric transfer hydrogenation conditions.

A series of new N-aryl-substituted thiomorpholine-3,5-diones were synthesized. Crystal structures of seven compounds were established on the basis of X-ray crystallography. Stable at room temperature diastereomers were detected for (2-phenyl)-substituted derivatives using 1H NMR. The dynamic stereochemistry of compound 36 was studied with variable-temperature 1H NMR and the mechanism of diastereomers interconversion was proposed on the basis of quantum chemical calculations.

A simple synthetic procedure for the preparation of mono-N-tosylated-1,2-diamines derived from (+)-3-carene is described. (+)-3-Carene is transformed into the corresponding N -tosylaziridine derivative using chloramine-T trihydrate. Subsequent ring opening with sodium azide followed by reduction of the azide function gives the optically pure mono-N-tosylated-1,2-diamine. This ligand is effective in asymmetric transfer hydrogenations of aromatic ketones. It can also be transformed into other chiral ligands by alkylation of the amino group for application in the addition of diethylzinc to benzaldehydes.

Suzuki reaction of tribromo-2,6-lutidine with (2-methoxyphenyl)boronic acid gave 3,4,5-tris(2-methoxyphenyl)-2,6-lutidine in the form of a mixture of three atropisomers that were stable at room temperature. Each isomer was isolated and fully characterized, including by X-ray structure determination. One of the isomers, being a racemic mixture, was separated into individual enantiomers by using semipreparative chiral HPLC. Their absolute stereochemistry was initially assigned on the basis of computational calculation of the CD spectra and finally confirmed by X-ray analysis.

In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins.

The highly functionalized tetrahydropyridine 4 was obtained in an indium(III) chloride catalyzed multi-component reaction from benzaldehyde, 4-methoxyaniline, and ethyl acetoacetate (=ethyl 3-oxobutanoate) in the presence of [1,1′-binaphthalene]-2,2′-diol (binol). It was found that binol played a beneficial role in this reaction, allowing a substantial decrease of the amount of indium salt. Also, simple organic Bronsted acids may serve as effective organocatalysts in this process.

A synthetic procedure leading to the preparation of a new family of enantiopure mono-N-tosylated-1,2-diamines derived from (R)-(+)-limonene is described. (+)-Limonene was transformed into the appropriate N-tosyl derivative using N-tosylaziridination based on chloramine-T trihydrate. Subsequent ring opening by sodium azide afforded the corresponding isomeric azides. Finally, reduction of the azide function gave enantiomerically pure mono-N-tosylated-1,2-diamines. The ligands obtained proved to be effective in the asymmetric transfer hydrogenation protocol on aromatic ketones and imines.

( R )-(+)-Limonene was transformed into mono- N -tosylated-1,2-diamine derivatives using an N -tosylaziridination procedure followed by sodium azide treatment and reduction on Pd/C. The ligands obtained proved effective in the asymmetric transfer hydrogenation protocol on aromatic ketones.

A mild and efficient method for the synthesis of fulgimides is presented in which the peptide coupling reagent BOP is employed for dehydratation of fulgenic acid monoamides (succinamic acids). The disclosed method proved to be superior to those described in the literature.

Two antibacterial and antifungal agents, chloroxylenol (4-chloro-3,5-dimethyl-phenol) and triclosan (5-chloro-2-(2’,4’-dichlorophenoxy)-phenol), were studied experimentally in solid state with an X-ray, 35Cl-nuclear quadrupole resonance (NQR) and 17O-nuclear quadrupole double resonance (NQDR) spectroscopies and, theoretically, with the density functional theory/quantum theory of atoms in molecules (DFT/QTAIM). The crystallographic structure of triclosan, which crystallises in space group P31 with one molecule in the asymmetric unit [a = 12.64100(10), b = 12.64100(10), c = 6.71630(10) A], was solved with an X-ray and refined to a final R-factor of 2.81% at room temperature. The NQR frequencies of 35Cl and 17O were detected with the help of the density functional theory (DFT) assigned to particular chlorine and oxygen sites in the molecules of both compounds. The NQR frequencies at 35Cl sites in chloroxylenol and triclosan were found to be more differentiated than frequencies at the 17O site. The former better describes the substituent withdrawing effects connected to π-electron delocalization within the benzene rings and the influence of temperature; whereas, those at the 17O site provide more information on O-H bond and intermolecular interactions pattern. The conformation adopted by diphenyl ether of triclosan in solid state was found to be typical of diphenyl ethers, but the opposite to those adopted when it was bound to different inhibitors. According to an X-ray study, temperature had no effect on the conformation of the diphenyl ring of triclosan, which was the same at 90 K and at room temperature (RT). The scattering of NQR frequencies reproduced by the DFT under assumption of the X-ray data at 90 K and RT is found to be a good indicator of the quality of resolution of the crystallographic structure. Copyright © 2012 John Wiley & Sons, Ltd.

Isothioureas, inhibitors of nitric oxide synthases, have been studied experimentally in solid state by nuclear quadrupole double resonance (NQDR) and X-ray methods and theoretically by the quantum theory of atoms in molecules/density functional theory. Resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in each molecule. The crystal packings of (S)-3,4-dichlorobenzyl-N-methylisothiouronium chloride with the disordered chlorine positions in benzene ring and (S)-butyloisothiouronium bromide have been resolved in X-ray diffraction studies. (14)N NQDR spectra have been found good indicators of isomer type and strength of intra- or intermolecular N-H···X (X = Cl, Br) interactions. From among all salts studied, only for (S)-2,3,4,5,6-pentabromobenzylisothiouronium chloride are both nitrogen sites equivalent, which has been explained by the slow exchange. This unique structural feature can be a key factor in the high biological activity of (S)-2,3,4,5,6-pentabromobenzylisothiouronium salts.

A series of new N-substituted benzimidazole derivatives was synthesized and their antifungal activity against Candida albicans was evaluated. The chemical step included synthesis of appropriate ketones containing benzimidazole ring, reduction of ketones to the racemic alcohols, and acetylation of alcohols to the esters. All benzimidazole derivatives were obtained with satisfactory yields and in relatively short times. All synthesized compounds exhibit significant antifungal activity against Candida albicans 900028 ATCC (% cell inhibition at 0.25 μg concentration98%). Additionally, racemic mixtures of alcohols were separated by lipase-catalyzed kinetic resolution. In the enzymatic step a transesterification reaction was applied and the influence of a lipase type and solvent on the enantioselectivity of the reaction was studied. The most selective enzymes were Novozyme SP 435 and lipase Amano AK from Pseudomonas fluorescens (E100).

Prochiral (E,E)-fulgide 8 was reacted with l -prolinol to afford cyclic (M)-fulgamide 10 in a two step reaction sequence. The UV-light-driven photocyclization of 10 proceeded stereospecifically, giving lignan analogue 1 in 40% yield. The structure of 1 was confirmed by X-ray crystallography.