1,2,3,4,6-penta-O-galloyl-β-d-glucose: A cholinesterase inhibitor from Terminalia chebula

The search for a novel pharmacotherapy from medicinal plants for neurodegenerative disorders has significantly advanced. Therefore, the present study was performed to evaluate the anticholinesterase activities of one hundred medicinal plants in Korea, where Terminalia chebula (T. chebula) fruits showed significant acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitions. Further bioassay monitored phytochemical exploration led to the isolation of 1,2,3,4,6-penta-O-galloyl-β-d-glucose (compound 1), which showed significant AChE and BChE inhibitory effects with IC₅₀ values of 29.9 ± 0.3 µM and 27.6 ± 0.2 µM, respectively. The inhibitory effect of compound 1 towards acetylcholinesterase was also evaluated using TLC and compared with tacrine as the positive control; the positive effect was confirmed. Furthermore, compound 1 also displayed strong antioxidant activity by the FRAP assay (IC₅₀ = 4.6 ± 0.2 µM). In conclusion, compound 1 may prove to be a potential natural anti-Alzheimer source based on noteworthy AChE and BChE inhibitions, and strong antioxidant activity.     

New class of acetylcholinesterase inhibitors from the stem bark of Knema laurina and their structural insights

Bioassay-guided extraction of the stem bark of Knema laurina showed the acetylcholinesterase (AChE) inhibitory activity of DCM and hexane fractions. Further repeated column chromatography of hexane and DCM fractions resulted in the isolation and purification of five alkenyl phenol and salicylic acid derivatives. New compounds, (+)-2-hydroxy-6-(10′-hydroxypentadec-8′(E)-enyl)benzoic acid (1) and 3-pentadec-10′(Z)-enylphenol (2), along with known 3-heptadec-10′(Z)-enylphenol (3), 2-hydroxy-6-(pentadec-10′(Z)-enyl)benzoic acid (4), and 2-hydroxy-6-(10′(Z)-heptadecenyl)benzoic acid (5) were isolated from the stem bark of this plant. Compounds (1-5) were tested for their acetylcholinesterase inhibitory activity. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and chemical derivatizations. Compound 5 showed strong acetylcholinesterase inhibitory activity with IC₅₀ of 0.573 ± 0.0260 μM. Docking studies of compound 5 indicated that the phenolic compound with an elongated side chain could possibly penetrate deep into the active site of the enzyme and arrange itself through π-π interaction, H-bonding, and hydrophobic contacts with some critical residues along the complex geometry of the active gorge.     

Complexes of copper(II) formate with 2-(phenylamino)pyridine and 2-(methylamino)pyridine: New copper formato paddle-wheel compounds

The derivatives of Cu(HCOO)₂ · 4H₂O with 2-(phenylamino)pyridine and 2-(methylamino)pyridine, [Cu₂(μ-HCOO)₄(PhNHpy)₂] (1), [Cu₂(μ-HCOO)₄(MeNHpy)₂] (2) and Cu(HCOO)₂(MeNHpy)₂ (3), have been synthesized and characterized. Compounds 1 and 2 show the paddle-wheel structure of [Cu₂(μ-HCOO)₄L₂], with four syn-syn bridging formato groups and two molecules of PhNHpy or MeNHpy coordinated to the axial positions, respectively. Intramolecular hydrogen bonds are formed in both cases: two in each dimer of 1 and four in the dimer of compound 2. The dimer units are oriented in two different directions. Dimers with the same orientation form rows along the “c” and the “a” axis in compounds 1 and 2, respectively, with a π-π stacking of the pyridine rings. In compound 1, an intercalation of the phenyl rings of contiguous rows of dimers gives rise to a succession of phenyl rings at a distance of 4.38 Å and an angle of 30.44° between alternate rings. They are antiferromagnetic. Signals of the triplet state are observed in their EPR spectra and the zero-field splitting parameter has been determined. Compound 3 obeys the Curie-Weiss law and the magnetic results indicate the absence of magnetic interaction between Cu(II) atoms.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Unusual stilbenoids and a stilbenolignan from seeds of Syagrus romanzoffiana

Stilbenoids, syagrusins A-B (1-2), and a stilbenolignan, 5-hydroxyaiphanol (3), along with three known phenylpropanoids (4-6), were isolated from seeds of Syagrus romanzoffiana. Compounds 1 and 2 possess unusual 1,4,4a,9a-tetrahydrofluoren-9-one and bicyclo[3.3.0]octanedione skeletons, respectively, whereas compound 3 is a stilbenolignan belonging to a very rare structural class of plant secondary metabolites. Their structures were elucidated by spectroscopic analyses. Compounds 1-3 exhibited moderate inhibitory activity against α-glucosidase with IC₅₀ values of 16.9 μM (1), 23.7 μM (2) and 12.8 μM (3), respectively.     

Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads—Specs1 (IC₅₀ = 3.279 μM) and Spec2 (IC₅₀ = 5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.     

α-Glucosidase inhibition and antihyperglycemic activity of prenylated xanthones from Garcinia mangostana

An ethanol extract of the fruit case of Garcinia mangostan, whose most abundant chemical species are xanthones, showed potent α-glucosidase inhibitory activity (IC₅₀ = 3.2 μg/ml). A series of isolated xanthones (1-16) demonstrated modest to high inhibition of α-glucosidase with IC₅₀ values of 1.5-63.5 μM. In particular, one hitherto unknown xanthone 16 has a very rare 2-oxoethyl group on C-8. Kinetic enzymatic assays with a p-nitrophenyl glucopyranoside indicated that one of them, compound (9) exhibited the highest activity (K_i = 1.4 μM) and mixed inhibition. Using, a physiologically relevant substrate, maltose, as substrate, many compounds (6, 9, 14, and 15) also showed potent inhibition which ranged between 17.5 and 53.5 μM and thus compared favorably with deoxynojirimycin (IC₅₀ = 68.8 μM). Finally, the actual pharmacological potential of the ethanol extract was demonstrated by showing that it could elicit reduction of postprandial blood glucose levels. Furthermore, the most active α-glucosidase inhibitors (6, 9, and 14) were proven to be present in high quantities in the native seedcase by a HPLC chromatogram.     

Synthesis and antiglycation potentials of bergenin derivatives

Bergenin (1), major bioactive compound isolated from methanolic extract of Mallotus philippinensis, displayed moderate AGE inhibition activity (IC₅₀ = 186.73 μM). A series of derivatives of bergenin (3a-k) containing variety of aromatic acids were synthesized under mild conditions by modification of sugar part. Selective esterification of hydroxyl groups on the sugar part enhanced antiglycation potential of bergenin. Compounds 3j and 3k exhibited potent antiglycation activity with the IC₅₀ values of 60.75 and 12.28 μM, respectively.     

From infinite tubular arrays to discrete molecules and back: An example of reversible ring-opening polymerization in silver(I)-diphosphazane chemistry

The reaction of AgX with the diphosphazane ligand, PrⁱN(PPh₂)₂ (L) gives the polymeric complexes, [Ag₂(μ-X)₂(μ-L)]_n (X = NO₃1a or OSO₂CF₃1b). Single crystal X-ray analysis of 1a reveals a novel structural motif formed by interlinking of giant 40-membered rings; the diphosphazane ligand L adopts a unique ‘C_s’ geometry. These polymeric complexes exhibit a completely reversible ring-opening polymerization-depolymerization relationship with the dinuclear and mononuclear complexes, [{Ag(μ-L)(X)}₂] (X = NO₃2a, X = OSO₂CF₃2b) and [Ag(κ²-L)₂]X (X = NO₃3a, X = OSO₂CF₃3b).     

Cytotoxic and antioxidant activities of diterpenes and sterols from the Vietnamese soft coral Lobophytum compactum

Two new diterpenes, lobocompactols A (1) and B (2), and five known compounds (3-7) were isolated from the methanol extract of the soft coral Lobophytum compactum using combined chromatographic methods and identified based on NMR and MS data. Each compound was evaluated for cytotoxic activity against A549 (lung) and HL-60 (acute promyelocytic leukemia) human cancer cell lines. Among them, compound 5 exhibited strong cytotoxic activity against the A549 cell line with an IC₅₀ of 4.97 ± 0.06 μM. Compounds 3, 4, and 7 showed moderate activity with IC₅₀ values of 23.03 ± 0.76, 31.13 ± 0.08, and 36.45 ± 0.01 μM, respectively. The cytotoxicity of 5 on the A549 cells was comparable to that of the positive control, mitoxantrone (MX). All compounds exhibited moderate cytotoxicity against the HL-60 cell line, with IC₅₀ values ranging from 17.80 ± 1.43 to 59.06 ± 2.31 μM. Their antioxidant activity was also measured using oxygen radical absorbance capacity method, compounds 1 and 2 exhibiting moderate peroxyl radical scavenging activity of 1.4 and 1.3 μM Trolox equivalents, respectively, at a concentration of 5 μM.     

Hybrid materials composed of tetravanadate motifs: Synthesis, structure and magnetic properties of the open framework structure solids [{M(C5H5N)4}2]V4O12 (M = Cu, Co)

Two new inorganic-organic hybrid materials - [{M(C₅H₅N)₄}₂]V₄O₁₂ (M = Cu, 1; M = Co, 2) have been synthesized and characterized by spectroscopic methods, X-ray powder diffraction, thermogravimetry, magnetometry and complete single crystal structure analysis. The structures of 1-2 are comprised of layers containing centrosymmetric {V₄O₁₂} rings connected to {M(C₅H₅N)₄} units by V-O-M bridges (M = Cu, 1; M = Co, 2). The layers are parallel to the (1 0 1) crystal planes and there are pyridine stacking interactions between layers. The effective magnetic moment, μ_eff, values for 1 and 2 are 1.9 μ_B and 3.9 μ_B, respectively, indicating some orbital contributions in each case. Both compounds exhibit Curie-Weiss magnetic behavior over the entire range above the critical temperature.     

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Four new copper(II) complexes with di-substituted s-triazine-based ligands

In this paper, two di-substituted triazine-based ligands, 6-chloro-N,N,N′N′-tetrakis-pyridin-2-ylmethyl-[1,3,5]triazine-2,4-diamine (L1), and 6-chloro-N,N′-bis-pyridin-2-ylmethyl-N,N′-bis-thiophen-2-ylmethyl-[1,3,5]triazine-2,4-diamine (L2), have been prepared. Reaction of CuCl₂·2H₂O and Cu(NO₃)₂·3H₂O with L1 and L2 results in the formation of [Cu₂Cl₄(L1)]·3MeOH (compound 1), [Cu₄(NO₃)₈(L1)₂]·2.07CH₂Cl₂·0.93MeOH (compound 2), [Cu₂Cl₄(L2)₂] (compound 3) and [Cu(NO₃)₂(L2)]·CH₂Cl₂ (compound 4), respectively, which have been fully characterized and determined by single-crystal X-ray crystallography, FT-IR, elemental analysis, thermogravimetric measurement and magnetic susceptibility. The dinuclear compound 1 shows strong π-π interactions between the neighboring pyridine rings. The nitrate-π (1,3,5-triazine ring) interaction with the distance of 2.755 Å in compound 2, is the closest contact reported so far. Compounds 3 and 4 are mononuclear copper(II) compounds, in which none of thiophene rings coordinates with copper(II) ion. In addition, the different orientations of two thiophene rings in compounds 3 and 4 lead to the π-π and CH₂Cl₂-π (thiophene ring) interactions in compound 4, but not in compound 3.     

Phenolic compounds with NF-κB inhibitory effects from the fungus Phellinus baumii

Chemical investigation of the fungus Phellinus baumii has resulted in characterization of five previously undescribed hispidin derivatives, phellibaumins A-E (1-5), as well as two pairs of new non-equivalent epimeric benzyl dihydroflavones, methylphelligrin A (9), epi-methylphelligrin A (10), methylphelligrin B (11), and epi-methylphelligrin B (12), together with five known compounds, interfungin B (6), phelligridin H (7), phelligridimer A (8), phelligrin A (13), and epi-phelligrin A (14). Phellibaumin A (1) was a novel hispidin derivative with a unique 3,4-dihydroxybenzofuran unit. These compounds exhibited NF-κB inhibitory activity with IC₅₀ values of 52.96 μM (1), 41.40 μM (2), 52.92 μM (5), 36.44 μM (9 and 10), and 22.46 μM (11 and 12), respectively.     

Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles

The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC₅₀ (EeAChE: 14 nM); IC₅₀ (eqBuChE: 5.2 ??M]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC₅₀ (EeAChE: 64 nM); IC₅₀ (eqBuChE: 9.6 ??M] showed that this compound is a mixed-type inhibitor (K_i = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K⁺-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.     

[Ir(acac)(η-C8H14)2]: A precursor in the synthesis of cyclometalated iridium(III) complexes

A new convenient synthesis and the crystallographic characterization of [Ir(acac)(coe)₂] (2, acac = acetylacetonato; coe = cis-cyclooctene) are described. The title compound crystallized from THF/ethanol in two modifications (monoclinic P2₁/c, 2a, and triclinic , 2b). Complex 2 represents an efficient starting material in the synthesis of mononuclear iridium(III) complexes containing cyclometalated 2-phenylpyridinato ligands using oxidative addition reactions of the corresponding ligands towards 2. Thus [Ir(acac)(ppy)₂] (3, ppy = 2-phenylpyridinato) and [Ir(ppy)₃] (4) (mer, 4a; fac, 4b) were prepared in excellent yields and short reaction times in a kind of one-pot procedure starting from [{Ir(μ-Cl)(coe)₂}₂] (1). Furthermore a convenient synthesis of [{Ir(μ-Cl)(ppy)₂}₂] (5) from 1 and Hppy is described.     

Construction of carbon chains on ruthenium and osmium carbonyl clusters

We have used the elimination of AuX(PR₃) (X = halide, R = Ph, tol) that occurs in reactions of alkynylgold(I)-phosphine complexes with M₃(μ-H)₃ (μ₃-CBr) (CO)₉ (M = Ru, Os) to prepare the complexes M₃(μ-H)₃(μ₃-CCCR)(CO)₉ [M = Ru, R = Ph 2, CCSiMe₃3, Fc 4, CCFc 6-Ru, CC[Ru(PPh₃)₂Cp] 8; M = Os, R = CCFc 6-Os, CCCCFc 7], Fc′{(μ₃-CCC)Ru₃(μ-H)₃(CO)₉}₂5, and bis-cluster-capped carbon chain complexes {M₃(μ-H)₃(CO)₉}₂{μ₃:μ₃-C(CC)_nC} (M = Ru, n = 2 9, 3 10-Ru; M = Os, n = 3 10-Os) and {(L)(OC)₈(μ-H)₃M₃}C(CC)_nC{Co₃(μ-dppm)(CO)₇} (n = 1, M = Ru, L = CO 11, PPh₃12-Ru/P; n = 2, L = CO 12-Ru, PPh₃13; M = Os, L = CO 12-Os) in good to excellent yields. X-ray structural determinations of 2-5, 6-Ru, 6-Os, 7, 9, 11, 12-Ru, 12-Os and 12-Ru/P are reported.     

Synthesis, crystal structure and magnetic properties of new dinuclear Mn(III) compounds with 4-ClC6H4COO and 4-BrC6H4COO bridges

Four new dinuclear Mn(III) compounds have been synthesised: [{Mn(bpy)(H₂O)}₂(μ-4-ClC₆H₄COO)₂(μ-O)}](ClO₄)₂ (1), [{Mn(EtOH)(phen)}₂(μ-O)(μ-4-ClC₆H₄COO)₂](ClO₄)₂ (2), [{Mn(bpy)(EtOH)}(μ-4-BrC₆H₄COO)₂(μ-O){Mn(bpy)(ClO₄)](ClO₄) (3) and [{Mn(H₂O)(phen)}₂(μ-4-BrC₆H₄COO)₂(μ-O)](ClO₄)₂ (4). The crystal structures of 2 and 3 are evidence for the tendency of the ethanol and the perchlorate to act as ligands. Due to the coordination of these groups, the environment of the manganese ions is elongated in the monodentate ligand direction, and this distortion is more important when this ligand is the perchlorate. The magnetic properties of the four compounds have been analysed: compounds 1, 3 and 4 show antiferromagnetic behaviour, with J = −6.33 cm⁻¹ for 1, J = −6.76 cm⁻¹ for 3 and J = −3.08 cm⁻¹ for 4 (H = −JS₁·S₂), while compound 2 shows a very weak ferromagnetic coupling. For this compound, at low temperature the most important effect on the χ_MT data is the zero-field splitting of the ion, and the best fit was obtained with |D_Mn| = 2.38 cm⁻¹ and |E_Mn| = 0.22 cm⁻¹.     

Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines

The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines (19-28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles (10-18) with suitable cycloalkanones is described. These molecules are potent, in the nanomolar range [IC₅₀ (EeAChE) = 7-101 nM], and selective inhibitors of acetylcholinesterase (AChE). The most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-14-yl)phenol (20) [IC₅₀ (EeAChE) = 7 ± 2 nM] is four-fold more active than tacrine. Kinetic studies on compound 20 showed that this is a mixed-type inhibitor of EeAChE with a K_i of 5.00 nM. However, racemic 20 was unable to displace propidium iodide, suggesting that the inhibitor does not strongly bind to the peripheral anionic site (PAS) of AChE. Docking, molecular dynamics stimulations, and MM-GBSA calculations agree well with this behavior.     

First microwave-assisted synthesis of an electron-rich phosphane and its coordination chemistry with platinum(II) and palladium(II)

The P-O ligand 3-(di(2-methoxyphenyl)phosphanyl)propionic acid (HL) was synthesized by a microwave-assisted reaction of a secondary phosphane. The coordination of HL to Pt^II yielded the neutral mononuclear complex trans-[PtCl(κ²-P,O-L)(κ-P-HL)] (1), while the reaction of PdClMe(η⁴-COD) (COD = 1,4-cyclooctadiene) with HL in the presence of NEt₃ gave the anionic Pd^II compound of the formula (HNEt₃)[PdClMe(κ²-P,O-L)] (2). Upon crystallization of the latter compound the neutral chloride-bridged dimetallic compound cis-[Pd(μ-Cl)Me(HL)]₂ (3) was obtained. HL, 1 and 3·CH₂Cl₂ have been characterized by single crystal X-ray structure analyses.