Adjacent Methoxy Research Articles

Enhancing Aromaticity of Alkenylbenzenes May Decrease Their Metabolic Activation and Reduce Their Potential Cytotoxicity: Lessons Learnt from the Investigation of Myristicin and Elemicin.

Metabolic activation studies of lead compounds are a crucial step in drug development and offer a key consideration during rational drug design. Myristicin (MRS) and elemicin (ELM), natural products belonging to alkenylbenzenes, share the backbone of 1-allyl-3-methoxybenzene. The backbone fuses with a methylenedioxy five-membered ring in MRS, while ELM is connected with two adjacent methoxy groups. ELM displayed powerful ability to induce cytotoxicity in cultured primary hepatocytes relative to MRS. Additionally, ELM exhibited superior efficiency in metabolic activation by CYP3A4, resulting in the formation of reactive metabolites carbonium ion, epoxides, and α,β-unsaturated ketone. Quantum chemical calculation and molecular dynamic studies revealed that the fused methylenedioxy 5-membered ring enhances the aromaticity of MRS, which affects the interaction between the allyl side chain and the heme for metabolic activation by the π-π stacking interaction with the aromatic amino acid residues of the host enzyme.

Discovery of a New Polymorph of 5-Methoxy-1H-Indole-2-Carboxylic Acid: Characterization by X-ray Diffraction, Infrared Spectroscopy, and DFT Calculations.

This study presents a new 5-methoxy-1H-indole-2-carboxylic acid (MI2CA) polymorph investigated by single-crystal X-ray diffraction, infrared spectroscopy, and density functional theory (ωB97X-D) calculations employing two basis sets (6-31++G(d,p) and aug-cc-pVTZ). The compound crystallizes in the monoclinic system, space group P21/c (a = 4.0305(2) Å, b = 13.0346(6) Å, c = 17.2042(9) Å, β = 91.871(5)°, Z = 4). In the crystalline structure, the formation of cyclic dimers via double hydrogen bonds O-H⋯O between MI2CA molecules was observed. Interactions between the NH groups of the indole rings and the adjacent methoxy groups, as well as C-H⋯O contacts, significantly influence the spatial arrangement of molecules. The results from DFT calculations, including dimeric and trimeric structures, agree well with the experimental structural and spectroscopic data. Analysis of the infrared spectra confirms the conclusions drawn from X-ray diffraction studies and reveals differences between the IR spectra of the newly obtained polymorph and that reported earlier in the literature. This comprehensive study sheds some light on the MI2CA polymorphism and is important for a potential pharmacological applications of this compound.

Spectroscopic Study on Aqueous Uranyl(VI) Complexes with Methoxy- and Methylbenzoates: Electronic and Steric Effects of the Substituents

Aqueous complexation of uranyl(VI) ions with methoxy- and methylbenzoates in 0.1 M NaClO4 solutions was studied by means of UV-vis absorption and Raman spectroscopy. The predominance of 1:1 complexation (uranyl to ligand) was verified for all uranyl carboxylates under acidic conditions (-log [H+] < 3.2), and absorption spectra, stability constants, and symmetric stretching frequencies of the uranyl group of the complexes were determined for the first time. For meta- and para-substituted benzoates, a linear free energy relationship (LFER) was observed between the equilibrium constants for the protonation (log βP) and uranyl complexation (log βU) reactions, and the electronic effects of the substituents were successfully described by the Hammett equation. In the case of ortho-substituted benzoates, the stability constant of uranyl 2-methoxybenzoate is slightly lower than the LFER trend, which is generally explained by the destabilization of cross-conjugation in the uranyl complex due to the steric hindrance between the reaction center and adjacent methoxy group. On the contrary, the stability constant of uranyl 2-methylbenzoate is comparable to the LFER trend, implying that the steric effect is relatively insignificant for the smaller methyl group. The utility of such thermodynamic correlations between the uranyl-substituted benzoates is useful for the molecular understanding and predictive modeling of chemical interactions between actinyl(VI) ions and various organic carboxyl groups.

Synthesis, characterisation and antimicrobial activities of mixed ligand complexes of Mn (II), Fe (II) and Co(II) containing N,N'-bis (o-anisaldehyde) p-phenylenediamine (tetradentate schiff base) and gylcine

Complexes of Mn(II), Fe(II) and Co(II) containing N, N’-bis[o-anisaldehyde]p-phenylenediamine tetradentate Schiff base as primary ligand and glycine as secondary bidentate ligand have been synthesized by reflux in 1:1:1 mole ratio and characterized both analytically and spectroscopically. Molar conductance measurement (69.02 to 86.30Ω–1 cm2 mol–1) of the complexes indicated they are weak electrolyte and magnetic susceptibility measurement shows values in range of 4.53 to 5.59BM indicating their paramagnetism. The infrared data suggested that the Schiff base coordinated via the two nitrogen atoms of the azomethine groups (1628 to 1680 cm-1) and the oxygen atoms of the adjacent methoxy groups (1341 to 1389 cm-1), while glycine coordinated via the nitrogen atom of the amino group (3060-3324 cm-1) and the oxygen atom of the carboxylate anion. Based on the analytical and spectroscopic data the complexes may be assigned an octahedral geometries and molecular formulae of the form [M(L)Gly], where M = Mn, Fe and Co, L=Schiff base and Gly = glycine. The Schiff base and its mixed ligand complexes were screened for antimicrobial activity against Staphylococcus aureus, Escherichia coli, Salmonella typhi, Mucor inducus and Aspergillus fumigatus. The complexes exhibited enhanced antimicrobial activity (10mm to 18mm) at 60 µg/disc as compared to 10mm activity of the uncoordinated Schiff base at the same concentration.Keywords: Mixed ligand complex; Schiff base, Glycine, p-phenylenediamine, o-anisaldehyde

SYNTHESIS, IN VITRO ANTIOXIDANT AND ANTIMICROBIAL EVALUATION OF 3-HYDROXY CHROMONE DERIVATIVES

Objective: The objective of the present study was to synthesize a series of 3-hydroxychromone derivatives and to evaluate its in vitro antioxidant and antimicrobial activities.Methods: 3-hydroxy chromones were synthesized using an algar flynn oyamada method which includes oxidative cyclization of 2-hydroxy chalcones in basic solution by hydrogen peroxide. 2-hydroxy chalcones were synthesized by Claisen-Schmidt condensation of substituted 2-hydroxy acetophenones with substituted aromatic aldehydes using polyethylene glycol-400 as a recyclable solvent. The synthesized compounds were evaluated for in vitro antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. In addition, these compounds were also screened for in vitro antibacterial and antifungal activity by agar cup method and Poison plate method, respectively.Results: The structures of the synthesized compounds were characterized by infrared, 1H nuclear magnetic resonance and mass spectroscopy. The antioxidant activity data revealed that all the synthesized derivatives exhibited good activity due to the presence of phenolic hydroxyl group, 4-oxo group and 2,3-double bond. Further, the activity increased with the introduction of a more phenolic hydroxyl group and adjacent methoxy group in the structure. The antimicrobial activity data showed that the compounds possess better antibacterial and antifungal activity which is attributed to the presence of phenolic hydroxyl group and 4-oxo group in the structure.Conclusions: The use of inexpensive, eco-friendly and readily available reagents, easy work-up and high purity of products makes the procedure a convenient and robust method for the synthesis of title compounds. The presence of phenolic hydroxyl group, 4-oxo group, and 2,3-double bond in the structure is responsible for their good antioxidant and antimicrobial activities.

Below-Room-Temperature C-H Bond Breaking on an Inexpensive Metal Oxide: Methanol to Formaldehyde on CeO2(111).

Upgrading of primary alcohols by C-H bond breaking currently requires temperatures of >200 °C. In this work, new understanding from simulation of a temperature-programmed reaction study with methanol over a CeO2(111) surface shows C-H bond breaking and the subsequent desorption of formaldehyde, even below room temperature. This is of particular interest because CeO2 is a naturally abundant and inexpensive metal oxide. We combine density functional theory and kinetic Monte Carlo methods to show that the low-temperature C-H bond breaking occurs via disproportionation of adjacent methoxy species. We further show from calculations that the same transition state with comparable activation energy exists for other primary alcohols; with ethanol, 1-propanol, and 1-butanol explicitly calculated. These findings indicate a promising class of transition states to search for in seeking low-temperature C-H bond breaking over inexpensive oxides.

Tuning the strain effect to induce selectivity through intramolecular nitrene insertion into an adjacent methoxy C[sbnd]H bond leading to form a new benzoxazole: experimental and computational studies

Pyrolysis of azido-meta-meconine yields only a single product 1D, which has been characterized spectroscopically (1H NMR, 13C NMR, HSQC, DEPT & MS). These results reveal that the fused five-member lactone ring can influence the product selectivity. The DFT calculations suggest the formation of favourable oxazolidine intermediate compared to azirine (1Z) and ketenimine (1H) intermediates. The isodesmic analysis showed that the fused lactone aryl nitrene (1N) would have more strain to form azirine (1Z) intermediate than the corresponding aryl nitrene (1M).

Crystal structure of 2-meth-oxy-2-[(4-meth-oxy-phen-yl)sulfan-yl]-1-phenyl-ethanone.

In the title β-thio­carbonyl compound, C16H16O3S, the adjacent meth­oxy and carbonyl O atoms are synperiplanar [the O—C—C—O torsion angle is 19.8 (4)°] and are separated by 2.582 (3) Å. The dihedral angle between the rings is 40.11 (16)°, and the meth­oxy group is coplanar with the benzene ring to which it is connected [the C—C—O—C torsion angle is 179.1 (3)°]. The most notable feature of the crystal packing is the formation of methine and methyl C—H⋯O(carbon­yl) inter­actions that lead to a supra­molecular chain with a zigzag topology along the c axis. Chains pack with no specific inter­molecular inter­actions between them.

5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: A comparative study using in vivo microdialysis

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150–290%) but remarkably increased 5-HT levels (540–900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

Concomitant Nitrene and Carbene Insertion Accompanying Ring Expansion: Spectroscopic, X-ray, and Computational Studies

Reinvestigation of the thermolysis of azido-meta-hemipinate (I) yielded, in addition to known II, unusual products III and IV. These products are formed via a rare intramolecular nitrene insertion into an adjacent methoxy C-H bond followed by an intermolecular reaction during a ring-expansion and a ring-extrusion reaction followed by a carbene insertion. The structures of the new compounds were confirmed using a battery of techniques, including HRMS (ESI-QTOF) and 2D NMR as well as X-ray crystallography for compound IV. Density functional theory methods were used to support the proposed mechanism of formation of the products.

4-Hydroxy-3-methoxybenzaldehyde thiosemicarbazone

In the title compound, C9H11N3S, there is an intra­molecular O—H⋯O hydrogen bond involving the OH group and the adjacent methoxy O atom. The mol­ecule is essentially planar, with the maximum deviation from the mean plane of the non-H atoms being 0.1127 (14) Å for the methyl C atom. In the crystal, mol­ecules are connected via centrosymmetric pairs of N—H⋯S and O—H⋯O hydrogen bonds into a two-dimensional network parallel to (10-3).

(2E,5E)-2,5-Bis(4-hydroxy-3-methoxybenzylidene)cyclopentanone ethanol monosolvate

In the title structure, C21H20O5·C2H5OH, the curcumine-type mol­ecule has a double E conformation for the two benzyl­idene double bonds [C=C = 1.342 (4) and 1.349 (4) Å] and is nearly planar with respect to the non-H atoms (r.m.s. deviation from planarity = 0.069 Å). The two phenolic OH groups form bifurcated hydrogen bonds with intra­molecular branches to adjacent meth­oxy O atoms and inter­molecular branches to either a neighbouring mol­ecule or an ethanol solvent mol­ecule. The ethanol O atom donates a hydrogen bond to the keto O atom. These hydrogen bonds link the constituents into layers parallel to (101) in the crystal structure.

Computational Mechanistic Study of the Hydrogenation of Carbonate to Methanol Catalyzed by the RuIIPNN Complex

Density functional theory computations have been carried out to study the mechanism of hydrogenation-based transformation of dimethyl carbonate to methanol, catalyzed by Ru(II)PNN catalyst. The energetic results show that the catalytic transformation includes three sequential stages consistently involving the catalyst: (stage I) transformation of dimethyl carbonate (3) to methyl formate (5) and methanol; (stage II) transformation of methyl formate 5 to formaldehyde and methanol; (stage III) hydrogenation of formaldehyde to methanol. Stages I and II proceed similarly and follow three steps: hydrogen activation, formation of a hemiacetal intermediate via stepwise hydrogen transfer to dimethyl carbonate in stage I or methyl fomate in stage II, and subsequent decomposition of the hemiacetal intermediate to afford methanol. Hydrogenation via carbonyl insertion into the Ru-H bond is less favorable than the stepwise hydrogen-transfer mechanism. Decomposition of hemiacetal takes places by first breaking the hemiacetal O-H bond to give an alkoxide complex, followed by deprotonation of the benzylic arm ligand to the adjacent methoxy group. Comparing the hydrogenation steps in the three stages, hydrogenation in stage I is most difficult, that in stage II is less difficult, and that in stage III is easiest in terms of both kinetics and thermodynamics. This can be ascribed to the stronger electrophilicity of the carbonyl group in methyl formate or formaldehyde than that in dimethyl carbonate and fewer steric effects between the catalyst and methyl formate or formaldehyde than that between the catalyst and dimethyl carbonate. Thermodynamically, both stages I and II are uphill, but stage III is downhill significantly, which is the driving force for the catalytic transformation. The study indicates that the methanol product could facilitate the hydrogen activation involved in the transformation, implying that transformation could be accelerated by initially adding methanol.

Structure-activity relationship for the first-in-class clinical steroid sulfatase inhibitor Irosustat (STX64, BN83495).

Structure–activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nm. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.

The orientation of protoberberine alkaloids and their binding activities to human serum albumin by surface-enhanced Raman scattering

Raman and surface-enhanced Raman scattering (SERS) technique are reliably used to compare relative intensity shifts and to investigate the adsorption geometry of protoberberine alkaloids on Ag nanoparticles. We report joint application of fluorescence and SERS spectroscopy to study the interaction between protoberberine alkaloids and human serum albumin (HSA). We propose SERS technique to improve the quenching interaction caused by protoberberine alkaloids which are used to be applied in recognition process of fluorescent drugs with large biomolecules. The fluorescence results show that the fluorescence intensity of HSA is significantly decreased in presence of protoberberine alkaloids. The SERS technique demonstrates obvious advantages over direct measurements in discriminating and identifying pharmaceutical molecules. By means of this method, we are able to detect important information concerning the orientation of protoberberine alkaloids when interacting with HSA. We also show that the nitrogen atom is free, but a benzene ring and two adjacent methoxy groups are involved in the spontaneously electrostatic inducement and subsequently binding with HSA.

1,3-Dihydroxy-2-methoxymethyl-9,10-anthraquinone fromRennellia ellipticaKorth.

The title compound, C16H12O5, common name: lucidin ω-methyl ether, exists as a planar mol­ecule (r.m.s. deviation = 0.04 Å). Within the mol­ecule, the 1-hydr­oxy group forms a hydrogen bond to the adjacent carbonyl O atom, and the 3-hydr­oxy group forms a hydrogen bond to the adjacent meth­oxy O atom. The meth­oxy O atom is disordered over two positions of equal occupancy.

Selective Cleavage of Methoxy Protecting Groups in Carbohydrates

The selective cleavage of methoxy protecting groups next to hydroxy groups is achieved using a radical hydrogen abstraction reaction as the key step. Under the reaction conditions, the hydroxy group generates an alkoxyl radical that reacts with the sterically accessible adjacent methoxy group, which is transformed into an acetal. In the second step, the acetals are hydrolyzed to give alcohols or diols. A one-pot hydrogen abstraction-hydrolysis procedure was also developed. Good yields were usually achieved, and the mild conditions of this methodology were compatible with different functional groups and sensitive substrates such as carbohydrates.

Estrogen A-ring structure and antioxidative effect on lipoproteins

The oxidative modification of lipoprotein particles is an important step in atherogenesis. Estrogens are known to be powerful antioxidants independently of their binding to the estrogen receptors and the hormonal functions. We explored the structural determinants for the antioxidant activity of a large number of estrogen derivatives ( n = 43) in an aqueous lipoprotein solution in vitro by monitoring formation of conjugated dienes. Our results indicate that estrogen derivatives with an unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups provide strongest antioxidant protection of low density lipoprotein (LDL) and high density lipoprotein (HDL). The electron donating methoxy groups may enhance the antioxidant effect by weakening the phenolic O H bond and providing stability to the formed phenoxyl radical. With some exceptions, compounds completely lacking unsubstituted hydroxyl groups in the A-ring exhibited no antioxidant effect, e.g. the most hydrophilic “tetrol” compound with three unsubstituted A-ring hydroxyl groups had no antioxidant effect. Moreover, additional hydroxyl groups in the B-, C- or D-ring seemed to weaken the antioxidant effect. Accordingly, both the presence of unsubstituted hydroxyl groups and adjacent substituents, as well as the lipophilicity of the derivatives determine the antioxidant activity of estrogen derivatives in aqueous lipoprotein solutions.

10-Methoxydibenz[b,f]azepine-5-carboxamide

The structure of the title compound, C16H14N2O2, contains a seven-membered ring that adopts a boat conformation, and the overall molecular shape is that of a butterfly. In the packing, the mol­ecules form a convoluted hydrogen-bonded polymer via a typical R22(8) graph-set dimer, between carbox­amide groups, and an R22(16) graph-set dimer formed through an interaction between the second carbox­amide NH group and an adjacent methoxy O atom (in each mol­ecule). The dihedral angle between the benzene rings is 56.09 (5)°.

Diffuse X-ray scattering from 4,4'-dimethoxybenzil, C16H14O4: analysis via automatic refinement of a Monte Carlo model.

A recently developed method for fitting a Monte Carlo computer-simulation model to observed single-crystal diffuse X-ray scattering has been used to study the diffuse scattering in 4,4'-dimethoxybenzil, C16H14O4. A model involving only nine parameters, consisting of seven intermolecular force constants and two intramolecular torsional force constants, was refined to give an agreement factor, omegaR = [sigma omega(deltaI)2/sigma omegaI2(obs)](1/2), of 18.1% for 118 918 data points in two sections of data. The model was purely thermal in nature. The analysis has shown that the most prominent features of the diffraction patterns, viz. diffuse streaks that occur normal to the [101] direction, are due to longitudinal displacement correlations along chains of molecules extending in this direction. These displacements are transmitted from molecule to molecule via contacts involving pairs of hydrogen bonds between adjacent methoxy groups. In contrast to an earlier study of benzil itself, it was not found to be possible to determine, with any degree of certainty, the torsional force constants for rotations about the single bonds in the molecule. It is supposed that this result may be due to the limited data available in the present study.