Aminomethyl Derivatives Research Articles

Synthesis, antioxidant and structural properties of modified ebselen derivatives and conjugates.

Ebselen is a drug in clinical trials for several diseases and degenerative conditions where oxidative stress is implicated. A series of novel ebselen analogues was synthesized, including hydroxy-, alkoxy- and aminomethylene derivatives, as well as hybrid species where the ebselen selenium atom is shared with other potent antioxidant structures, such as cyclic selenenyl sulfide, cyclic seleninate ester and spirodioxyselenurane moieties. Conjugates of ebselen with cholesterol, prednisolone and the radical inhibitor BHT were also prepared. The products were tested for antioxidant activity in an NMR-based assay by measuring the rate of consumption of benzyl thiol or the production of dibenzyl disulfide in the presence of hydrogen peroxide when catalyzed by the ebselen analogues. Activities ranged from 12 to 0.12 times that of ebselen. The oxidation of the 2-hydroxymethylene derivative of ebselen was faster than thiolysis in the initial step and the overall rate was further accelerated under basic conditions. The corresponding selenenyl sulfide analogue underwent very slow disproportionation under neutral conditions that was enhanced by the presence of a base catalyst. During investigation of possible fluxional behaviour of a bis-amide analogue, an unusual tetraphenyphosphonium salt of a tricoordinate selenium pincer anion was discovered with exceptionally potent catalytic activity, 130 times that of ebselen. In addition to rate measurements, X-ray crystallography and DFT computational methods were also employed to gain further structural and mechanistic insights.

Solvent and Substituent Size Influence on the Cyclochiral Rigidity of Aminomethylene Derivatives of Resorcin[4]arene.

Resorcin[4]arenes (R[4]A) are a group of macrocyclic compounds whose peculiar feature is the presence of eight hydroxyl groups in their structure. The directional formation of intramolecular hydrogen bonds with their participation leads to the formation of a cyclochiral racemic mixture of these compounds. Their stability strongly depends on the substituent and especially the environment in which they are located. The paper discusses the cyclochiral nature of aminomethylene derivatives of R[4]A (AMD-R[4]A). Their cyclochiral rigidity in non-polar solvents has been shown. The influence of the size of the alkyl groups in the amino substituents of AMD-R[4]A on their cyclochiral nature was noted. To calculate the reaction paths for their racemization, the nudged elastic band (NEB) method was employed using the semi-empirical DFT (GFN1-xTB) approach. The calculated activation barrier energies for their racemization in chloroform, obtained through various semi-empirical quantum chemical methods (SE), Hartree-Fock (HF), and density functionals theory (DFT), show good correlation with experimental observations. Among the tested methods, the B38LYP-D4 method is highly recommended due to its fast computational speed and accuracy, which is comparable to the time-consuming double-hybrid DH-revDSD-PBEP86 approach.

In vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol.

Indonesia is the world's primary producer of clove. In order to find new utilization for clove and new biologically active compounds, eugenol, the main constituent of clove, has been converted to its derivatives. This study aims to examine in vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol. Fibrosarcoma was induced by injection of benzo(a)pyrene solution. The test compounds were given per oral at 20, 40, and 80 mg/Kg body weight, once a day for 30 days. As a result, all the tested compounds showed activity in reducing the cancer incidence rate. All the tested compounds were also found to reduce tumor weight. Benzoxazine derivatives gave slightly better activity compared to aminomethyl derivatives. The strongest activity was exhibited by 6-allyl-3-(furan-2- ylmethyl)-8-methoxy-3,4-dihydro-2H-benzo(e)(1,3)oxazine. All four benzoxazine and aminomethyl compounds derived from eugenol that were tested exhibited anticancer activity in mice fibrosarcoma.

SYNTHESIS OF AMINOMETHYL DERIVATIVES OF 3-MERCAPTO-2- HYDROXYPROPYL-1-ISOBUTYL ETHER AND THEIR STUDY AS PROTECTIVE ADDITIVES TO LUBRICANT OILS

The electrochemical corrosion prevention of engines and mechanisms is a task of great national, economic and defense importance. Lubricating oils commonly used in engineering do not have sufficient protective properties and are unable to effectively protect it from corrosion, both during operation and during short-term and long-term inactivity. One of the simplest and most rational ways to solve this problem is the use of lubricants containing effective protective (conservation) additives, which, without worsening the normal working properties of oils provide them conservation properties. By the action of 3-mercapto-2- hydroxypropyl-1-isobutyl ether, taken as a synthon, with secondary aliphatic and heterocyclic amines under the conditions of the Mannich reaction, a number of aminomethyl derivatives were synthesized. Aminomethyl derivatives of 3-mercapto-2-hydroxypropyl-1-isobutyl ether are dissolved well in oils and are stable during storage. The protective properties of the synthesized compounds were studied in M-12 oil. The best test results were obtained with 3-piperidinomethilthio-2-hydroxypropyl-1-isobutyl ether - at a concentration of 1% to the lubricating oil M-12, the corrosion of a steel plate in a humid chamber is 3%, in sea water after 24 hours – 5%, the corrosion of a steel plate under the action of a 0.1% acid solution HBr – 3,5%. These results are higher than those of the standard - industrial additive urea succinimide. (SIM).

Средне-щелочные алкилфенолятные присадки

The article presents the results of research on the sintesis of medium alkaline alkylphenolate additives. Additives are calcium salts of the condensation products of alkylphenols with formaldehyde and ammonia or various amines (monoethanolamine, benzylamine and allylamine) have been synthesized and studied. The physicochemical and functional properties of the synthesized products were studied by standard methods.It has been shown that all aminomethyl derivatives of alkylphenols have multifunctional properties and are superior to their analogs ИХП-101, ИХП-109 and ВНИИНП-370 in terms of their functional properties. In addition, the additives obtained on the basis of nonylphenol in terms of anticorrosion and antioxidant properties are somewhat superior to those obtained on the basis of alkylphenol (C8–C12) due to their homogeneous composition. Thus, all synthesized compounds are multifunctional, and additives containing a secondary nitrogen atom (calcium salt of dialkyldioxybenzylamine) and a benzyl radical at the nitrogen atom (calcium salt of N-benzyldialkyldioxybenzylamine) have the highest antioxidant efficiency.

Synthesis of fusidane triterpenoid Mannich bases as potential antibacterial and antitumor agents

Mannich bases (8 examples) were synthesized via aminomethylation of fusidane propargyl esters. In vitro antimicrobial screening against key ESKAPE pathogens showed that the fusidic acid based Mannich products exhibit a high antimicrobial effect against Gram-positive bacteria Staphylococcus aureus and the fungus Cryptococcus neoformans. Moreover, the cytotoxic effect of fusidic acid and its analogs, which showed high antibacterial activity, was determined by MTT assay on cancer HepG2, HCT-116, SH-SY5Y, MCF-7, A549 and conditionally normal cells HEK293. A remarkable cytotoxic activity of fusidic acid propargyl ester and its aminomethylene derivatives against cancer and nontumoral HEK293 cells with IC50 values within 4.2–25 µM was found.

Synthesis of Aminomethyl Derivatives of 2,6-Dihydroxynaphthalene

Synthesis of Aminomethyl Derivatives of 2,6-Dihydroxynaphthalene

New insights into the reactivity of aminomethylene derivatives of resorc[4]arene: amine group transfer, conformational analysis, reaction mechanism

Using the example of aminomethylene derivatives of resorc[4]arene and their Michael reaction with 4-hydroxycoumarin, the possibility of transferring an amine molecule from substrate to product is demonstrated. The conformation of the aminocoumarin derivatives of resorc[4]arene formed is controlled by the polarity of the solvent. For one of the products, conformational analysis was performed by kinetic sampling using metadynamics (MTD). The energies of the final set of conformers were calculated by DFT (r2scan-3c). A reaction mechanism based on multiscale (ONIOM) Nudged Elastic Band (NEB-TS) reaction profile calculations is discussed.

BIOCIDAL ACTIVITY OF AMINOMETHYL DERIVATIVES OF 2-MERCAPTOBENZOXAZOLE

The biocidal activity of the aminomethyl derivatives of 2-mercaptobenzoxazole synthesized by us and being of interest as potential antimicrobial additives to petroleum products and cutting fluids, was studied. The aminomethylation reaction proceeded with the participation of methylene-bis-amines. As a result, the appropriate N-substituted benzoxazolin-2-thiones were obtained. Their structure was proved by NMR 1H. Due to the poor solubility of the synthesized compounds in petroleum products, their salts with petroleum naphthenic acid were obtained for microbiological testing. The results of tests in lubricating oil M-8 show that the naphthenic salts of the synthesized compounds exhibit biocidal activity and their fungicidal properties are higher than bactericidal ones. The petroleum naphthenic acid used in the test in its pure form in the composition of the M-8 lubricating oil is not biostable and is affected by microorganisms. N-piperidinomethylbenzoxazolin-2-thione in the composition of the coolant proved to be a biocide, and its bactericidal properties are higher than fungicidal ones. The results of a microbiological study of an aqueous solution of this compound showed high bactericidal properties in the absence of effectiveness against mold fungi.

Synthesis and evaluation of the antioxidant properties for some novel aminomethyl derivatives of 2,6-diisobornylphenol bearing a pinane moiety

Synthesis and evaluation of the antioxidant properties for some novel aminomethyl derivatives of 2,6-diisobornylphenol bearing a pinane moiety

Synthesis and evaluation of 2,3,4,9-tetrahydro-1H-carbazole derivatives as selective acetylcholinesterase inhibitors: Potential anti-Alzheimer’s agents

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and cognition skills. Dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in Alzheimer's disease. Hence, our focus is to synthesize cholinesterase inhibitors. A series (22 compounds) of 6- and 9-substituted derivatives of 2,3,4,9-tetrahydro-1H-carbazole have been prepared and in vitro evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by Ellman’s method. By comparing selectivity with standard drug donepezil, amino derivative 3, methylamino derivative 4 and butyl nitro derivative 17 have been found to be selective AChE inhibitors. Borsche-Drechsel cyclization reaction has been carried out to synthesize 2,3,4,9-tetrahydrocarbazole ring followed by nitration, reduction and derivative synthesis.

In Vitro and In Silico Study of 5-[(4-Methylpiperazin-1-yl) methyl]dehydrozingerone and 5-(Morpholin-4-ylmethyl) dehydrozingerone as Lipoxygenase and Xanthine Oxidase Inhibitor

The present study was to evaluate the two aminomethyl derivatives of dehydrozingerone: 5-[(4-methylpiperazin-1-yl)methyl]dehydrozingerone and 5-(morpholin-4-ylmethyl)dehydrozingerone as lipoxygenase and xanthine oxidase inhibitors. Nordihydroguaiaretic acid, allopurinol and the parent compound dehydrozingerone were used as comparative compounds. Results indicated that 5-[(4-methylpiperazin-1-yl)methyl] dehydrozingerone and 5-(morpholin-4-ylmethyl) dehydrozingerone inhibited the lipoxygenase enzyme with half-maximal inhibitory concentration of 219.13 and 269.39 μM, respectively. Their activities were comparable to nordihydroguaiaretic acid with a half-maximal inhibitory concentration of 216.84 μM. The compounds were also found to inhibit the xanthine oxidase enzyme with half-maximal inhibitory concentration of 102.34 and 230.52 μM, respectively, but their activities were lower than allopurinol with half-maximal inhibitory concentration of 34.09 μM. Dehydrozingerone was found inactive both as a lipoxygenase inhibitor and xanthine oxidase inhibitor. Besides, in silico study was carried out to predict the binding interaction between the enzymes and the compounds compared to each of positive controls. In conclusion, 5-[(4-methylpiperazin-1-yl)methyl] dehydrozingerone has lipoxygenase inhibitory activity comparable to nordihydroguaiaretic acid, but they have lower xanthine oxidase inhibitory activity than allopurinol.

Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol

Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol

Abstract 6224: Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA)

Abstract The antibiotic heliomycin (resistomycin) has been studied since the 1950s, however, its low solubility in aqueous media has restricted its systemic bioavailability and therapeutic potential. We recently synthesized a series of novel aminomethyl derivatives that are readily soluble in aqueous solution. In this study, we examined their antiproliferative properties and underlying molecular mechanisms in p53 wild-type and p53-mutated cancer cells. We continuously monitored the cellular impact of these compounds using the xCELLigence System, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values. The results from the system showed that heliomycin and its derivatives exhibited different biological effects on tumor cells. To further our understanding of the interactions between the novel derivatives and cellular targets, we utilized the cellular thermal shift assay (CETSA). Our CETSA results revealed that some of the derivatives that were directly engaged with tNOX enhanced its thermal stability, which in turn resulted in a marked attenuation of the intracellular NAD+/NADH ratio. This attenuated ratio signifies a decrease in the NAD+-dependent activity of Sirtuin 1 (SIRT1) deacetylase and triggers apoptosis/autophagy, with varying amounts of decrease depending on the cellular environment. We have successfully transformed heliomycin into derivatives that are much more soluble, allowing the more efficient modulating of biological activities - a significant step closer towards finding a novel anti-cancer candidate. Citation Format: Pin Ju Chueh, Atikul Islam, Xiao Qi Chen, Shi Han Chiu, Alexander S. Tikhomirov, Andrey E. Shchekotikhin. Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6224.

Synthesis, structure, spectroscopic studies and magnetic properties of Cu2N2O4-, Cu2N2O2(S2)-, Cu2N2S4-chromophores based on aminomethylene derivatives of pyrazole-5-one(thione)

The aminomethylene derivatives of pyrazole-5-one (6) and pyrazole-5-thione (7) were synthesized in the reaction of 2-aminophenol (4) with corresponding 1-phenyl-3-methyl-5-X-pyrazole-4-carbaldehyde (1, X = hydroxy) or (2, X = sulfanyl). Reaction of 2-aminobenzenethiol (5) with 1-R-3-methyl-5-sulfanyl-pyrazole-4-carbaldehydes (2, R = phenyl and 3, R = isopropyl) results in the formation of disulfide compounds 8 and 9. The structures of compounds 6–9 were determined by IR and NMR spectroscopy and elemental analysis.The reaction of each ligand 6–9 with copper(II) acetate monohydrate in ethanol resulted in dinuclear metal-chelates with Cu2N2O4, Cu2N2O2S2, Cu2N2S4 chromophores. All complexes were characterized with C, H, N elemental analysis, FT-IR, ESR and X-ray absorption spectroscopy. The structures of the complexes 11 and 13 were determined by X-ray single-crystal diffraction. The variable-temperature magnetic susceptibility measurements in the 2–300 K temperature range were performed and the influence of the type of bridging atoms on the magnetic and spectral properties was discussed. The nature of magnetic and spectral properties of the copper chelates was analyzed using DFT quantum-chemical calculations within broken-symmetry and time dependent (TD DFT) approximations, correspondingly.

Antioxidants Effect of Two Aminomethyl Derivatives of 2-Methoxyphenol on Thermal and Storage Oxidative Stability of Coconut Oil

The antioxidants effect of two aminomethyl derivatives of 2-methoxyphenol: 4,6-di[(morpholin-4-yl)methyl]-2-methoxyphenol (DMMMP) and 5-[(pyrrolidin-1-yl)methyl]vanillic acid (PMVA) on enhancing thermal and oxidative storage stability of coconut oil was performed using tert-butylhydroxyquinone (TBHQ) as a comparative standard. The efficacy on thermal stability test was carried out by heating at 180 oC for 1, 3, and 6 hours, while the efficacy on the storage stability test was performed using an accelerated method by heating at 60oC for 5 weeks. The concentrations for MDMMP was 200, 350, and 500 ppm; for PMVA was 200, 275, and 350 ppm; and for TBHQ was 200 ppm. Free fatty acid (FFA) level, peroxide value (PV), and p-anisidine value (p-AV) were used as parameters to assess the level of oxidative stability of coconut oil. The results showed that the addition of DMMMP 200, 350, and 500 ppm, and PMVA 200 and 275 ppm did not inhibit FFA, peroxide, and aldehyde formation. In thermal stability study, PMVA (350 ppm) could inhibit the free fatty acid release, and formation of secondary oxidation products compounds on thermal stability comparable to TBHQ (200 ppm) addition, but only TBHQ that could inhibit peroxide formation for 6 h. In storage stability, DMMMP (all concentration) could not delay the fatty acid release, while PMVA (all concentration) and TBHQ (200 ppm) delayed that for 2 and 5 weeks, respectively. DMMMP (all concentration) delayed peroxide formation for 2 weeks, while PMVA (all concentration) and TBHQ (200 ppm) delayed peroxide formation for 5 weeks. All compounds only delay the formation of secondary oxidation products for 1 week. In conclusion, the efficacy of PMVA as an antioxidant against thermal and storage oxidative stability of coconut oil is higher than DMMMP but lower than TBHQ.

Complexation of borate with pentitols, hexitols and their derivatives as a functional group of a boron-selective adsorbent

In order to elucidate the characteristics of anchor groups suitable for boron-selective adsorbents, complexation reactions of the borate ion with pentitols, hexitols and their methylamino derivatives were investigated by NMR spectroscopies and DFT calculations. The borate ion bound with these polyols to form various types of complexes, among which the ones binding with vicinal hydroxy groups in an intermediate position of the carbon chain would make a significant contribution to their stability. The threo-form five-membered ring chelate complexes exhibited much higher stabilities compared to the erythro-form ones, which means that the polyol capable of forming more threo-forms and fewer erythro-forms gives a higher affinity toward boron. l-Iditol had the highest affinity toward boron among the studied pentitols and hexitols, because it could form three kinds of threo-form complexes binding at the (C2,C3), (C3,C4) and (C4,C5) positions. Consequently, 1-deoxy-1-methylamino-l-iditol, which is a derivative of l-iditol, will be the best functional group for a boron-selective adsorbent of all the analogous polyol derivatives.

SYNTHESIS OF ETHYL ETHER OF 4(4-HYDROXYPHENYL)- AND 4′-METHYL-4(4-HYDROXYPHENYL)CYCLOHEXANCARBONIC ACIDS AND THEIR AMINOMETHYLATED DERIVATIVES

The article presents the results of cycloalkylation of phenol with ethyl cyclohexane- and 4-methylcyclohexenecarboxylic esters in the presence of a zeolite-Y catalyst impregnated with phosphoric acid. It has been established that to perform the cycloalkylation of phenol with ethyl cyclohexenecarboxylic acid in the presence of a zeolite-Y catalyst impregnated with orthophosphoric acid, the optimal conditions are: temperature 120 °С, reaction time 5 h, molar ratio of phenol to ether 1 : 1 mol/mol. And amount of catalyst is 10% for taken phenol. The yield of the target product was 74.7% of the theory for taken phenol, and selectivity - 93.8% for the target products. It was found that under optimal reaction conditions cycloalkylation (temperature 110 °C, reaction time 4 h, the ratio of phenol to ether 1 : 1, the amount of catalyst 7%) of phenol with ethyl 4-methylcyclohexenecarboxylic acid yield of ethyl 4 (4-hydroxyphenyl) -4'-methylcyclohexane-carboxylic) acid was 78.3% of the theory per phenol taken, and the selectivity was 95.7% for the desired product. The synthesis of aminomethyl derivatives of 4-hydroxyphenylcyclohexanecarboxylic acids in the presence of formalin and aniline was also carried out. As a result of aminomethylation, ethyl esters of 4 (4-hydroxy-3-phenylaminobenzyl) cyclohexane- and 4 (4-hydroxy-3-phenylaminobenzyl) -4'-methylcyclohexanecarboxylic acid were obtained. The yields of the target products were 67.3 and 71.7%, respectively, from the theory on taken ether. The structure and composition of the products were determined using IR and 1H NMR spectroscopy. And the purity of the products obtained was studied by chromatographic analysis. Ethyl esters of 4 (4-hydroxy-3-phenylaminobenzyl) cyclohexane- and 4 (4-hydroxy-3-phenylaminobenzyl) -4'-methylcyclohexanecarboxylic acid can be used as an antioxidant to diesel fuel and turbine oil T-46.

Structural Basis of 7‐Deazaguanine Modification of DNA in Bacteria and Phage

Two important modifications of tRNA, the 7‐deazaguanine nucleosides queuosine (Q) and archaeosine (G+), are biosynthesized from GTP in bacteria and archaea, respectively, in a well characterized multi‐enzyme pathway leading to the shared advanced intermediate, 7‐cyano‐7‐deazaguanine (preQ0). In bacteria, preQ0 is converted to an aminomethyl derivative that is then inserted in tRNA by the bacterial tRNA‐guanine transglycosylase (TGT) enzyme. In archaea, preQ0 is inserted directly in tRNA by the archaeal TGT before conversion to G+. Recently, in 230 bacterial and phage genomes, a genomic island that contains a paralog of TGT was identified, which led to the discovery of Q, G+ and preQ0 deoxy derivatives in the DNA of some of these organisms. This gene cluster was renamed DpdA‐K, for “7‐deazapurine in DNA.” The G+‐modified DNA of E. coli bacteriophage 9g has been shown to resist restriction by >140 Type II restriction endonucleases (REases), consistent with a role of the modification as a defense mechanism. Recent experiments have shown that DpdA is a DNA‐guanine transglycosylase that catalyzes the insertion of preQ0 at a specific palindromic sequence in DNA. Here we report overexpression, purification, and crystallographic analysis of S. Montevideo DpdA (SmDpdA, ~47 kDa). The crystal structure, determined at 2.25‐Å resolution by multi‐wavelength anomalous diffraction methods, reveals a TIM‐barrel enzyme similar to the bacterial TGT in overall fold, active site and structural Zn2+ site. However, a large DpdA‐specific insertion in the TIM barrel provides an extended positively charged 26‐Å wide surface groove, consistent with a DNA binding surface. Free docking of a DNA duplex using the HADDOCK server places DNA to this surface in a fashion reminiscent of DNA binding to the ubiquitous Zn2+‐dependent DNA repair enzyme apurinic/apyrimidinic endonuclease IV. The structure and docking model suggest that DpdA bends its substrate DNA by 60° and flips the modification‐site guanine base out of the helix for transglycosylation. The results also inform the design of a substrate DNA duplex for future crystallization of the nucleoprotein complex.Support or Funding InformationNIGMS grant GM110588 and GM132254 to M.A.S., and The California Metabolic Research Foundation (SDSU).

Synthesis and Anti-inflammatory Activity of 2-Methoxy-4-(1-phenyl-3- methyl-1H-pyrazol-5-yl)phenol) and Its Aminomethyl Derivatives

Using heat-induced protein denaturation technique, a series of novel synthesized 1,5-diarylpyrazole compounds, namely 2-methoxy-4-(1-phenyl-3-methyl-1H-pyrazol-5-yl)phenol (1) and its aminomethyl derivatives (2a-e) were evaluated for their anti-inflammatory potentiality. The structures of the synthesized compounds were elucidated using FTIR, NMR (1H & 13C) and mass spectral data. The study found that the activity of aminomethyl derivatives (2a-e) was higher than that of parent compound 1. In this series, aminomethyl derivatives bearing dimethylamino-methyl, diethylaminomethyl and pyrrolidinomethyl moieties (2a, 2c and 2e, respectively) were more active than diclofenac sodium, which was used as a standard. A study on the structure-activity relationship (SAR) suggested that the activity of aminomethyl moiety of the compound was influenced by its pKa value. Thus, novel compounds act as potential anti-inflammatory agents.