Diethyl Malonate Research Articles

Antibacterial Activities of 3-Substituted Coumarin-Scaffolds Synthesized under Microwave Irradiation

Global infections, such as diarrhea and acute respiratory disease, have urged the researchers in this area to discover coumarin-scaffold antibacterial agents, most widely used therapeutic drugs worldwide. This research aims to synthesize 3-substituted coumarins using microwave-assisted and evaluate their antibacterial activities against Escherichia coli and Staphylococcus aureus. In this study, salicylaldehyde with numerous activated methylenes has been used to synthesize 3-substituted coumarins following Knoevenagel condensation assisted by microwave irradiation. The highest yield of 3-acetylcoumarin was achieved using ethyl acetoacetate at the molar ratio of 1.2:1 (mol/mol) and 30 mol% of diethylamine using 100W microwave irradiation for 60 s under neat condition (43.65+0.50%). Moreover, ethyl coumarin-3-carboxylate (16.33%) was successfully synthesized using the optimum condition of 3-acetylcoumarin from diethyl malonate as activated methylene with a longer reaction time (900 s). However, the trial to afford 3-cyanocoumarin was failed from ethyl cyanoacetate and malononitrile as activated methylenes under the optimum condition of 3-acetylcoumarin. The inhibition zones of 3-acetylcoumarin and ethyl coumarin-3-carboxylate on disc diffusion assay towards E. coli at concentrations higher than 250 ppm showed weak activity, ranging from 1.9-3.6 mm. In contrast, both compounds showed no inhibition zone against S. aureus at all tested concentrations. This finding reveals that 3-substituted coumarins can be synthesized by low wattage microwave irradiation and solvent-free with moderate yield with ethyl acetoacetate is the most reactive methylene. Furthermore, this work proposes some corrections to assign proton and carbon chemical shifts in 3-substituted coumarins by analyzing HSQC and HMBC experiments in NMR measurement.

Synthesis of Novel Diastereomer Pyrimido[1,2-a]Benzimidazoles by Using Silica Sulfuric Acid/Ethylene Glycol

The scope of the reaction of 2-aminobenzimidazole, aldehydes and diethyl malonate in the presence of silica sulfuric acid/ethylene glycol was investigated. The reaction gave two unexpected products, 2-hydroxyethyl 3-hydroxy-4-aryl-2-oxo-tetrahydropyrimidobenzimidazole-3-carboxylates 2 and 4-aryl-hydropyrimido[1,2-a]- benzimidazol-2(1H)-ones 3 without isolation of the expected ethyl 4-aryl-2-oxo-1,2,3,4-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-3-carboxylates 1. NMR spectroscopic data and X-Ray analysis were used for assignment and confirmation the structures of the unexpected products. 2-Hydroxyethyl carboxylate derivatives 2 may be obtained via formation of 1 as intermediates, which were subjected to trans-esterification by ethylene glycol and oxidation of the proton on pyrimidine ring at position-3 to afford products 2. The unexpected products 3 may be obtained via formation of compounds 1 that was subjected to deesterification followed by decarboxylation to afford compounds 3.

Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones.

This study aims are the synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1- methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines. Many derivatives of quinoline-2-on have been interested to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinoline-pyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities. α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity. 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α,β-unsaturated ketones in the presence of piperidine as catalyst. 2- Amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method. Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin- 2'-on-3'-yl)pyrimidines with yields of 58-74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f. New substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

Palladium-catalyzed three-component 1,4-aminoarylation of [60]fullerene with aryl iodides and N-methoxysulfonamides, and further transformations

The palladium-catalyzed three-component 1,4-aminoarylation of [60]fullerene afforded 1,4-(aryl)(sulfonamide)[60]fullerenes, of which the sulfonamide group could be replaced by a (hetero)aryl, malonate ester or allyl group in the presence of FeCl3.

Ag-Catalyzed or Ag/PPh3-Catalyzed Chemoselective Switchable Cascade Reactions of N-Propargyl Thiocarbamoyl Fluorides and Malonate Esters.

The divergent chemoselective synthesis of 2-methylene-2,3-dihydrothiazoles and 4-benzylidene pyrrolidine-2-thiones (most with E stereoselectivity) from N-propargyl thiocarbamoyl fluorides and malonate esters in moderate to excellent yields with a broad substrate scope and functional group tolerance has been accomplished. AgNTf2 catalyst at 60 °C in dichloroethane provided 4-benzylidene pyrrolidine-2-thiones. AgOTf catalyst and PPh3 ligand in refluxing acetonitrile resulted in a complete switch in the reactivity of formed α,α-diester thioamide intermediates followed by isomerization to access 2-methylene-2,3-dihydrothiazoles.

Enantiospecific Total Synthesis and Absolute Configuration Assignment of Chabrolobenzoquinone H.

Chabrolobenzoquinone H (1), a meroditerpene metabolite with cytotoxic activity, is synthesized via a stereoselective Julia-Kocienski olefination between a chiral pool derived aliphatic PT-sulfone and a benzoquinone aldehyde partner. The latter was obtained via consecutive chain extension steps involving a Stille coupling and a stereospecific olefin cross-metathesis reaction followed by malonic ester synthesis and a Krapcho decarboxylation. Furthermore, this total synthesis securely determined the absolute configuration of the targeted natural product.

Ag(I)-Catalyzed/Acid-Mediated Cascade Cyclization of ortho-Alkynylaryl-1,3-dicarbonyls to Access Arylnaphthalenelactones and Furanonaphthol Libraries via Aryl-Disengagement.

ortho-Alkynylarylketone derivatives were employed as key precursors for a one-pot synthesis of arylnaphthalenelactone and furanonaphthol libraries. In this work, we discovered a cost-effective protocol to prepare arylnaphthalenelactones in one-pot using inexpensive starting material, malonate ester, which was conveniently functionalized leading to a variety of structures. Moreover, we also found an unexpected oxy-dearylation reaction which could be used to synthesize furanonaphthol analogs. These novel methods could be applied to a broad range of substrates to give the corresponding products in up to 83% yield. Notably, these classes of compounds exhibited more significant inhibition against protein-tyrosine phosphatase 1B (PTP1B) enzyme than a standard compound, ursolic acid.

Spectral, structural and cytotoxicity studies on the newly synthesized n'1,n'3-diisonicotinoylmalonohydrazide and some of its bivalent metal complexes

The reaction of diethyl malonate with isonicotinic hydrazide resulted in the formation of a new ligand, N'1,N'3-diisonicotinoylmalonohydrazide (H4INM), which was characterized by elemental and spectral studies. The existence of the free ligand in keto form was shown by its spectral data. The ligand reacted with Cu(II), Co(II), Ni(II) and Zn(II) acetates to produce bimetallic complexes. The ligand chelated to the metal ion in binegative tetradentate fashion via malonyl carbonyl oxygen and N2H atoms except in Zn(II) complex, where it acted as neutral tetradentate through the isonicotinyl carbonyl oxygen and N1H atoms. The various spectral measurements revealed that all complexes had an octahedral geometry except the Cu(II) complex which has square planar structure supported by the ESR spectral data. Moreover, the DFT quantum chemical calculations were performed and the HOMO-LUMO energy gap of the ligand and complexes were comparable to the optical band gap (Eg) estimated using Tauc's equation. Furthermore, isolated compounds’ in vitro cytotoxic activity against Hela (Epithelioid Carcinoma) and WISH (Human amnion) cell lines of was investigated. According to the results, the ligand exhibits moderate and weak effect against the Hela and WISH cell lines, respectively. While, the metal complexes exhibited more potent effect against WISH than against Hela, with IC50 ranging from 23.65 ± 1.7 to 46.28 ± 3.4 and 56.36 ± 3.5 to 83.88 ± 4.7 µM, respectively.

Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population.

Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.

Photoinduced Atom Transfer Radical Addition/Cyclization Reaction between Alkynes or Alkenes with Unsaturated α-Halogenated Carbonyls.

We have developed a photochemical ATRA/ATRC reaction that is mediated by halogen bonding interactions. This reaction is caused by the reaction of malonic acid ester derivatives containing bromine or iodine with unsaturated compounds such as alkenes and alkynes in the presence of diisopropylethylamine under visible light irradiation. As a result of various control experiments, it was found that the formation of complexes between amines and halogens by halogen-bonding interaction occurs in the reaction system, followed by the cleavage of the carbon–halogen bonds by visible light, resulting in the formation of carbon radicals. In this reaction, a variety of substrates can be used, and the products, cyclopentenes and cyclopentanes, were obtained by intermolecular addition and intramolecular cyclization.

Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts.

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).

Newly synthesized imidazolotriazole, imidazolotriazine, and imidazole-pyrazole hybrid derivatives as promising antimicrobial agents

Novel 1-(3-(4-bromophenyl)-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)ethan-1-one 1 was synthesized through a one-step reaction and allowed to react with ethyl bromoacetate followed by hydrazine hydrate to produce 1-(1-(4-bromophenyl)-2-hydrazinyl-4-methyl-1H-imidazol-5-yl)ethan-1-one (4), which was subjected to various cyclization reactions in the presence of carbon disulfide, benzoyl chloride, acetic anhydride, triethyl orthoformate, phenyl isothiocyanate, and potassium thiocyanate to obtain imidazolotriazoles 6–11. Moreover, imidazole-pyrazole hybrids 12–14 were obtained upon treatment of 2-hydrazino-imidazole derivative 4 with different active methylene compounds, namely, diethyl malonate, ethyl cyanoacetate, and acetylacetone. Finally, imidazolotriazines 15–17 and imidazole-pyrrole hybrid 18 and 19 were prepared by heating derivative 4 in the presence of diethyl oxalate, bromoacetic acid, 1,2-dichloroethane, maleic anhydride, and phthalic anhydride. All newly prepared derivatives containing an imidazole nucleus were evaluated against Escherichia coli (Gram-negative bacteria, NCTC-10416), Staphylococcus aureus (Gram-positive bacteria, NCTC-7447), and Candida albicans (fungi; NCCLS 11). Compounds 16, 6, 12 and 18 presented excellent antimicrobial potency against Gram-positive bacteria which were 1.64%, 3.28%, 9.84%, and 16.39% higher than that of the common reference drug streptomycin, respectively. Furthermore, compounds 6, 12, 15, 16, and 18 showed excellent antimicrobial activities against Gram-negative bacteria, outperforming streptomycin by 38.77%, 30.61%, 67.35%, 48.98%, and 24.49%, respectively. Finally, compound 13 exhibited an excellent antifungal performance, which was 6.94% higher than that of the common reference drug griseofulvin.

Atom-economic thiophosphoroselenenylations of C–H acid esters and amides

Three improved thiophosphoroselenenylation procedures of CH-acids, including derivatives of malonic and acetyl-, phosphono-, 4-nitrophenyl- and 3-pyridylacetic acids, have been described and compared to previously reported thiophosphoroselenylation of diethyl malonate using bis(disopropoxyphosphinothioyl)diselenide alone or with the aid of methyl iodide. The use of iodine makes it possible to utilize both equivalents of the selenenylating agent. The procedures work well for the majority of nucleophiles in a pKa range between more acidic malononitrile or Meldrum acid and less acidic phenylacetates. The reaction carried out on diethyl malonate in boiling rectified ethanol yields selenoacetate, which cannot be obtained by direct phosphoroselenenylation. Crystal structure of one of the selenomalonamides confirms the stabilization effects of both carbonyl oxygens on selenium atom. The P-Se bond splitting, using TBAF in 3-molar excess in the presence of alkylating agent yields the respective C,Se-dialkyl derivatives.

Addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones

Michael addition of malonic esters to azoalkenes generated in situ from α-bromo- and α-chlorohydrazones was accomplished. Both aliphatic and aromatic substrates bearing different functional groups are tolerated. The use of a strong base (sodium hydride) for generation of azoalkenes and deprotonation of malonate was found to be essential for a successful coupling. Synthetic potential of the obtained β-hydrazonoalkylmalonates was demonstrated by their smooth conversion into five- and six-membered N-heterocycles, functionalized hydrazides, 2-(2-oxo-2-arylethyl)malonates and 2-arylethylmalonates.

A new lipase (Alip2) with high potential for enzymatic hydrolysis of the diester diethyladipate to the monoester monoethyladipate

Several putative lipase genes from the genome of the yeast Blastobotrys (Arxula) raffinosifermentans (adeninivorans) LS3 were overexpressed in the yeast itself and screened for the desymmetrization of the dicarboxylic acid diester diethyl adipate (DEA) into the monoester monoethyl adipate (MEA). MEA can serve as a monomeric spacer group for functional polymers used in medical chemistry and dental applications.The selected lipase Alip2-c6hp was intracellularly located. After overexpression of the corresponding gene, it was purified and biochemically characterized using p-nitrophenyl butyrate as the substrate for standard activity tests. In fed-batch cultivation with constructed yeast strain B. raffinosifermentans G1212/YRC102-Alip2-c6h for large scale production of the Alip2-c6hp biocatalyst enzyme activities up to 674 U L−1 were reached.Several tested diesters were hydrolyzed selectively to monoesters. Under optimized conditions, the purified enzyme Alip2p-c6h converted 96 % of the substrate DEA to MEA within 30 min incubation, whereby only 1.6 % of the unwanted side-product adipic acid (AA) was formed. At room temperature the dicarboxylic acid esters diethyl malonate (DEM), diethyl succinate (DES), dimethyl adipate (DMA) and dimethyl suberate (DMSub) were completely hydrolyzed to their corresponding monoesters. A high yield of 87 % and 25 % could also be achieved with the dioldiesters 1,4-diacetoxybutane (DAB) and diacetoxyhexane (DAH).In conclusion the potential of the lipase Alip2-c6hp expressed in B. raffinosifermentans is very promising for selective hydrolysis of DEA to MEA as well as for the production of other monoesters.

Synthesis and anticancer property of two Sm(III) compounds based on tetrazole ligands

Developing new drugs for the treatment of cancer is of great significance. Coordination compounds based on tetrazole-carboxylates are potential candidates for the treatment of cancer. Two metallic compounds coordinated and controlled by bifunctional tetrazolate-carboxylate H3L1 and L2 ligands [H3L1 = N,N-di(2′-carboxymethyl terazole-5-yl) amine and L2 = 2-(5-pyridin-2-yl-tetrazol-2-yl)malonic acid diethyl ester] have been synthesized and characterized by single crystal X-ray diffraction analysis. The [Sm(L1)(H2O)3]·4H2O (1) displayed a 2-D network while [Sm(L2)3(OH)3] (2) with a mononuclear cluster structure. Nanoparticles (NPs) of the two compounds can be prepared by PEG-2000 (Polyethylene glycol-2000) co-precipitation method. In vitro MTT assay on HeLa cells showed that 2 NPs with a lower IC50 (half maximal inhibitory concentration) of only 1.3 μM is lower than that of 1 NPs (1.6 μM), indicating that the higher cytotoxicity of compound 2 NPs. The results showed that [Sm(L1)(H2O)3]·4H2O (1) and [Sm(L2)3(OH)3] (2) NPs were capable of inhibiting cell proliferation in vitro and may be potential candidates against cancer.

Anthocyanins from a single botanical source can be used as a replacement for hemalum and eosin

ABSTRACT For various reasons, histologists in several parts of the world have tried to replace hematoxylin and eosin with locally available plant dyes of the anthocyanin family. Blue or violet nuclear stains have been created by combining an anthocyanin with iron or aluminum ions at low pH. Obtaining a pink or red cytoplasmic counterstain, however, has not been achieved previously, even with a red solution of anthocyanin, because the chemistry of the colorant does not allow bonding to cytoplasmic materials and collagen. We used two extracts from the petals of common mallow, Malva sylvestris, to create both a blue nuclear stain and a red counterstain. The two extracts contained two chemically distinct types of anthocyanins. The first extract contains vic-hydroxyls capable of complexing aluminum ions; its flavylium core is cationic. The second type lacks vic-hydroxyls on its core structure, but includes pendant glucosides that contain a malonic acid ester with a free carboxyl substituent. The precise identity of the first anthocyanin currently is unknown, but likely is one or more of the common anthocyanins such as cyanidin, delphinidin or petunidin, which complex readily with aluminum. The second anthocyanin is malonated malvidin, which does not complex with aluminum, but is anionic at the pH used here. The overall visual effect of applying the two anthocyanin extracts is remarkably similar to that of hemalum plus eosin.

Base-mediated reactions of diethyl malonates derivatives with perfluorinated olefins: Novel synthetic routes to multifunctional ionomer precursors

A novel synthetic method for the preparation of per- and polyfluorinated unsaturated 2-substituted malonates is presented involving the deprotonation of the starting diethyl malonate by a strong base, followed by in situ addition of the C-nucleophile to the terminal double bond of the perfluorinated olefin. Subsequent elimination of the corresponding leaving groups and restoring of the double bond leads to the target bifunctional perfluorinated olefins. In the case of unsubstituted diethyl malonate, the elimination is accompanied by a prototropic rearrangement with a double bond migration and the addition of a second equivalent of the C-nucleophile forming the tetrafunctional internal olefins. The reaction conditions, factors affecting the reactivity and regioselectivity of the process, the choice of reagent as well as the course of competitive reactions are also discussed.

Photoinduced Atom Transfer Radical Addition Reaction of Olefins with α-Bromo Carbonyls.

The irradiation of halogen-bonded complexes with light leads to the homolysis of carbon-halogen bonds and the formation of the corresponding carbon radical species. However, the only methodology reported for these halogen-bonding complexes is using CBr4 as the halogen-bond donor and its applicability is of great interest. In this study, the atom transfer radical addition (ATRA) reaction of olefins using bromomalonates as halogen-bonding donors was developed. Using 4-phenylpyridine as the halogen-bonding acceptor, the desired reaction proceeded well under external irradiation of 380 nm light to furnish the corresponding ATRA reaction product. The ATRA reaction was effective in generating the corresponding products for a variety of olefins. Furthermore, the ATRA reaction was applicable to bulky ketones, substrates, and malonate esters. The intermediates of the reaction were identified and a plausible reaction mechanism was proposed.

Metal complexes with dihydrazone of malonic acid dihydrazine

This research includes synthesis and characterization of transition metal complexes of Cu (II), Co (II) and Ni (II) with hydrazone Schiff base ligand. Schiff base lagand was synthesized by reaction of malonic ester dihydrazide and 5-bromo salicylaldehyde. The structure of obtained complexes was studied by IR and electron spectroscopy. Keywords: hydrazone Schiff base ligand; copper complex; nickel complex; cobalt complex; IR and UV-Vis spectroscopy.