Malonic Acid Derivatives Research Articles

Quality Assurance System when Studying the Pharmacological Safety of Etmaben

Quality assurance plays a key role in preclinical research, where every detail must be strictly controlled and verified. Standard operating procedures are essential part of any quality assurance system, defining precisely the steps and methods of implementing certain tasks or processes in a laboratory. In this article, the main components of a quality assurance system are discussed using the example of studying the pharmacological safety of a malonic acid derivative.

Organocatalytic enantioselective decarboxylative protonation of α-alkyl-α-aryl malonate monoesters.

In contrast to the well-established enzymatic enantioselective decarboxylative protonation (EDP), the corresponding chemocatalytic reactions of acyclic malonic acid derivatives remain challenging. Herein, we developed a biomimetic EDP of α-alkyl-α-aryl malonate monoesters using a chiral 1,2-trans-diaminocyclohexane-based N-sulfonamide as an organocatalyst. The method demonstrates excellent chemical yields, good enantioselectivity, mild reaction conditions, and the generation of only CO2 as waste.

Electrochemical Synthesis of Unnatural Amino Acids via Anodic Decarboxylation of N-Acetylamino Malonic Acid Derivatives.

Broad application of α,α-disubstituted cyclic amino acid derivatives in medicinal chemistry urges for analogue design with improved pharmacokinetic properties. Herein, we disclose an electrochemical approach toward unnatural THF- and THP-containing amino acid derivatives that relies on anodic decarboxylation-intramolecular etherification of inexpensive and readily available N-acetylamino malonic acid monoesters under Hofer-Moest reaction conditions. The decarboxylative cyclization proceeds under constant current conditions in an undivided cell in an aqueous medium without any added base. A successful bioisosteric replacement of the 1-aminocyclohexane-1-carboxylic acid subunit by the THP-containing amino acid scaffold in cathepsin K inhibitor balicatib helped to reduce lipophilicity while retaining low nanomolar enzyme inhibitory potency and comparable microsomal stability.

Green electrocatalytic Assembling of Salicylaldehydes, Kojic Acid, and Malonic Acid Derivatives into 2‐amino‐4H‐chromenes as Potent Anti‐inflammatory Agents

AbstractGreen electrocatalytic multicomponent assembly of salicylaldehydes, kojic acid and malonic acid derivatives in n‐propanol in the presence of potassium iodide as an electrolyte in an undivided cell results in the formation of 4‐(3‐hydroxy‐6‐(hydroxymethyl)‐4‐oxo‐4H‐pyran‐2‐yl) substituted 2‐amino‐4H‐chromenes in 86–98 % yields. This new electrocatalytic multicomponent process is a facile and efficient environmentally benign way to the functionalized 2‐amino‐4H‐chromenes, containing in the fourth position kojic acid fragment, which are perspective compounds for different biomedical applications, among them in the treatment of human inflammatory diseases. Python‐automated docking procedure was carried out and the results support anti‐inflammatory potential of the synthesized compounds.

Electrochemically induced assembling of isatins, kojic acid, and malonic acid derivatives into substituted spiro[indole‐3,4′‐pyran]‐2(1H)‐one scaffold and predicting potential protein targets

AbstractElectrochemically induced multicomponent assembling of isatins, kojic acid, and malonic acid derivatives in n‐propanol in the presence of sodium iodide as an electrolyte in an undivided cell results in the formation of unsymmetrical spiro(indole‐3,4′‐pyrano[3,2‐b]pyranes) in 86–98% yields. The optimized reaction conditions and a mechanistic rationale for this catalytic electrochemical transformation are presented. This new electrocatalytic multicomponent process is a facile and efficient environmentally benign way to the functionalized unsymmetrical spiro(indole‐3,4′‐pyrano[3,2‐b]pyranes), containing inserted kojic acid fragment, which are perspective compounds for different biomedical applications, among them anticonvulsant, anti‐cancer, anti‐AIDS agents, and anti‐inflammatory remedies. All synthesized compounds were investigated using a molecular docking procedure. The results of prediction were incorporated in one pool of potential targets. The automated method was proposed and performed for the docking procedure. It is distinct from screening by higher accuracy, and it is much more scalable than the classic docking procedure. It was found that the synthesized compounds are potential ligands for 4OHK (glucokinase regulatory protein) and 3V2B (human poly[adp‐ribose] polymerase 15) proteins.

Substituted Malonic Acid Half Oxyesters (SMAHOs): Green Nucleophiles for Organic Synthesis

AbstractSubstituted malonic acid half‐oxyesters (SMAHOs) constitute an original family of malonic acid derivatives. They could be mostly used as pro‐nucleophiles through decarboxylative processes, making them enolate equivalents for the elaboration of greener methodologies. In addition to the native ester function, the presence of a substituent on the malonic position affords additional opportunities for structural diversification. These reagents are particularly well‐suited for the development of organocatalyzed processes, which has recently led to olefination and addition reactions as relevant synthetic routes to elaborated structures under mild conditions.

Development of the "Dissolution" Test Method for Tablets of Sodium 4,4'-(propanediamido)dibenzoate with Sustained Release

Introduction. Non-alcoholic fatty liver disease is one of the most common chronic diseases of this parenchymal organ among the adult population. The search and creation of supporting drugs is an urgent task of modern pharmacy. The malonic acid derivative, sodium 4,4'-(propanediamido) dibenzoate, synthesized by the employees of the Department of Organic Chemistry of the SPСPU, has antisteatous activity, is a potential agent for the treatment of liver diseases. Sustained release tablets were prepared based on sodium 4,4'-(propanediamido)dibenzoate. An integral part of the pharmaceutical development of a medicinal product is the development of a method for conducting the Dissolution test and the selection of optimal conditions, which became the purpose of this study.Aim. To develop the "Dissolution" test method for the sustained-release tablets based on sodium 4,4'-(propanediamido)dibenzoate.Materials and methods. The objects of research are the active pharmaceutical ingredient sodium 4,4'-(propanediamido)dibenzoate, as well as sustained-release tablets based on this substance. Equilibrium biopharmaceutical solubility was determined by UV-spectrophotometry. To establish the conditions for the "Dissolution" test, an ERWEKA DT-620 dissolution tester (ERWEKA GmbH, Germany) was used.Results and discussion. The suitability of the UV-spectrophotometry method for the quantitative determination of sodium 4,4'-(propanediamido) dibenzoate in solutions was determined. The established high biopharmaceutical solubility of sodium 4,4'-(propanediamido)dibenzoate in a buffer solution with a pH of 6,8, as well as in a 0,01 M solution of hydrochloric acid with a pH of 2,6, determined the choice of these media for the "Dissolution" test of the dosage form. The apparatus "Rotating basket" (rotation speed of 100 rpm in a dissolution medium with a volume of 1000 ml) was reasonably chosen for the test on the basis of the obtained linear dependence of the rate of release of the substance on time, as well as the best test results by the end of the experiment.Conclusion. A study of the biopharmaceutical properties of the original substance with antisteatous activity has been carried out. High biopharmaceutical solubility was established in media with pH 2,6 and pH 6,8. The conditions of the "Dissolution" test for sustained-release tablets based on the original sodium 4,4'-(propanediamido)dibenzoate were experimentally substantiated.

Novel 2-(Diphenylmethylidene) Malonic Acid Derivatives as Anti-HIV Agents: Molecular Modeling, Synthesis and Biological Evaluation.

HIV, the virus that causes AIDS (acquired immunodeficiency syndrome), is one of the world's most severe health and development challenges. In this study, a novel series of 2-(diphenyl methylidene) malonic acid derivatives were designed as triple inhibitors of HIV reverse transcriptase, integrase, and protease. Docking models revealed that the target compounds have appropriate affinities to the active sites of the three HIV key enzymes. The synthesized malonic acid analogs were evaluated for their activities against the HIV virus (NL4-3) in HeLa cells cultures. Among them, compound 3 was the most potent anti-HIV agent with 55.20% inhibition at 10 μM and an EC50 of 8.4 μM. Interestingly, all the synthesized compounds do not show significant cytotoxicity at a concentration of 10 μM. As a result, these compounds may serve as worthy hits for the development of novel anti-HIV-agents.

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs).

The use of mono-substituted malonic acid half oxyesters (SMAHOs) has been hampered by the sporadic references describing their preparation. An evaluation of different approaches has been achieved, allowing to define the best strategies to introduce diversity on both the malonic position and the ester function. A classical alkylation step of a malonate by an alkyl halide followed by a monosaponification gave access to reagents bearing different substituents at the malonic position, including functionalized derivatives. On the other hand, the development of a monoesterification step of a substituted malonic acid derivative proved to be the best entry for diversity at the ester function, rather than the use of an intermediate Meldrum acid. Both these transformations are characterized by their simplicity and efficiency, allowing a straightforward access to SMAHOs from cheap starting materials.

1,6-heptadiynes based cyclopolymerization functionalized with mannose by post polymer modification for protein interaction

Carbohydrate functionalized polymers or Glycopolymers have earned a great deal of interest in recent times for their potential biomedical applications. In the present study, a mannose containing glycopolymer was synthesized by cyclopolymerization of malonic acid derivative using second generation Hoveyda Grubbs′ catalyst. Post-polymerization modification was done to install a propargyl moiety. Finally, functionalization of the propargylated polymer with 2-azidoethyl mannoside using azide-alkyne “click chemistry” furnished the target glycopolymer which was successfully characterized using NMR, FT-IR, mass spectroscopy and advanced polymer chromatography. The glycopolymer was found to self-assemble into capsule and spherical shape in water and DMSO respectively and these morphologies were observed through SEM and TEM. Upon interaction with Con A, the mannose containing glycopolymer showed an increment in aggregation induced fluorescence with increasing concentration of the lectin. In vitro cytotoxicity studies on MCF 7 cell line showed 90% cell viability up to glycopolymer concentration of 500 μg/mL.

Phosphorylated 2-Chloroethynes in the Reactions with Malonic Acid Derivatives: Azirine or Oxazole?

Phosphorylated 2-Chloroethynes in the Reactions with Malonic Acid Derivatives: Azirine or Oxazole?

Ozonolysis of α-angelica lactone: a renewable route to malonates

α-Angelica lactone, derived from the platform chemical Levulinic acid, can be efficiently converted into malonic acid derivatives and 3-oxopropionate acetals by ozonolysis.

An in situ masking strategy enables radical monodecarboxylative C-C bond coupling of malonic acid derivatives.

The utilization of malonic acids in radical decarboxylative functionalization is still underexploited, and the few existing examples are primarily limited to bisdecarboxylative functionalization. While radical monodecarboxylative functionalization is highly desirable, it is challenging because of the difficulty in suppressing the second radical decarboxylation step. Herein, we report the successful radical monodecarboxylative C–C bond coupling of malonic acids with ethynylbenziodoxolone (EBX) reagents enabled by an in situ masking strategy, affording synthetically useful 2(3H)-furanones in satisfactory yields. The keys to the success of this transformation include (1) the dual role of a silver catalyst as a single-electron transfer catalyst to drive the radical decarboxylative alkynylation and as a Lewis acid catalyst to promote the 5-endo-dig cyclization and (2) the dual function of the alkynyl reagent as a radical trapper and as an in situ masking group. Notably, the latent carboxylate group in the furanones could be readily released, which could serve as a versatile synthetic handle for further elaborations. Thus, both carboxylic acid groups in malonic acid derivatives have been well utilized for the rapid construction of molecular complexity.

NBS/DBU-Promoted One-Pot Three-Component Cycloaddition of Malonic Acid Derivatives, Nitrosoarenes, and Alkenes: Synthesis of Isoxazolidines.

A general DBU-mediated one-pot three-component cycloaddition reaction of easily accessible malonic acid derivatives, nitrosoarenes, and alkenes has been successfully established with the aid of NBS to provide direct access to highly functionalized isoxazolidine derivatives with generally good to excellent yields, broad functional group tolerance, and excellent regio- and diastereo-selectivities under mild conditions. The mechanism study shows that the NBS-mediated formation of bromomalonic acid derivatives from malonic acid derivatives and DBU-promoted synthesis of nitrone intermediates via the reaction of bromomalonic acid derivatives with nitrosoarenes are key steps.

The mechanisms of action of water-soluble aminohexanoic and malonic adducts of fullerene C60 with hexamethonium on model lipid membranes

In an attempt to understand the possibility of applications of the fullerene-based systems for transporting various polar compounds like hexamethonium through the blood–brain barrier, we studied the influence of a series of derivatives of fullerene C60 in the form of salts with hexamethonium bis-anion, namely the adducts of fullerenols with 6-aminohexanoic acid (IEM-2197), and two bis-adduct malonic acid derivatives of fullerene with addents bound in two hemispheres (IEM-2143) and in equatorial positions (IEM-2144), on model membranes. We showed that IEM-2197 induced the disintegration of the bilayers composed of DOPC at the concentrations more than 2 mg/ml. IEM-2144 and IEM-2143-induced ion-permeable pores at concentrations of 0.3 and 0.02 mg/ml, respectively; herewith, IEM-2143 was characterized by the greater efficiency than IEM-2144. IEM-2197 did not significantly affect the phase behavior of DPPC, while the melting temperature significantly decreased with addition of IEM-2144 and IEM-2143. The increase in the half-width of the main transition peaks by more than 2.0 °C in the presence of IEM-2144 and IEM-2143 was observed, along with the pronounced peak deconvolution. We proposed that the immersion of IEM-2144 and IEM-2143 into the polar region of the DOPC or DPPC bilayers led to an increase in the relative mobility of tails and formation of ion-permeable defects. IEM-2197 demonstrated the more pronounced effects on the melting and ion permeability of PG- and PS-containing bilayers compared to PC-enriched membranes. These results indicated that IEM-2197 preferentially interacts with the negatively charged lipids compared to neutral species.

Synthesis, Characterization and evaluation of Anti-inflammatory and Antimicrobial Properties of some Cinnamic Acid Derivatives

Background: Cinnamic acid and derivatives are widely spread in plants. They are important intermediates in the synthesis of many aromatic compounds and are known to have diverse biological activities.Objectives: To synthesize, characterize and evaluate some cinnamic acid derivatives, for possible antimicrobial and anti-inflammatory activities.Material and methods: Different cinnamic acid derivatives were synthesized by Knoevenagel condensation reaction between malonic acid and various derivatives of benzaldehydes in the presence of pyridine and hydrochloric acid. The cinnamic acid epoxide was formed in the presence of hydrogen peroxide and KOH, while dihydro-cinnamic acid and paramethoxy-dihydro-cinnamic acids were formed by reducing cinnamic acid and paramthoxy-cinnamic acid respectively with raney nickel in the presence of 10% KOH. The final products were purified on column chromatography (CC), eluting with petroleum spirit/ethyl acetate. All the synthesized compounds were unequivocally characterized using the combination of UV-Vis Spectroscopy, infra-red (FTIR), 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy. In-vivo anti-inflammatory activities of the synthesized compounds was investigated using egg albumin-induced paw oedema in rat; while antimicrobial activity was evaluated by agar diffusion method.Results: The compounds were obtained in high yield (30 – 97 %) and purity. 3,4-dioxomethylene cinnamic acid produced the highest (60.8%) and significant (p < 0.05) anti-inflammatory effect at the 2nd hour of the highest dose. Dihydro-cinnamic acid and cinnamic acid epoxide with 4mg/kg dose produced 55.5% and 54.9% inhibition of inflammation respectively at the second hour, while para-methoxy-cinnamic acid at the second hour with 2 mg/kg dose level produced 54.0% inhibition. The reference compound; diclofenac produced no significant inhibition of inflammation at 4mg/kg dose level. All the compounds showed mild antimicrobial activities against the tested organisms.Conclusion: The findings from the study indicate that the synthesized compounds possess mild anti-inflammatory, with weak antibacterial and antifungal activities.
 Keywords: anti-inflammatory, antimicrobial, cinnamic acid derivatives, Knoevenagel

Expanding the Versatile Reactivity of Diazido Malonic Acid Esters and Amides: Decarboxylation and Imine Formation

Herein, we advance our understanding on the divergent reaction pathways that are possible, starting from diazido diethyl malonate (easily generated through the oxidative diazidation of diethyl malonate with iodine and sodium azide in DMSO at room temperature): when treated with amines, diazidated malonamides are rapidly formed, many of which then undergo a formal substitution reaction with alkylamines leading to imino malonamides under basic conditions. Using the established conditions of CuAAC click reactions with terminal alkynes, the diazidated malonamides are alternatively transformed into their corresponding bistriazole derivatives, a reaction that is also achievable with diazido diethyl malonate. We now demonstrate that the malonic diester bistriazoles undergo a smooth decarboxylation in the presence of amines, creating novel bistriazole variants derived from acetamides. All protocols presented herein are experimentally simple and enhance the variety of products obtainable from malonic acid derivatives.

Electrosynthesis Using Carboxylic Acid Derivatives: New Tricks for Old Reactions.

Electrosynthetic organic chemistry is an old discipline that takes its root in Faraday's seminal works. The field has a rich history and is in the midst of a renaissance, due to the growing impetus of the chemical community to develop greener, more economical, and more efficient synthetic methodologies. Indeed, electrosynthesis relies on one of the greenest and cheapest reagents in the world: the electron itself. In this Account, the recent developments in the use of carboxylic acid derivatives in electrosynthesis are summarized. Until lately, the fate of the monoelectronic reduction of aromatic esters in nonprotic solvents remained unclear. Recent investigations have shown that aromatic esters are reduced and form surprisingly long-lived radical anions. Under the right conditions, these radical anions decompose into the corresponding carboxylates and alkyl radicals. These principles have been used to develop a novel electrochemical alcohol deoxygenation reaction using aromatic esters as stable and versatile radical precursors. In contrast to esters, the electrochemistry of carboxylic acids has been intensively studied. Pioneering works by Faraday and Kolbe in the late 1800s have revealed that the anodic oxidation of carboxylic acids leads to a radical decarboxylation. Interestingly, radical recombination is observed due to the very high concentration of radicals in the vicinity of the electrode. Such radical recombination is rarely observed during classical homogeneous radical reactions. The "Kolbe" reaction and its carbocationic variation have been intensively used across the fields due to their versatility. As we will develop in this Account, almost two hundred years after its discovery, the anodic decarboxylation of carboxylic acids is still relevant to modern organic chemists. For instance, we will examine how the non-decarboxylate Kolbe reaction of aromatic acids forms aroyloxy radicals and how oxycarbonyl radicals could be generated from hemioxalates. Finally, the carbocationic variant of the Kolbe reaction, known as the Hofer-Moest reaction, will be examined in the context of two newly developed reactions: a green MOM-type ether formation and the use of malonic acid derivatives as carbonyl synthons. Electrosynthesis is a powerful synthetic tool. Even if it might still be underutilized at the moment, there is little doubt that it will become one of the "classic" methods to activate small organic molecules in a very near future.

Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes.

Recently, gold(III) porphyrins have gained great interest as anticancer drugs not only for the stability of gold(III) but also for the functionalization of the porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bimetal compounds containing a gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined with the phototoxicity of the porphyrin. The three complexes differ in the type of diamine ligand around platinum(II): ammonia (NH3), cyclohexanediamine (CyDA), and pyridylmethylamine (Py). The synthesis was carried out using the complexation of activated malonic acid derivatives with aquadiaminoplatinum(II) complexes, and the products were characterized by IR, NMR, mass spectra, and elementary analysis. The cytotoxic activity of the conjugates was screened in both healthy cell lines and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to that of the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the greatest cytotoxic effect among the series. The results showed that Au(III)/Pt(II) conjugates are more potent by 2-5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective toward cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC50 of the dyad AuP-PtCyDA is 43% lower than that of AuTPP but is more selective toward healthy cells. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of other reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. In addition, the increase in cancer cell death obtained after light irradiation is totally absent in healthy cells, demonstrating the specificity of this PDT treatment on cancer cells. Our findings imply that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect in comparison to traditional homometallic Pt(II) drugs.

Multicomponent assembling of salicylaldehydes, kojic acid and malonic acid derivatives

A multicomponent one-pot environmentally benign transformation of salicylaldehydes, kojic acid and malononitrile or its derivativies, catalyzed by sodium acetate, in a small amount of ethanol results in efficient formation of new substituted 2-amino-4-[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl]-4H-chromene-3-carbonitriles or -3-carboxylates in 75–96% yields.