Perkin Reaction Research Articles

Synthesis and biological evaluation of esculetin derivatives as antidiabetic agents

Esculetin derivatives 4a-4j (including six novel hydroxylated/halogenated derivatives 4a, 4d, 4e, 4f, 4g, 4h) were synthesized through Perkin reaction with 2,4,5-trihydroxybenzaldehyde and appropriate phenylacetic acid as raw materials, and screened for α-glucosidase and α-amylase inhibitory activities. Among these compounds, compound 3-(3-iodophenyl)-6,7-dihydroxy-2H-chromen-2-one (4d) showed promising hypoglycaemic activity with half maximal inhibitory concentration (IC50) values of 0.18±0.03 mM and 1.82±0.18 mM against α-glucosidase and α-amylase, respectively, classifying it as a mixed-type inhibitor. Compound 4d could statically quench the intrinsic fluorescence of enzymes, which bound to enzymes mainly through hydrogen bonding and hydrophobic interactions affecting the microenvironment of proteins. Compound 4d also exhibited antioxidant activity, which demonstrated good scavenging effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radicals. Furthermore, compound 4d still maintained a certain degree of hypoglycemic and antioxidant activities after simulated gastrointestinal digestion. The oral toxicity study showed that compound 4d had no significant effect on the serum biochemical indices and organs of mice, indicating its safety profile. This study suggests that esculetin may be a potential skeleton to the development of hypoglycaemic drugs.

1-(Dicyanomethylene)-3-hydroxy-1H-indene-2-carboxylic Acid

Bulk heterojunction solar cells are among the most promising organic solar cells (OSCs). One of the two important parts of OSCs are acceptors, and the development of the design and synthesis of non-fullerene acceptors involves an electron-deficient heterocyclic central core and anchor acceptor malonitrile derivatives of 3-methylene-2,3-dihydro-1H-inden-1-ones. In this communication, an intermediate for the synthesis of this compound, 1-(dicyanomethylene)-3-hydroxy-1H-indene-2-carboxylic acid, was prepared by the Perkin reaction of 2-(3-oxoisobenzofuran-1(3H)-ylidene)malononitrile with tert-butyl acetoacetate in the presence of acetic anhydride and triethylamine. The structure of the newly synthesized compound was established by means of elemental analysis, high-resolution mass spectrometry, 1H NMR, 13C NMR and IR spectroscopy, and mass spectrometry.

Synthesis and Spectroscopic Characterization of Selected Water-Soluble Ligands Based on 1,10-Phenanthroline Core.

Water-soluble ligands based on a 1,10-phenanthroline core are relatively poorly studied compounds. Developing efficient and convenient syntheses of them would result in new interesting applications because of the importance of 1,10-phenanthrolines. In this manuscript, we describe novel and practical ways to introduce a carboxyl and, for the first time, a phenol and dithiocarboxyl group under mild reaction conditions. This strategy enables highly efficient and practical synthesis of suitable organosulfur compounds with high added value, high chemoselectivity, and a broad substrate range. We present the selective conversion of a hydroxydialdehyde in the form of 10-hydroxybenzo[h]quinoline-7,9-dicarbaldehyde into its derivative, unique hydroxydicarboxylic acid, by an oxidation procedure, giving 10-hydroxybenzo[h]quinoline-7,9-dicarboxylic acid. A similar procedure resulted in the formation of 9-methyl-1,10-phenanthroline-2-carboxylic acid by oxidation of commercially available neocuproine. An alternative method of obtaining 1,10-phenanthroline derivatives possessing carboxylic acid group can be based on the hydrolysis of ester or nitrile groups; however, this synthesis leads to unexpected products. Moreover, we apply Perkin condensation to synthesize a vinyl (or styryl) analog of 1,10-phenanthroline derivatives with phenol function. This reaction also demonstrates a new, simple, and efficient strategy for converting methyl derivatives of 1,10-phenanthroline. We anticipate that the new way of converting methyl will find wide application in chemical synthesis.

Coronenes with push-pull geometries from macrocycle-forming Perkin condensations.

Although the Perkin reaction has been successful in producing ester-substituted conjugated macrocycles with four or six building blocks, macrocycles composed of only two elements remained elusive until now. Through the development of a building block derived from phenanthrene with two glyoxylic acid substituents in a pincer-like arrangement, formation of a two-block macrocycle was induced when paired with a complementary phenylenediacetic acid unit. The addition of ether functions to the phenanthrene building block not only improved the yields, but led to macrocycles with push-pull geometries. Photocyclisation of the resulting cyclophanes efficiently yield tetra- and hexasubstituted coronenes.

In-silico Studies, Synthesis, and Evaluation of Anti-inflammatory Activity of Novel Pyrimidine Scaffold

Background: The heterocyclic nucleus pyrimidine is present in several natural and synthetic chemical analogues and has proved its broad medicinal applications. Further, pyrimidine in the form of parent structure or basic skeleton of RNA and DNA is involved in controlling the immune functioning, and in turn, inflammatory reactions. Objective: The objective of the present study is to evaluate some novel pyrimidine analogues for antiinflammatory action. Methods: Molecular docking studies of Indomethacin and selected analogues were carried out with the COX-2 enzyme (PDB: 4ZOL). The synthesis of derivatives of 4-Phenyl-6-(phenylamino)pyrimidine-2-ol derivatives was begun by following Perkin condensation between substituted acetanilides and substituted aromatic aldehydes to yield an intermediate, which in turn produces the required nucleus for treatment with urea. All synthesized compounds were evaluated for in vivo and in vitro anti-inflammatory activity. Results: The docking interaction reflects a good dock score when compared with indomethacin, a potent Anti-inflammatory drug. In the majority of the compounds, pyrimidine was able to form hydrogen bonding while the rest of the part was involved in hydrophobic bonding. All compounds were synthesized in good yield and confirmed by physical and spectral studies. In vitro studies showed that compounds 5a and 5e were better at controlling inflammation than the conventional treatment Antipyrine, while in vivo data showed that compounds 5a, 5c, 5e, and 5h were better at controlling inflammation than the standard drug Antipyrine. Conclusion: The compound with more than one electron releasing group on the aniline moiety of pyrimidine yields a decent result in the synthetic and experimental studies, but the absence of an electron withdrawing group favours stronger anti-inflammatory activity on the target.

Synthesis and antioxidant, antimicrobial, and antiviral activity of some pyrazole-based heterocycles using a 2(3H)-furanone derivative

Some pyrazole-based heterocycles such as pyrrolone, pyridazinone, and imidazole derivatives were synthesized utilizing the pyrazolyl-2(3H)-furanone derivative 3, which was obtained in a good yield via Perkin condensation of 5-chloro-4-formyl-3-methyl-1-phenylpyrazole with 3-(4-methylbenzoyl)propionic acid in the presence of cyclo-dehydrating agent (sodium acetate and acetic anhydride). Also, the acid hydrazide obtained was reacted with some carbonyl reagents such as acetic anhydride, benzoyl chloride, 4-chlorobenzaldehyde, and 1,3-diphenyl-4-formylpyrazole, aiming to achieve new pyrrolone derivatives. The antioxidant, antimicrobial, and antiviral activity screening of some synthesized compounds demonstrated that some of them offered strong potencies. An experimental trial was undertaken to explore the effect of different substances and applied against avian influenza HPAI-H5N1 (AIV) to evaluate the antiviral replication in specific pathogen-free chicken embryos. All the compounds were screened for their antimicrobial activities, and most of tested compounds showed potent inhibition growth activity toward Haemophilus (Gram-negative bacteria), Staphylococcus aureus (Gram-positive bacteria), and Candida albicans fungus. Upon antimicrobial screening, it was observed that the majority of the compounds were found to be active against Staphylococcus aureus, Haemophilus, and Candida albicans as compared to standard drugs. This experiment shows the potential usage of these compounds as antiviral agents and can be considered as a viable means to control the economically important avian influenza of poultry. These compounds can thus be recommended for their antiviral, antibacterial, and antifungal property and can very well be used as immunostimulants.

Synthesis and antioxidant activity of some pyrazole-based heterocycles using a 2(3H)-furanone building block

Some pyrazole-based heterocycles, such as pyrrolone, pyridazinone, and imidazole derivatives were synthesized utilizing the pyrazolyl-2(3H)-furanone derivative 3, which was obtained in a good yield via Perkin condensation of 5-chloro-4-formyl-3-methyl-1-phenylpyrazole with 3-(4-methylbenzoyl)propionic acid in the presence of cyclo-dehydrating agent (sodium acetate and acetic anhydride). Also, the acid hydrazide obtained was reacted with some carbonyl reagents like acetic anhydride, benzoyl chloride, 4-chlorobenzaldehyde, and 1,3-diphenyl-4-formylpyrazole, aiming to achieve new pyrrolone derivatives. The antioxidant activity screening of some synthesized compounds demonstrated that pyridazinone and N-phenylhydrazide derivatives showed the most exceptional potencies.

Synthesis of PMCA (P-Methoxy Cinnamic Acid) using Perkin Reaction and Its Activity as Photo Protective and Antifungal Agent

<p class="Standard"><span>This study aimed to synthesize p-methoxy cinnamic acid through the Perkin reaction and to determine its activity as a photoprotective and antifungal agent against Candida albicans. The PMCA compound was synthesized by reacting p-methoxy benzaldehyde with acetic anhydride using a sodium acetate catalyst in a sonicator at 50oC for 60 minutes. The synthesized was a white precipitate with a % yield of 2.09% and a melting point of 172-175<sup>o</sup>C. ATR-FTIR identified this compound with several functional groups, C=O, OH carboxylic acid, para-substituted benzene, and C=C. Analysis by GC-MS showed a single peak at a retention time of 11.710 minutes with m/z 178. Characterization of this compound by 1H-NMR spectrometry showed several chemical shifts showing the presence of OH groups of carboxylic acids, C=C groups, aromatic benzene groups, and methoxy. The results of this characterization indicated that the synthesis product was PMCA. The antioxidant activity of PMCA using the DPPH radical gave IC50 at a concentration of 352.6138 ppm. In vitro sunscreen activity against PMCA compounds provided high protection at a concentration of 30 ppm with SPF 32,505. The antifungal activity against Candida albicans showed inhibition zones of 0.257cm± 0.044, 1.397cm± 0.093, and 1.533cm± 0.111, respectively at concentrations of 5%, 10%, and 15%. The PMCA compounds can be synthesized through the Perkin reaction assisted by ultrasonic waves and can potentially be photoprotective and antifungal agents.</span></p>

The Perkin Strategy for the Synthesis of Large Carboxy‐Substituted Polycyclic Aromatic Compounds

AbstractAn efficient and versatile synthetic approach has been developed for the synthesis of large carboxy‐substituted polycyclic arenes. This strategy relies on Perkin reactions between arylacetic and arylglyoxylic acids for the formation of flexible precursors. A subsequent rigidification step, by catalyst‐ or light‐induced intramolecular cyclization reactions, then yields fully condensed polycyclic aromatic compounds. Protection and deprotection techniques have been developed to allow the controlled assembly of a large number of building blocks. This method can now be applied to the formation of planar or non‐planar, linear or macrocyclic species of various sizes.

The predicted models of anti-colon cancer and anti-hepatoma activities of substituted 4-anilino coumarin derivatives using quantitative structure-activity relationship (QSAR)

ObjectivesThe objective of this work was to predict anti-colon and anti-hepatoma cancer activity of newly designed substituted 4-anilino coumarin derivatives using quantitative structure–activity relationship (QSAR). MethodsThe optimization of the derivatives including molecular and electronic properties data to generate the QSAR were resulted from H-GGA DFT/BPV86 method calculation combined with Hartree-Fock 6-31G basis set. The QSAR models were delivered in multiple linear regression (MLR) and the drug design was accomplished by considering the descriptors constructing the best QSAR models for each biological activity. ResultsThis research accomplished two best validated QSAR models for predicting anti-colon cancer and anti-hepatoma activities of substituted 4-anilino coumarin derivatives. There were 17 of newly designed substituted 4-anilino coumarin derivatives which their anticancer activity (Log IC50) were predicted using our both QSAR models. The QSAR predictions inform that the compound 25 and compound 19 have the best predicted anti-colon cancer and anti-hepatoma activities, respectively. ConclusionThe results revealed that this approach can be used to assist in the action of anticancer drug discovery. Moreover, the retrosynthesis analysis of both compounds are also explained in a logic reverse of organic synthetic steps through Knoevenagel and Perkin reactions.

Dynamic covalent synthesis of conjugated macrocyclic maleimides with interesting solvatochromic luminescent properties

Donor-acceptor (D-A) diaryl maleimides have received widespread attention due to their outstanding aggregation-enhanced emissive (AEE) properties. Herein, we report a novel rectangular D-A conjugated macrocyclic tetramaleimide with two phenyl and two 2,7-pyrene moieties as the sidewalls, while the maleimides as four corner linkers via dynamic and reversible Perkin reactions under thermodynamic control. Due to the sensitive D-A conjugation effects resulted from the multipole moments by four maleimides, such unique macrocycle exhibits unusual solvatochromic luminescent properties with a typical D-A charge transfer (CT) emission feature in the polar solvents, but pyrene-like emission characteristics in the nonpolar solvents regardless of the concentrations.

A novel conformationally adaptive macrocyclic tetramaleimide with flipping pyrene sidewalls

The synthesis, structure, and properties of pyrene-based conformationally adaptive macrocycles are described. This new type of conformationally adaptive macrocycle was constructed through Perkin reaction, followed by imidization. By changing the condensation partner as the linking unit, a family of conjugated macrocycles with different sizes of the cavity was synthesized, which provide a simple and modular synthetic strategy towards the conformationally adaptive macrocycles. Furthermore, the macrocycles provide two well-defined conformations through flipping pyrene subunit, which were unambiguously determined by single-crystal X-ray diffraction analysis. The conformational interconversion barrier was determined by density functional theory (DFT) calculations. This new macrocycle also demonstrated unique properties, such as vapochromic behavior and aggregation emission enhancement effect. Furthermore, we have also investigated the effect of the linker on the shape and photophysical properties of the resulting macrocyclic products.

Xylochemical Synthesis and Biological Evaluation of Shancigusin C and Bletistrin G.

The biological activities of shancigusin C (1) and bletistrin G (2), natural products isolated from orchids, are reported along with their first total syntheses. The total synthesis of shancigusin C (1) was conducted by employing the Perkin reaction to forge the central stilbene core, whereas the synthesis of bletistrin G (2) was achieved by the Wittig olefination followed by several regioselective aromatic substitution reactions. Both syntheses were completed by applying only renewable starting materials according to the principles of xylochemistry. The cytotoxic properties of shancigusin C (1) and bletistrin G (2) against tumor cells suggest suitability as a starting point for further structural variation.

Synthesis, Characterization, and Applications of Coumarin Derivatives: A Short Review

Coumarin and its derivatives represent one of the most active curriculums of compound possessing a broad spectrum of biological activity along with other applications such as insecticide and fragrance. There are various methodologies developed for the synthesis of coumarins. Classical routes to coumarins include Pechmann condensation, Knoevenagel condensation, Perkin reaction, and Wittig condensation reactions. Researchers have carried out adjustments and improvements to increase the efficacy and overcome the limitations from the classical route. In this review outline, coumarin derivatives were characterized by using FTIR and Hydrogen NMR spectroscopy. This review paper focuses on various synthesis and characterization techniques to analyze coumarin derivatives and their potential application in various fields.

A Review on Synthesis and Pharmacological Activity of Coumarins and Their Analogs

Background: Coumarins were reported to possess antimicrobial, antiinflammatory, antiplasmodial, antimalarial, and enzyme inhibitory properties. Furthermore, coumarins are a type of vitamin K antagonists. Coumarins had been first organized through perkin reaction; besides Knoevenagel condensation was mentioned as a critical synthetic approach for the synthesis of 3-substituted coumarins. Moreover, Pechmann, Reformatasky and Witting reactions were stated for the preparation of coumarins. Methods: We undertook a structured search of the method of preparation, the chemical reactivity and biological properties that are associated with coumarins and their analogous. Results: Coumarins display a wide range of Src Kinase and cholinesterase inhibitor activities and application of coumarins as antidiabetic, antipsychotic and antiproliferative agents has been addressed. Other properties of coumarins such as their role in antitumor, anticancer, and as antioxidants have also been reviewed. Conclusion: This review concluded that coumarin ring was mixed with other rings, a synergistic effect for each of the ring in their biological activities was obtained, such compounds were exploited to improve various important molecules which provide scaffolds for drug improvement. These compounds were used to broaden a special molecule that gives scaffolds for drug improvement.

Synthesis of polyesters mimicking polyethylene terephthalate and their thermal and mechanical properties

Poly (dihydroferulic acid) (PHFA) from biorenewable vanillin was reported before as an alternative replacement of polyethylene terephthalate (PET). Thermal properties of PHFA were found to be very close to those of commercial polyethylene terephthalate (PET). However, PHFA was insoluble in common organic solvents, and it was difficult to measure molecular weight of the obtained polymer due to difficulty of performing gel permeation chromatography (GPC) analysis. In order to modulate the physical properties of PHFA, here we report a new kind of polyester synthesized from ethyl vanillin instead of vanillin as a starting material. Ethyl group on the monomer was found to disrupt the crystallinity, improve the thermal properties and increase the solubility of the obtained polymer. 3-(4-acetoxy)-3-ethoxyphenyl) propanoic acid (AEPPA) was obtained from the reaction between ethyl vanillin and acetic anhydride through Perkin reaction and subsequent hydrogenation. Polycondensation of AEPPA was achieved using zinc acetate catalyst and resulted in poly (3-(4-acetoxy)-3-ethoxyphenyl) propanoic acid) with 75% yield and high solubility in common organic solvents. Thermal transition temperatures of the obtained polymer are very close to those of commercial PET. Polycondensation was further extended to copolymerization of AEPPA and monomers derived from vanillin and syringaldehyde. Synthesized copolymers also showed higher solubility and tunable thermal properties compared to the PHFA from vanillin.

Synthesis of Cinnamic Acid Based on Perkin Reaction Using Sonochemical Method and Its Potential as Photoprotective Agent

<p>Cinnamic acid plays a vital role in the synthesis of other important compounds and as a precursor for the synthesis of commercial cinnamon esters used in perfumery, cosmetics, and pharmaceutical industries. The aim of this research is to synthesize cinnamic acid using sonochemical methods. Cinnamic acid was synthesized using Perkin reaction by reacting 0.05 mole of benzaldehyde with 0.073 mole of acetic acid anhydride and 0.03 mole of sodium acetate as a catalyst in the Erlenmeyer flask and then the mixture was put in a sonicator for 60 minutes at 70 <sup>o</sup>C. The synthesized compound was tested organoleptic properties, and the melting point was measured. The chemical structure was elucidated using FT-IR, H-NMR, and <sup>13</sup>C-NMR. The photoprotective activity was examined from its antioxidant and SPF values. The synthesized compound was found in the form of a shiny white fine crystal which had distinctive odor with a yield of 4.98% and the melting point was found at 133<sup> o</sup>C. In the structure elucidation using FT-IR (the aromatic ring absorption at the wave number 1580 cm<sup>-1</sup> -1600 cm<sup>-1</sup>. The wave number 1625 cm<sup>-1</sup>is an aromatic conjugated alkene group, while wave number 1689.4 cm<sup>-1 </sup>is a carbonyl group. The wave number 2500 cm<sup>-1 </sup>– 3250 cm<sup>-1 </sup>is an OH carboxylic acid group) , H-NMR (7.410 (<em>m</em>, 5H, Ar-H); 7.425(<em>t</em>, 1H); 7.572 (<em>d</em>, 1H); 8.057 (d, 1H,C=CH) and <sup>13</sup>C-NMR (129.309 ppm; 130.998 ppm; 134.58 ppm; 170.017 ppm) showed that when compared with the standard compound as the reference, the synthesized compound was confirmed to be cinnamic acid. The antioxidant activity test showed that at the concentration of 20 ppm the synthesized compound was able to reduce free radicals by 46.69%. This finding showed that the synthesized compound had antioxidant activity.</p>

Ultrasmall Cs-AlMCM-41 basic catalysts: Effects of aluminum addition on their physico-chemical and catalytic properties

Abstract In this study, ultra-small MCM-41 mesoporous solids ( 2 /Al 2 O 3 ratio of 5, 20, 30 and ∞ (designated as CsM-5, CsM-20, CsM-30 and CsM-∞, respectively) have been prepared. The effects of SiO 2 /Al 2 O 3 ratio on the formation, physico-chemical and catalytic properties of CsMCM-41 nanoparticles were studied. The results show that incorporation of high content of Al atoms into the framework reduces the ordering of the mesostructure, and hence the porosity of the solids decreases. By using CsOH as mineralizer, the morphology and the size of CsMCM-41 were also tuned from 3-D nanospheres (CsM-5: 29 nm and CsM-20: 27 nm) to hollow nanospheres with very thin walls (CsM-30: 25 nm, CsM-∞: 20 nm) when Al content was decreased. The basicity of CsMCM-41 nanoparticles was also affected by the Al and Cs contents and consequently; their catalytic behavior has been evaluated in the base-catalyzed reactions such as aldol condensation of heptanal with benzaldehyde, and Perkin condensation of benzaldehyde with acetic anhydride under microwave heating conditions. CsM-20 displays the best catalytic activities among the samples studied, achieving 87.2% conversion and 78.4% selectivity to jasminaldehyde under optimum reaction conditions, while it also shows comparable catalytic performance as NaOH homogeneous catalyst in the Perkin condensation reaction.

An efficient Perkin synthesis of 13 C-labelled cinnamic acids from acetic acid as the source of the rare isotope.

A variation of the Perkin reaction using a nonenolizable anhydride as the condensation agent allows for the effective conversion of valuable carboxylic acids to the corresponding cinnamates.

Antioxidant, anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives.

During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-β-phenyl-α,β-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a-1n and one (Z)-2,3-DPA-derivative 1l' using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ± 3.53%, IC50 = 20.04 ± 1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ± 2.93%, IC50 = 30.64 ± 1.27 μM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (-7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (-5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 μM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 μM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.