Active Methylene Research Articles

Novel Coumarin‐Pyrazole‐Thiazoles Hybrids: Synthesis, Anticancer Activity, Molecular Docking and In Silico ADMET prediction Studies

AbstractA novel series of coumarin‐pyrazole‐thiazoles hybrids was designed. The methodology depended on a simple condensation reaction of 3‐(2‐oxo‐2H‐chromen‐3‐yl)‐1‐phenyl‐1H‐pyrazole‐4‐carboxaldehyde with a variety of thiazole compounds having amino or active methylene groups. In addition, another series of 1‐(thiazol‐2‐yl)‐3‐(2‐oxo‐2H‐chromen‐3‐yl)‐1H‐pyrazole‐4‐carboxaldehydes was also achieved by applying Vilsmeier‐Haack formylation on 3‐[1‐(2‐(thiazol‐2‐yl)hydrazineylidene]ethyl)‐2H‐chromen‐2‐ones. The obtained products were verified by spectral techniques such as IR, NMR, and mass spectra. To screen their abilities to inhibit cancer cell growth, these compounds were investigated against three tumor cell lines (MCF‐7, HepG2, and HCT116) using a standard method called SRB. The products 3 e, 7 b, 12 c and 14 a have considerable cytotoxic effects comparable to Doxorubicin. These products caused significant cell death by late apoptosis in all tumor cell lines. Furthermore, they preferentially induced G2 cell cycle arrest in MCF‐7 and HepG2 cells, while causing G1 cell cycle arrest in HCT116 cells. The molecular docking of these bioactive products showed good binding affinities with Cyclin‐dependent kinase 8 (CDK‐8). The ADMET‐predicted drug‐likeness properties of these bioactive compounds enable them to can used as promising anticancer agents.

DABCO‐catalyzed highly regioselective synthesis of novel 4H‐pyrano[2,3‐b]quinoline derivatives: One‐pot three‐component reaction

AbstractA regioselective synthesis of 4H‐pyrano[2,3‐b]quinoline derivatives via DABCO‐mediated Knoevenagel condensation/heterocyclization sequence has been executed. In this way some new fused heterocyclic compounds were synthesized from 2‐chloroquinoline‐3‐carbaldehyde as a versatile and efficient synthetic building block. The one‐pot three‐component reaction of 2‐chloroquinoline‐3‐carbaldehyde and diverse cyclic active methylenes for construction of highly substituted quinolines scaffold has been accomplished under mild condition. The strategy included herein shows significant advantages, including a facile process with easy purification, excellent yields, wide applicability, available substrates, and cost‐effective/eco‐friendly solvent and catalyst.

Exploring novel bromo heterocyclic scaffold and theoretical explanation of their biological actions

In this elucidation, we synthesized different heterocyclic compounds through (E)-1-(2‑bromo-4-methylphenyl)-3-(4-bromophenyl)prop‑2-en-1-one(3) which is synthesized from the aldol condensation between 4-bromobenzaldehyde and 1-(2‑bromo-4-methylphenyl)ethan-1-one in the basic condition in excellent yield. Furthermore, the chalcone 3 showed also varied activity with nitrogen nucleophiles and active methylene and displayed different heterocyclic rings which were confirmed through different spectral analyses such as FT-IR, 1HNMR, 13CNMR, and mass spectrum. Moreover, the synthesized heterocyclic exhibited antimicrobial properties against various microbial strains (Gram-positive, Gram-negative, and fungal strains) through the well diffusion methodology and comparable with Ampicillin and Mycostatin drugs. Furthermore, the synthesized compounds demonstrated various radical scavenger properties and antioxidant activities. These biological analyses demonstrated various binding energies and interactions with proteins and were validated through molecular docking studies using distinct protein pockets interaction. Additionally, the Frontier Molecular Orbitals (FMO), which are physical descriptors of optimal structures that are connected with biological evaluations and demonstrate the activities of these compounds due to presence of two bromine atom which effect on electron deficiency and increase its action which examined via the DFT/B3LYP/6-311G basis set.

Synthesis of Some Novel Thiophene Analogues as Potential Anticancer Agents.

The aim of this study involves the synthesis novel thiophene analogues that can be used as anticancer medications through a strategic multicomponent reaction connecting ethyl 4-chloroacetoacetate (1), phenyl isothiocyanate, and a series of active methylene reagents, including ethyl acetoacetate (2), malononitrile, ethyl cyanoacetate, cyanoacetamide 6a-c, N-phenyl cyanoacetamide derivatives 13a-c, and acetoacetanilide derivatives 18. This reaction was facilitated by dry dimethylformamide with a catalytic quantity of K2CO3. The resultant thiophene derivatives were identified as 4, 8a-b, 9, 12a-d, 15a-c, and 20a-b. Further reaction of compound 4 with hydrazine hydrate yielded derivative 5, respectively. When compound 1 was refluxed with ethyl 3-mercapto-3-(phenylamino)-2-(p-substituted phenyldiazenyl)acrylate 10a-e in the presence of sodium ethoxide, it produced thiophene derivatives 12a-d. Comprehensive structural elucidation of these newly synthesized thiophene-analogues was accomplished via elemental and spectral analysis data. Furthermore, the study delves into the cytotoxicity of the newly synthesized thiophenes was evaluated using the HepG2, A2780, and A2780CP cell lines. The amino-thiophene derivative 15b exhibited an increased growth inhibition of A2780, and A2780CP with IC50 values 12±0.17, and 10±0.15 μM, respectively compared to Sorafenib with IC50 values 7.5±0.54 and 9.4±0.14. This research opens new avenues for developing thiophene-based anticancer agents.

Exploring novel benzene sulfonamide derivatives: Synthesis, ADME studies, anti-proliferative activity, docking simulation, and emphasizing theoretical investigations

In this investigation, we elucidated the different heterocyclic containing benzenesulphonamide utilizing Microwave irradiation as a green energy source. Firstly the synthesis of (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)-4-methylbenzene sulfonamide (4) from the nucleophilic substitution reaction between 4-methylbenzenesulfonyl chloride and 1-(4-aminophenyl)ethan-1-one in pyridine, yielding N-(4-acetylphenyl)-4-methylbenzenesulfonamide (3), then the aldol condensation with bromobenzaldehyde in basic condition to afford the corresponding benzene sulfonamide chalcone 4 which is building block for different heterocycles. So its reactivity with different active methylene derivatives such as ethyl cyanoacetate and acetylacetone and nitrogen nucleophiles such as hydrazine hydrate and hydroxylamine using microwave irradiation in excellent yield. All synthesized compounds were investigated through spectral analysis such as FT-IR, 1HNMR, 13C NMR, and mass spectrum. Moreover, the synthesized compounds were screened through their ADME properties and were tested for antitumor activity against HepG2 hepatocellular carcinoma and MCF-7 breast cancer, exhibiting excellent efficacy compared to standard drugs, especially the heterocycles 6,8, 10, and 13 compared with Doxorubicin drug Furthermore, Molecular simulations with different proteins confirmed these results with PDBID:4hdq and 5H38. Additionally, the DFT analysis of optimized structures investigated their physical descriptors, Frontier Molecular Orbitals (FMO) which correlated them with the biological evaluation and showed the stabilities of these compounds.

Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Design, synthesis, characterization, structure-activity relationship, and molecular docking studies of novel 2,3-dihydropyrimidin-4(5H)-one and pyrimido[5,4–c] pyridazine-4-carbonitrile derivatives with biological evaluation

The key starting material, 2-imino-6-phenyl-2,3-dihydropyrimidin-4(5H)-one 1, was the focus of our approach due to the fact that it has an endocyclic active methylene group adjacent to the carbonyl function at position-5. We also further investigated the heterocyclization of the target products 3a–d with diverse carbon nucleophiles to generate fused pyrimidines. The authors provide a simple synthesis of heretofore unreported findings from two series of the novel 2,3,5,6-tetrahydropyrimido [5,4-c]pyridazine-4-carbonitriles 4a–d and 6a–c. The structures of the newly synthesized compounds have been confirmed via analytical and spectroscopic data. All compounds were screened against bacterial species (Escherichia coli, Bacillus megaterium, and Bacillus subtilis), and their antifungal activity was also tested against fungal species (Fusariumproliferatum, Trichodermaharzianum, and Aspergillus niger). Moreover, the minimum inhibitory concentration (MIC) was detected for all the studied compounds and revealed that all compounds had good to moderate results compared to the standby ones. Density function theory (DFT) at B3LYP via the 6–31 G (d,p) basis set has been calculated to explore the electronic properties of all studied compounds. Structure-activity relationship (SAR) was reported based on their electronic structure. Furthermore, molecular docking studies were conducted to evaluate the DFT results and visualize the activity of the compounds. The results displayed that those compounds (3b and 4a-d) were excellent scaffolds acting as antimicrobial agents.

Synthesis, Characterization, and Optimization of Novel Furan-ring Fused Chalcones via Radical Cyclization of α,β-Unsaturated Ketones and Cyclic Ketone

Abstract: Novel Furan-ring Fused Chalcones (FFC) were synthesized using a radical cyclization reaction of α,β-unsaturated ketones with cyclic ketone as the model reaction to attain this goal. In this study, traditional and microwave-assisted methods for the efficient and cost-effective synthesis of furan-ring fused chalcones in mild reaction conditions are compared and optimized. The goal is to develop a reliable and adaptable synthetic technique that may be used to produce these useful chalcone derivatives quickly and effectively. The optimal experimental conditions for these reactions were carefully determined using two independent methodologies: conventional (Method A) and microwave (Method B). The results indicated that the proposed method B could be used effectively in the future to synthesize novel furans with short reaction times and acceptable yields (87-94 %), and products were purified by column chromatography and preparative thin layer chromatography (PTLC). All new compounds were characterized by 1H-NMR, 13C-NMR, LC-MS, and elemental analyses.

Synthesis of Sulfo(xo)nium Diacylmethylides

AbstractSulfo(xo)nium diacylmethylides (sulfur ylides) are simple, stable, readily prepared, and versatile synthons. Compared with the sulfo(xo)nium monoacylmethylides, they can be compatible with more rigorous reaction conditions and showcase unique characteristics due to their excellent stability. This concept article provides an account for the syntheses of sulfo(xo)nium diacylmethylides, including the utilization of active methylene compounds, carbene precursors, sulfo(xo)nium monoacylmethylides, and electron‐deficient alkynes as substrates, with discussions on substrate scopes, proposed mechanisms, selected product examples, and applications. Challenges for further exploration and prospect on sulfo(xo)nium diacylmethylides in the future are also suggested.

The Surprising Reactivity of Chloromethyl Chlorosulfate with Active Methylene Compounds

AbstractCondensation of chloromethyl chlorosulfate (1) with alkyl 1,3‐keto esters under phase‐transfer catalysis (PTC) conditions led to methylene bridged bis‐acetoacetates through a sequential chloromethylation‐β‐elimination‐Michael addition process. The latter compounds further evolved towards polyfunctional dihydrofuran and tetrahydropyran derivatives by competitive chloromethylation/chlorination reaction. In aprotic organic solvent, chlorination of the methylene active group is the main process and proceeded by reaction of the enolate of acetoacetate with the chlorine atom bound to the sulfonyl group of 1. The reactivity of some other active methylene compounds under PTC conditions was investigated. Acetylacetone reacted similarly to ethyl acetoacetate providing O‐heterocycles while ethyl cyanoacetate gave diethyl 2,4‐dicyanoglutaric acid diethyl ester together with 2‐diethyl 1,2‐dicyanocyclopropane‐1,2‐dicarboxylate. A plausible reaction mechanism is proposed whose the key feature is the competitive halogenation/chloromethylation of the intermediate methylene bridge dimeric active methylene compounds followed by intramolecular cyclization.

Synthesis, Characterization and Antimicrobial and Anticancer Evaluations of Some Novel Heteroannulated Difuro[3,2-c:3',2'-g]Chromenes.

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3',2'-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6-8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds.

Solvent solute interaction (IEFPCM model), Michael addition-based anticancer drug synthesis, FTIR, NMR, and UV–visible investigations of spirooxindole-pyranoindole (2AIPC) − in vitro and in silico anti-cancer activity

Herein, click chemistry was chosen to synthesize 2AIPC using Knoevenegel and Michael addition reactions. In this synthesis, Lewis base was attracted by the generation of sp3 hybridized carbanion at active methylene group in the reactants for propagation reaction proceeding towards conducting the Michael addition product. The synthesized 2AIPC was characterized by NMR(13C and 1H), UV, FTR and FT-IR analytical tools; it was also evaluated utilizing density functional theory. According to DFT analyses, the comparative study of the functional groups of 2AIPC molecule was successfully described using Raman and FT-IR spectra with simulated spectra. NLO behaviour and charge exchange utilizing the hyperpolarizability and FMO band gap characteristics were also investigated. Through computational studies using MEP, FUKUI, RDG, and NBO, intermolecular interaction and the reactive area of the synthesized molecule were demonstrated.Moreover, the anticancer activity under the in-vitro analysis was tested, and the molecule showed 61.04 % GI against the K-562 leukemia cells at 10-5 M. Molecular docking also evaluated cytotoxicity by in silico study against leukemia-related proteins (60QN, 6OQC, 1EMR, and 606F). The docked complexes showed binding affinities of −7.82, −7.1, −6.9, and −6.71 kcal/mol. A nucleophile elimination process at 2AIPC’s main amino group may also increase the molecule’s potential to be a more effective lead medication.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Synthesis, Antimicrobial Evaluation, DFT, and Molecular Docking Studies of Pyrano [4,3-b] Pyranone and Pyrano[2,3-b]Pyridinone Systems.

Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic system 6 and spiro hybrid molecule 7. Also, the reaction of DHA 1 with cyanoacetamide derivatives 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworks 9 and 12, respectively. Also, in silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively.

Lewis Acid-Catalyzed Tandem Reaction Strategy for the Synthesis of Dihydrophenalene-Fused Lactones.

A Lewis acid-catalyzed tandem reaction strategy for the construction of a dihydrophenalene-lactone tetracyclic skeleton has been disclosed. Starting with 2-naphthol-tethered ketones and active methylene esters, the tandem reaction catalyzed by Sc(OTf)3 proceeded well to afford an array of dihydrophenalene-fused lactones with moderate to high efficiency and diastereoselectivity. Moreover, the synthetic utility of this protocol was demonstrated by easy gram-scale preparation and diverse product transformations.

Phosphine-Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin.

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

Influence of Hydroxyl Groups on the Oxidative Reaction Characteristics of Active Groups in Lignite at Room Temperature.

In this paper, through the Fourier infrared spectrum analysis of the Inner Mongolia Hulunbeier Yannan coal mine lignite sample, phenyl and active groups, methoxy (-OCH3) and methylene (-CH2-), were taken as the research objects, and a simple small molecule model of hydroxyl (-OH) at the ortho, meta, and para positions of active groups was constructed. The structural optimization and simulation calculation of simple small molecules were carried out by Gaussview 6.0.16 and Gaussian 16 software at room temperature and pressure. The DFT-B3LYP method and 6-311G(d,p) basis set were used to study the effect of the -OH position on the oxidation reaction characteristics from various aspects of electrostatic potential, frontier orbital, activation energy, enthalpy change, and Gibbs free energy change. The results show that the coexistence of the active groups -OCH3 and -CH2- with -OH makes the small molecule model add an active site, that is, the oxygen atom in -OH, which makes the active groups generate hydrogen radicals (H•). Comparing different positions of -OH, the analysis shows that -OH at the ortho position has a vital impact on the oxidation reaction, and the oxidation reaction releases the largest amount of heat and has the fastest occurrence rate, making it easier to overcome energy barriers and making the reaction easier to proceed. The purpose of this study is to reveal the interaction and complex reaction path of lignite through an in-depth study of its properties, structural composition, and reaction behavior and to accurately grasp its chemical composition, thermal properties, and microstructure, so as to lay a foundation for further efficient conversion and comprehensive utilization.

SrCaAl mixed metal oxides derived from LDH precursor as a novel and efficient solid base catalyst for Knoevenagel condensation reaction: Multivariate optimization study

The Knoevenagel condensation reaction is one of the most important reactions in the industry for the synthesis of organic materials, medicinal, and biological compounds. In this work, we have proposed an original and efficient solid-base catalytic system for the Knoevenagel condensation reaction. For the first time, a mixed oxide catalyst derived from hydrotalcite-like Sr0.5Ca2.5Al precursor was synthesized by co-precipitation method and subsequently calcined for 5 h at 850 °C. The catalysts were characterized by various techniques. The Sr0.5Ca2.5Al mixed oxide was also compared with the usual Ca3Al sample in terms of structural characteristics and catalytic activity in the Knoevenagel reaction between active methylene compounds and benzaldehyde. The findings revealed that the Sr0.5Ca2.5Al mixed oxide sample is considerably active in this reaction compared to the Ca3Al sample due to its stronger basicity. The kinetics of the Knoevenagel condensation reaction over the Sr0.5Ca2.5Al catalyst was investigated and indicated that it follows from the second-order model. The stability and reusability of the catalyst sample were studied and it was found that the Sr0.5Ca2.5Al catalyst has high stability and a good lifetime. The effects of reaction time, amount of catalyst, and reaction temperature on benzaldehyde conversion (%) and product selectivity (%) were assessed in this study using the Box-Behnken design. The appropriateness of the quadratic regression model was evaluated through the ANOVA method. Under optimal conditions, the conversion percentage of benzaldehyde and product selectivity reached 97% and 84%, respectively.

Nitrile Furanics via Copper‐Catalyzed Dehydration of Aldoximes and Knoevenagel Condensation

AbstractIn this work two synthetic approaches to introduce nitrile moieties into bio‐based derived furanic compounds were investigated, i. e., dehydration of aldoximes and Knoevenagel condensation. Both methodologies have been first tested and optimized on furfural and thus exploited on 5‐hydroxymethyl‐2‐furfural (HMF) and 5,5’‐oxy(bismethylene)‐2‐furaldehyde (OBMF). The syntheses of furfural, HMF and OBMF aldoximes were efficiently conducted (also in large scale) under mild reaction conditions and short reaction time. The subsequent dehydration to nitrile furanic compounds was carried out in the presence of catalytic amount of copper acetate monohydrate. Furthermore, Knoevenagel condensations were performed on furfural, HMF and OBMF with different Activated Methylene Group compounds, using for the first‐time dimethyl carbonate as the reaction media. Most of the resulting products were isolated as pure via simple liquid‐liquid extraction in good to excellent yields. Future applications of these compounds might include aldoxime reduction into amine furanics ‐ herein also preliminary investigated ‐ and hydrolysis of the nitrile derivatives in the related carboxylic acid (or ester) furanics. All these products are interesting monomers for the preparation of bio‐based polymers.

Bmim][CF3COO] as a Solvent and a Catalyst for the Knoevenagel Condensation

Abstract: A facile and green strategy for the Knoevenagel condensation reaction of aryl aldehydes and active methylene compounds using [Bmim][CF3COO] ionic liquid as a solvent and a catalyst has been introduced. The method features some advantages, such as good to excellent yield of products, relatively short reaction time, mild reaction conditions, broad substrate scope, and scalability. Moreover, the ionic liquid solvent could be conveniently recycled and reused up to three times without any considerable loss of catalytic activity. Twelve products were obtained in high yields, and their structures were confirmed by NMR data. A plausible reaction mechanism involving the role of the ionic liquid catalyst was also suggested.