Active Methylene Research Articles

Synthesis, DFT investigation, molecular docking analysis, ADMET studies, and biological evaluation of a novel series of imidazolidinone derivatives as potential antimicrobial agents

In this study, we constructed twenty novel imidazolidinone derivatives via the reaction of 2-(methylthio)-3,5-dihydro-4H-imidazol-4-one derivatives (1a-c) with some active methylene reagents and nitrogen nucleophiles. The synthesized compounds were confirmed through spectral analysis such as 1H NMR, 13C NMR, FT-IR, and MS. Moreover, the synthesized compounds were optimized and utilizing the DFT/B3LYP/6-31(G) basis set to investigate their energies and the presence of two forms of isomers (E and Z). The results confirmed the stability of the E form. ADMET of new imidazolidinones was also studied to investigate their lipophilicity and Lipinski's rule for determination of their physiological biological analysis. Also, the antimicrobial activity of new compounds on Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, Streptococcus mutans, Candida albicans, and Aspergillus Nigar using the inhibition zone technique were evaluated. The results demonstrate that compound 11c showed higher activity rather than other compounds due to the presence of piperazine moiety out of the plane of the benzene ring. Additionally, the docking study showed an electrostatic bonding interaction of the hydrogen of 11c and the amino acids of two proteins such as PDBID: 3t88 and 2wje.

A Ru-Based Complex for Sustainable One-Pot Tandem Aerobic Oxidation-Knoevenagel Condensation Reactions.

Our novel binuclear complex-anchored Ru(III) catalyst, designed and assembled by sonicating 2,2'-(4,6-dihydroxy-1,3-phenylene)bis(1H-benzo[d]imidazole-4-carboxylic acid), Ru(DMSO)4Cl2 and 4-methylpyridine, demonstrates remarkable efficiency and selectivity. It promotes one-pot reactions, including active methylenes and benzyl alcohols in water, via a tandem aerobic oxidation/Knoevenagel condensation process, yielding benzylidene malononitrile in excellent yields. The catalyst's ability to oxidize benzyl alcohols to aldehydes, which then undergo Knoevenagel condensation with active methylenes, makes it a multifunctional catalyst. Notably, the catalyst can be successfully retrieved and recycled for five successive rounds with no significant decrease in catalytic efficiency. The ICP study showed that no catalyst leaching was observed, indicating that the designed catalyst is indeed heterogeneous. The Ru catalyst outperformed other documented catalysts in terms of lower dose, shorter duration, decreased working temperature, and the absence of dangerous additives. This demonstrates the catalyst's robustness and sustainability, making it a promising candidate for future organic conversions and industrial uses.

Synthesis and Cytotoxicity of Novel β-Ala-Phthalazine-Based Derivatives as VEGFR2 Inhibitors and Apoptosis-Inducers Against Liver Cancer

Some novel β-Ala-phthalazine derivatives were synthesized from the parent methyl 3-(2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetamido)propanoate (1). Then, ester 1 underwent hydrazinolysis to produce the hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(3-hydrazineyl-3-oxo propyl) acetamide (2). Under the azide coupling technique, hydrazide 2 formed azide 3 which was further coupled with some amines and amino acid esters hydrochloride to produce the corresponding novel dipeptides 4a–h and 5a–d, respectively. Finally, hydrazide 2 was condensed and/or cyclized with some ketones and/or active methylene compounds resulting in the formation of various derivatives 6a-e. Compounds 2, 6c, and 6d demonstrated significant cytotoxicity, with IC50 values of 1.33, 0.41, and 0.38 μM compared to Sorafenib (IC50 = 2.93 μM). Compounds 6d exhibited potent VEGFR2 inhibition by 97.6% with an IC50 value of 21.9 μM compared to Sorafenib (94.7% and IC50 value of 30.1 μM). The 6d treatment significantly increased apoptotic activity by 23.6-fold, causing a halt in cell proliferation at the G2/M phase. Ultimately, it exhibited a strong affinity for the VEGFR2 protein, with a binding energy of −26.8 Kcal/mol, and it established binding contacts with the crucial amino acids involved in the interaction.

Synthesis, characterization, and color performance of bis-azo and bis-pyrazole derivatives for dyeing of polyester

In this study, a novel series of bis-azo dyes 3–10 were synthesized via a two-step process. Initially, benzene-1,4-bis(diazonium) chloride was reacted with several active methylene compounds, such as ethyl acetoacetate, acetyl acetone, ethyl cyanoacetate, and malononitrile. yielding the corresponding bis-azo dyes 3–6. Subsequently, these dyes were cyclized through condensation with phenylhydrazine, resulting in the formation of bis-pyrazole derivatives 7–10. Comprehensive spectroscopic characterization, employing techniques like infrared (IR), nuclear magnetic resonance (NMR), and ultraviolet-visible (UV–Vis) spectroscopy, along with elemental analysis, elucidated the structural features, and electronic transitions of the synthesized dyes. The electronic absorption properties were investigated experimentally and computationally, revealing bathochromic and hypsochromic shifts influenced by substituents and tautomeric forms. The dyes showcased excellent dyeing performance on polyester fabrics, exhibiting notable color strength, perspiration fastness, light fastness, and wash fastness. Theoretical investigations of the electronic properties were conducted utilizing Density Functional Theory (DFT) methodology, employing the B3LYP functional with the 6–31G(d,p) basis set, enabling a comprehensive understanding of the structure-performance relationships governing the dyeing behavior of these dyes on polyester.

Production of Phenyldiazene Derivatives Using the Biosynthetic Pathway of an Aromatic Diazo Group-Containing Natural Product from an Actinomycete.

The diazo group is an important functional group in organic synthesis because it confers high reactivity to the compounds and has been applied in various chemical reactions, such as the Sandmeyer reaction, Wolff rearrangement, cyclopropanation, and C-N bond formation with active methylene compounds. Previously, we revealed that 3-diazoavenalumic acid (3-DAA), which is potentially produced by several actinomycete species and contains an aromatic diazo group, is a biosynthetic intermediate of avenalumic acid. In this study, we aimed to construct a production system for phenyldiazene derivatives by adding several active methylene compounds to the culture of a 3-DAA-producing recombinant actinomycete. First, acetoacetanilide and its derivatives, which have an active methylene and are raw materials for arylide yellow dyes, were individually added to the culture of a 3-DAA-producing actinomycete. When their metabolites were analyzed, each expected compound with a phenyldiazenyl moiety was detected in the culture extract. Moreover, we established a one-pot in vitro enzymatic production system for the same phenyldiazene derivatives using a highly reactive diazotase, CmaA6. These results showed that the diazo group of natural products is an attractive tool for expanding the structural diversity of natural products both in vivo and in vitro.

Tandem Knoevenagel‐Aldol Cyclization Towards Di and Trisubstituted Pyridines: Use of Malonaldehyde and Diethyl Malonate for the Synthesis of Indolizine

AbstractAn effective method for the construction of a multi‐functionalized pyridine motif of indolizine using the [4+2] annulation pathway involves tandem Knoevenagel‐aldol cyclization as a critical step in the process. The production of an indolizine scaffold with a hydroxy group at the C6 position and an ethyl ester/aldehyde group at the C7 position was successfully accomplished using this approach with an excellent yield, with the use of a reagent that contains active methylene and operates under mild conditions. This straightforward and simple protocol allows extensions of the core moiety in a quick and dependable manner.

Solvent-free and efficient heterogeneous Biginelli reactions catalyzed by copper (II)-incorporated iminophenol-based porous organic polymer

The copper (II)-incorporated iminophenol containing porous polymer (Cu-TAzo-TAPB), which was reported to be a recyclable catalyst for click reactions, is now exploited as an efficient catalyst in the solvent-free one-pot process to make 3,4-dihydropyrimidinone derivatives (DHPMs) by a three-component condensation reaction of urea/thiourea, aldehydes, and active methylene compounds. Usually, these reactions are complicated to carry out in a neutral medium. We describe here an eco-friendly method to produce Biginelli products with 5 mol% catalyst loading with a simple isolation technique. The high product yields show the effective Biginelli reaction technique. The catalyst is highly stable and easily recoverable for reuse without significant loss of catalytic efficiency.

Sequential Knoevenagel condensation/cyclization reaction using Meldrum’s acid

Sequential Knoevenagel condensation/cyclization using cyclic active methylene compounds such as Meldrum’s acid have been studied. The reaction of 2-(1-phenylvinyl)benzaldehyde and Meldrum’s acid, dimedone, or 1,3-indandione with piperidine/AcOH or L-proline at room temperature for 17–18 h gave cyclized indene derivatives in 63–80% yield. The reaction of 2-(3,5-dimethoxyphenyl)benzaldehyde and Meldrum’s acid at room temperature for 17 h gave a fluorene derivative in 98% yield. Furthermore, the reaction of 2-(3,5-dimethoxybenzyl)benzaldehyde and Meldrum’s acid with piperidine at room temperature for 18 h gave a dihydroanthracene derivative bearing Meldrum’s acid in 83% yield. The reaction of 2-(3,5-dimethoxybenzyl)benzaldehyde and Meldrum’s acid with piperidine at 110 °C for 2 h gave Meldrum’s acid fragmentated dihydroanthracene derivative in 48% yield. The reaction mechanisms of the cyclization steps and Meldrum’s acid fragmentation have been examined by the DFT calculations.

Novel Organosulfur Building Blocks for Heterocycle Synthesis

AbstractThe present article provides a personalized account of our recent work on the synthesis of substituted and fused five-membered heterocycles using various organosulfur building blocks, derived primarily through base-mediated condensation of active methylene compounds with (het)aryl/alkyl dithioesters, which have not been previously explored. We initially describe the ring-opening transformations of 4-[(methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones, leading to the synthesis of functionalized oxazoles, thiazoles, and bisoxazoles. We then go on to focus on the synthesis of substituted benzothiophenes, indoles, and benzofurans, as well as their hetero-fused analogs. These compounds are synthesized via transition-metal-catalyzed intramolecular C–heteroatom (C–S, C–N, C–O) bond formation (via cross-coupling or C–H bond functionalization) of various reactive organosulfur intermediates, derived from base-mediated condensation of 2-bromo(het)arylacetonitriles, acetates, or desoxybenzoins or the corresponding 2-unsubstituted precursors. Finally, we highlight the synthetic applications of a new class of previously unexplored organosulfur building blocks, namely, unsymmetrically substituted 1,3-bis(het)aryl-1,3-monothioketones, derived via base-mediated condensation of ketones with (het)aryl/alkyl dithioesters, for the regioselective synthesis of substituted pyrazoles, isoxazoles, thiophenes, imidazoles, and benzothiophenes.1 Introduction2 4-[(Methylthio)-het(aryl)-methylene]-2-phenyl/2-(2-thienyl)-5-oxazolones: Versatile Templates for the Synthesis of Oxazoles, Thiazoles, and Bisoxazoles3 Synthesis of Benzothiophenes, Indoles, and Benzofurans via Transition-Metal-Catalyzed Intramolecular C–Heteroatom Bond Formation4 1,3-Bis(het)arylmonothio-1,3-diketones and 1,3-Bis(Het)aryl-3-(methylthio)-2-propenones: Versatile Intermediates for the Regioselective Synthesis of Five-Membered Heterocycles5 Conclusion

Synthesis of New Heterocyclic Derivatives from 4-(3, 5-Dimethyl-1-phenyl-1H-pyrazol-4-ylazo)- benzoic acid

In this work pyrazolin derivatives were prepared from the diazonium chloride salt of 4-aminobenzoic acid. Azo compounds were prepared from the reaction of an ethanolic solution of sodium acetate and calculated amount of active methylene compound namely, acetyl acetone to obtain the corresponding hydrazono derivative (1). Cyclocondensation reaction of compounds (1) with hydrazine hydrate and phenyl hydrazine in boiling ethanol affording the corresponding pyrazoline-5-one derivatives of 4-aminobenzoic acid (2,3). Then compound (3) was reacted with thionyl chloride to give the corresponding acid chloride derivative(4), followed by conversion into the corresponding acid hydrazide derivative (5) carboxylic acid thiosemicarbazide (11), esters (14,15), thioesters (16,17) and amides (18,19), when treated hydrazine hydrate, thiosemicarbazide, alcohols, alkylthiol and secondary amines in dry refluxing benzene; respectively. Schiff's bases (6-8) were prepared by refluxing of compound (5) with different aldehydes and ketons, then two compounds from the Schiff's bases were cyclized with ?-mercapto acetic acid to give (9 and 10). Furthermore, 1,2,4-triazole derivative (12) have been also prepared by refluxing thiosemicarbazide derivative with sodium hydroxide solution (4%) followed acidification of the result using (10%)hydrolic acid. Moreover, a thiadiazole derivative (13) has been prepared by treatment of thiosemicarbazide derivative with concentrated sulfuric acid as cyclyzing agent. Finally, oxadiazole derivative (20) has prepared by condensation of its acid hydrazide derivative with carbon disulfide in basic medium.

The GaCl3-Catalyzed Knoevenagel Condensation To Achieve Acceptor-Donor-Acceptor Small-Molecule Acceptors: A DFT Mechanistic Study.

Herein, the reaction mechanism for the GaCl3-catalyzed Knoevenagel condensation of 2-formylindacenodithieno[3,2-b]thiophene (ITIC-CHO) and active methylene compound 1,1-dicyanomethylene-3-indanone (IC) to synthesize ITIC in the presence of acetic anhydride was investigated using the density functional theory (DFT) method. The calculated results indicate that this reaction follows a bimolecular GaCl3 catalytic mechanism. The free energy span for the monomolecular GaCl3 catalytic mechanism is the highest (31.8 kcal/mol), followed by the trimolecular GaCl3 catalytic mechanism (26.4 kcal/mol) and the bimolecular GaCl3 catalytic mechanism (26.3 kcal/mol). The trimolecular GaCl3 path and bimolecular GaCl3 path are competitive, but the former path is limited by the concentration of GaCl3. The inclusion of GaCl3 could stabilize the transition states of C-H activation. Compared to the GaCl3-catalyzed Knoevenagel condensation, that catalyzed by pyridine is not advantageous, owning a high energy span of 31.7 kcal/mol. These agree well with experimental results. This work could provide a novel theoretical understanding of the Knoevenagel condensation, which could inspire the development of a synthesis strategy for electron acceptor materials.

Diethyl Mesoxalate, A Representative Tricarbonyl Compound – A Useful Synthetic Tool Possessing Diverse Reactivities

AbstractDiethyl mesoxalate, a vicinal tricarbonyl compound, possesses multiple functionalities that facilitate diverse chemical conversions. The central carbonyl group with two ester functionalities exhibits high electrophilicity to accept nucleophilic attacks of various reagents. This unusual electrophilicity enables the reaction with acid amides that are not common nucleophiles in organic syntheses. Condensation with active methylene compounds or amines leads to electron‐deficient alkenes and imines, respectively, which can be transformed into more complex polyfunctionalized compounds by a second nucleophilic addition. Chemical transformations between the central and adjacent ester carbonyls furnish new ring systems that are useful in material and pharmaceutical sciences. The central carbonyl group can also be built into a ring system by reacting with reagents possessing nucleophilic and electrophilic sites. Furthermore, the central carbonyl serves as a dienophile that undergoes cycloaddition to form functionalized heterocyclic compounds in a single step.

Extending the Carbon Chain Length of Carbohydrate-Derived 5-Substituted-2-furaldehydes by Condensing with Active Methylene Compounds under Organocatalytic Conditions.

This work reports a high-yielding, organic solvent-free, gram-scale synthesis of novel Knoevenagel condensation products by reacting carbohydrate-derived 5-substituted-2-furaldehydes (SFLs) with active methylene compounds (AMCs) using various organic amines and inorganic bases as catalysts. Among the base catalysts examined, piperidine performed best, affording satisfactory selectivity and yield of the targeted Knoevenagel condensation products owing to the subtle balance between its nucleophilicity and basicity. The reaction was optimized on various reaction parameters, such as temperature, duration, solvent, catalyst loading, and molar ratio of the reactants. Even though the SFLs exhibited significantly different reactivity, a general synthetic protocol was developed successfully, affording good to excellent isolated yields (70-96%) of the novel Knoevenagel condensation products at ambient temperature. Moreover, the Knoevenagel products were purified by triturating with eco-friendly solvents (e.g., ethyl acetate and n-heptane) without chromatographic purification.

Design and evaluation of sulfadiazine derivatives as potent dual inhibitors of EGFRWT and EGFRT790M: integrating biological, molecular docking, and ADMET analysis.

A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFRWT and EGFRT790M protein kinases, with IC50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFRWT and EGFRT790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFRWT and EGFRT790M, with binding scores of -6.40 kcal mol-1 and -7.53 kcal mol-1, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol-1, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFRWT and EGFRT790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.

Thiourea-Ammonium Chloride Mediated Knoevenagel Condensation as an Intermediate in the Synthesis of Pyrimidine Scaffolds under Solvent-free Condition

Abstract: In this paper, we have reported solvent solvent-free method for Knoevenagel condensation reaction of various aldehydes with active methylene compounds using thiourea and ammonium chloride. The developed method demonstrated high efficiency in the formation of C-C bond. The reaction proceeds smoothly under mild and solvent-free conditions and the products obtained are in excellent yield in very short duration. This method is applicable to a wide range of aldehydes with active methylene compounds.

Photo-Activated Carbon Dots as Catalysts in Knoevenagel Condensation: An Advance in the Synthetic Field

Photoinduced chemical reactions and the development of new materials represent a current and significant topic. We present a sustainable and eco-friendly approach to the Knoevenagel condensation reaction involving carbonyl and active methylene compounds. Our method utilizes photo-activated carbon dots (CDs) derived from 5-hydroxymethylfurfural (5HMF) within an aqueous medium and does not require acidic, basic, or thermal conditions. This protocol operates effectively with aromatic, aliphatic, and heteroaromatic aldehydes and ketones. The 5HMF-derived-CDs can be reused four times without significant loss of activity. Moreover, this methodology is suitable for scaling up reactions, thereby highlighting its potential for industrial applications.

Novel emissive styryl dyes from 9-methoxy anthracene: Synthesis, photophysical, thermal stability, viscosity, and DFT study

Novel styryl colorants based on anchoring methoxy with anthracene as a donor linked with various active methylene acceptor groups to derive a conjugated π-system along with push-pull geometry were synthesized and well characterized. Photophysical properties were studied in different polarity solvents. The impact of solvent polarizability is delivered in redshifts in absorption and emission spectra, in addition to enhancing the quantum yield. The benzoxazole and benzimidazole moieties in 4c and 4d demonstrated heat stability of more than 300 °C. Fluorescent intensity is directly proportional to the viscosity and 4a demonstrates a notable viscosity sensor through 1.36 fold increase in intensity. In comparison to other styryl dyes, 4c and 4d were shown to have higher values in DMSO for polarizability (53.3496 × 10−24 esu and 53.7459 × 10−24 esu) and first-order hyperpolarizability (86.3467 × 10−30 esu and 89.1941 × 10−30 esu) as well as second-order hyperpolarizability (1768.9121 × 10−36 esu and 1740.6940 × 10−36 esu) due to presence of heterocyclic character. NLO properties of all the styryl dyes 4a-4e are within the fundamental boundary limits. The 4d (benzoxazole) dye exhibited a small HOMO-LUMO energy gap of 2.8825 eV, whereas the 4b and 4e dyes had a larger band gap due to the presence of a carbonyl group.

Microwave-assisted synthesis, characterization, and molecular docking studies of new chlorophthalazine derivatives as anticancer activity

A series of phthalazine derivatives have been synthesized using green protocol methods under microwave irradiation. This involved subjecting chlorophthalazine to microwave irradiation and employing various reagents, including hydrazine derivatives, primary and secondary amines, and active methylene, to generate the novel phthalazine derivatives. Subsequently, a comparison was made between the yield percentage and reaction time of the resulting products obtained from conventional methods and those obtained through microwave irradiation. The structures of all new compounds were confirmed by physical properties and spectral analysis. The phthalazine compounds demonstrated significant anticancer activity against three cancer cell lines and showed promising selectivity when compared with doxorubicin. Compound 6 exhibited the best anticancer activity, with IC50 1.739 µM, 0.384 µM, and 1.52 µM against MCF7, HCT116, and HepG2 cell lines, respectively. The docking results confirmed that the drugs exert their activity by inhibiting PARP-1. The binding scores were in accordance with the experimental IC50, with compound 6 exhibiting the best binding score and retaining the essential binding interactions with the active site. The results of our computational research have revealed that our phthalazine compounds possess a unique structure that effectively inhibits PARP-1.

Dual electrochemical signal “signal-on-off” sensor based on CHA-Td-HCR and CRISPR-Cas12a for MUC1 detection

Mucin 1 (MUC1) is frequently overexpressed in various cancers and is essential for early cancer detection. Current methods to detect MUC1 are expensive, time-consuming, and require skilled personnel. Therefore, developing a simple, sensitive, highly selective MUC1 detection sensor is necessary. In this study, we proposed a novel “signal-on-off” strategy that, in the presence of MUC1, synergistically integrates catalytic hairpin assembly (CHA) with DNA tetrahedron (Td)-based nonlinear hybridization chain reaction (HCR) to enhance the immobilization of electrochemically active methylene blue (MB) on magnetic nanoparticles (MNP), marking the MB signal “on”. Concurrently, the activation of CRISPR-Cas12a by isothermal amplification products triggers the cleavage of single-stranded DNA (ssDNA) at the electrode surface, resulting in a reduction of MgAl-LDH@Fc-AuFe-MIL-101 (containing ferrocene, Fc) on the electrode, presenting the “signal-off” state. Both MB and MgAl-LDH@Fc-AuFe-MIL-101 electrochemical signals were measured and analyzed. Assay parameters were optimized, and sensitivity, stability, and linear range were assessed. Across a concentration spectrum of MUC1 spanning from 10 fg/mL to 100 ng/mL, the MB and MgAl-LDH@Fc-AuFe-MIL-101 signals were calibrated with each other, demonstrating a “signal-on-off” dual electrochemical signaling pattern. This allows for the precise and quantitative detection of MUC1 in clinical samples, offering significant potential for medical diagnosis.

Synthesis and Electrophilic Trifluoromethylthiolation Properties of 1-Methyl-4-(trifluoromethylthio)piperazine (MTTP).

A cyclic diamine, 1-methyl-4-(trifluoromethylthio)piperazine (MTTP, 1), prepared by a one-step reaction from commercial materials, is a shelf-stable and powerful electrophilic trifluoromethylthiolating (CF3S) reagent with wide reactivity profile. Activation of 1 with triflic acid (TfOH) yields two reactive species A and B, depending on the molar ratios of TfOH/1. B showed unprecedented high reactivity, making possible the trifluoromethylthiolation of electron-deficient aromatic systems. In addition, B accomplished the trifluoromethylthiolation of active methylene compounds under acidic conditions.