Active Methylene Reagents Research Articles

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.

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.

Photocatalytic sequential C-H functionalization expediting acetoxymalonylation of imidazo heterocycles.

The importance of functionalized imidazo heterocycles has often been featured in several impactful research both from academia and industry. Herein, we report a direct C-3 acetoxymalonylation of imidazo heterocycles using relay C-H functionalization enabled by organophotocatalysis starring zinc acetate in the triple role of an activator, ion scavenger as well as an acetylating reagent. The mechanistic investigation revealed a sequential sp2 and sp3 C-H activation, followed by functionalization driven by zinc acetate coupled with the photocatalyst PTH. A variety of imidazo[1,2-a]pyridines and related heterocycles were explored as substrates along with several active methylene reagents, all generating the products with excellent yields and regioselectivity, thus confirming excellent functional group tolerability.

Antimalarial Activity of Tri- and Tetra-Substituted Anilino Pyrazoles

Pyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure-activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties.

Regioselective Synthesis, Structural Characterization, and Antiproliferative Activity of Novel Tetra-Substituted Phenylaminopyrazole Derivatives.

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two N-methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.

Knoevenagel‐Cyclization Cascade Reactions of Substituted 5,6‐Dihydro‐2H‐Pyran Derivatives

AbstractThe diastereoselective domino‐Knoevenagel‐IMHDA reactions of 5,6‐dihydro‐2H‐pyran derivatives containing an o‐formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel‐[1,5]‐hydride shift‐cyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6‐dihydro‐2H‐pyran‐3‐yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X‐ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC50 values down to 2.99 μM.

Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12–0.25 µM) compared to Vancomycin (1–2 µM), and MBC values ranging from (0.5–1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.

Reactions under increased pressure: The reactivity of functionally substituted 3-oxo-2-arylhydrazones toward active methylene reagents in Q-tube

A one-pot two-component reaction of 3-oxo-2-arylhydrazones with active methylene nitriles under high pressure in a Q-tube safe reactor was reported. Comparison between conventional and Q-tube safe reactor-assisted synthesis of organic compounds was done by comparing total reaction time and percentage yield. The results show that the compound 5-cyano-6-oxo-1,4-diphenyl-1,6-dihydro-pyridazine-3-carboxylic acid ethyl ester (3) was synthesized within 2 h in a yield of 97%. In addition, the pyrazolo[3,4-c]pyridines 5b and 5c were obtained in yields of 93 and 95% within 1 h reaction time, respectively. The obtained results suggest that Q-tube safe reactor-assisted syntheses were led to higher product yields within very short reaction times.

Synthesis and biological activity of a new class of enaminonitrile pyrazole

The present work illustrates the treatment of 5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (1) with maleic, phthalic anhydrides, acetyl chloride, and benzene sulfonyl chloride to afford the pyrazole derivatives 2-5. The treatment of pyrazole derivative 1 with some active methylene reagents namely: malononitrile, cyanoacetamide, ethyl acetoacetate afforded the pyrazolopyridine 6-9. Reaction of compound 1 with acetic anhydride gave the pyrazolopyrimidinone 10, which was allowed to react with P2S5 and POCl3 to give the thione 11 and the chloro 12 derivatives. The reaction of compounds 11 and 12 with thiosemicarbazide under different conditions gave 13 and 14. Compound 12 when reacted with hydrazine hydrate and p-toluidine gave compounds 15 and 16. The reaction of compound 10 with ethyl chloroacetate gave compound 17 which was allowed to react with thiosemicarbazide to give 22 and also to consecutive reactions with hydrazine hydrate, carbon disulfide, piperidine, hydrazine hydrate to give compounds 18-21. Finally, compound 1 was reacted with chloroacetic acid, hydrated hydrazine, urea, thiourea, benzaldehyde and triethylamine to give compounds 23-29. The newly prepared compounds were characterized by using IR, 13C-NMR, 1H-NMR, and mass spectral data. Some new pyrazole derivatives showed highly antibacterial activities.

Synthesis and anticancer assessment of some new 2-amino-3-cyanopyridine derivatives

The 2-Aminonicotinonitrile derivative was reacted with different bi-functional reagents such as formamide, thiourea, acetic anhydride, and phthalic anhydride under optimized conditions to give pyrimidine, thiourea, acetamide, and isoindoline derivatives, respectively, When it was treated with active methylene reagents as malononitrile, phenacyl bromide, and ethyl bromoacetate under varied experimental modulation, it afforded 1, 8-naphthyridine, ethyl, and methylamino nicotinonitrile derivatives, respectively. Also, it was reacted with p-toluene sulfonyl chloride, chloroacetyl chloride, and benzoyl chloride to give sulfonamide, 2-chloro-N-acetamide, and benzamide derivatives, respectively. Likewise, it was reacted with diethyl malonate, ethyl cyanoacetate, and cyano acetic acid to give ethylpropanoate, naphthyridine, and cyano acetamide derivatives, respectively. However, treatment of ethylpropanoate and cyano acetamide derivatives with hydrazine hydrate gave pyrazole and 5-amino-pyrazole nicotinonitrile derivatives, respectively. In addition, it was reacted with p-anisaldehyde, phenyl isocyanate, and triethyl orthoformate to give benzylamino nicotinonitrile, phenyl urea, and N-formamide derivatives, respectively. Furthermore, it was reacted with nitrous acid then coupled with aniline; it was also reacted with isatine and 1,3- dibromo propane to give oxoindoline derivative, and the dimer. Elemental analyses, together with spectroscopic data including IR, 1H-NMR in addition to 13C-NMR and mass spectra submit proofs for the chemical structures for all compounds.

Synthesis of new pyrazoles, oxadiazoles, triazoles, pyrrolotriazines, and pyrrolotriazepines as potential cytotoxic agents

Abstract4‐Oxo‐4‐phenylbutanehydrazide (1) reacted with many active methylene reagents such as acetylacetone, diethylmalonate, ethylacetoacetate, ethylcyanoacetate, benzoyl‐acetonitrile, and malononitrile under neat conditions to afford the corresponding pyrazoles (2–7), also, treatment of butanehydrazide (1) with electrophilic reagents as triethylorthoformate, dimethylformamide‐dimethylacetal, acetic anhydride, and carbon disulfide to give 1,3,4‐oxadiazoles (8,10,11) and N′‐acetyl‐butanehydrazide (9). Reacted of butanehydrazide (1) with potassium thiocyanate gave 1,2,4‐triazoles (12). Similarly, treatment of (1) with chloroacetamide gave 1,2,4‐triazinones (13). The pyrrolotriazinones (14) was obtained by cyclization of (13). Also, butanehydrazide (1) was utilized as a starting material for the synthesized of new Schiff bases as N′‐(4‐sub‐benzylidene)‐phenylbutane‐hydrazide (15a‐c), which are used as an initiative to prepare new compounds such as 1,2,4‐triazepinones (16a‐c), pyrrolotriazepinones (17a‐c), 1,2,4‐triazines (18a‐c), and pyrrolotriazines (19a‐c) by reacted of (15a‐c) with each chloroacetamide or formamide. The chemical structure of the newly prepared compounds was determined through the spectrum data, including IR, NMR, and MS. The prepared compounds were tested for their in vitro antitumor activities. The compounds 17a‐c, 16a‐c, and 19a‐c displayed activity against several types of cancer cell lines.

Synthesis of Some New 1, 3, 4-Oxadiazole, Pyrazole, and Pyrimidine Bearing Thienopyrazole Moieties.

According to the literature survey, pyrazole is a unique template that is associated with several biological activities. This article highlighted the research work of many researchers reported in the literature for synthesis and different pharmacological activities of the pyrazole nucleus. In the present work, pyrazol- 3-one 1 was reacted with cyanoacetic acid hydrazide and elemental sulfur to afford the corresponding thieno[3,2-c]pyrazol-6-carbohydrazide 3 derivatives. The latter compound reacted with some electrophilic reagents such as DMF-DMA, triethylorthoformate, arylidenemalononitriles and chalcones under neat conditions to give substituted oxadiazole and pyrazole, respectively. The treatment of compound 3 with active methylene reagents such as acetylacetone, diethylmalonate, ethyl acetoacetate and ethyl cyanoacetate under suitable conditions afforded pyrazole derivatives 10, 11, 13, and 15, respectively. Novel pyrazolothienopyrimidine 27 and 30 were prepared from precursor 26 with carbon disulfide and triethylorthoformate, respectively. The chemical structures of the newly synthesized compounds were established by elemental and spectral analyses including IR, and 1HNMR in addition to 13C-NMR and mass spectra. A novel substituted pyrazole, pyrimidine and pyrazolothienopyrimidine were obtained via Gewald synthesis of thiophene and fused thiophene and Mannich reactions of 5-amino-3-phenyl-1Hthieno[ 3,2-c]pyrazole-6-carbohydrazide. A series of some newly azoles and azines were prepared via reaction of thieno[3,2- c]pyrazol-6-carbohydrazide derivative 3 as starting material with some electrophilic and nucleophilic reagents. The structures of target compounds were established by elemental analyses and spectral data. Pyrazole is a unique template that is associated with several biological activities. This article highlighted the research work of many researchers reported in the literature for synthesis and different pharmacological activities of the pyrazole nucleus. In the current investigation, we have developed new and efficient methods for the synthesis of thieno[3,2-c]pyrazol-6-carbohydrazide derivatives. In addition, we have explored the preparative potential of these substances as intermediates for the synthesis of substituted pyrazoles and fused pyrazoles 10-30, respectively.

An Eco-Friendly Synthesis of Some Novel Chromene-Based Heterocyclic Compounds of Biological Interest

The target chromonylchalcone 3-(3-(4-oxo-4H-chromen-3-yl)-acryloyl)-2H-chromen-2-one was synthesized by reacting 3-acetylcoumarin with 3-formylchromone. The chromonylchalcone was reacted with active methylene reagents, thiourea, hydrazines, aromatic amines, and sodium azide to afford new heterocyclic compounds. The newly prepared compounds were screened for their anti-microbial and anti-inflammatory activities.

Novel Pyrano[2,3‐d]thiazole and Thiazolo[4,5‐b]pyridine Derivatives: One‐pot Three‐component Synthesis and Biological Evaluation as Anticancer Agents, c‐Met, and Pim‐1 Kinase Inhibitors

AbstractPreparation of pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives through multicomponent reactions (MCRs) was achieved by the reaction of 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)thiazol‐4(5H)‐one with various active methylene reagents such as ethyl cyanoacetate or malononitrile in basic conditions containing diverse aromatic aldehyde. Furthermore, this study aims to evaluate the in vitro cytotoxic activity of the synthetic compounds against six cancer cell lines, and all the prepared compounds revealed valuable activity compared with the CHS‐828, which is the 2‐[6‐(4‐chlorophenoxy)hexyl]‐1‐cyano‐3‐pyridin‐4‐ylguanidine as the standard drug. Some of the pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives showed the highest antitumor activity towards the six cancer cell lines. Moreover, (c‐Met) enzymatic activity of the most potent compounds showed that compounds 3b 2‐(2‐amino‐4,5,6,7 tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐(2‐hydroxy‐phenyl)‐7H‐pyrano[2,3‐d]thiazole‐6 carbonitrile and 5e 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐phenyl‐4,7‐dihydrothiazolo[4,5‐b]pyridine‐6‐carbonitrile were with higher activities than foretinib. Three compounds were selected to examine their Pim‐1 kinase where compounds 3b and 7b showed the highest inhibitions.

Glycerol: A Promising Benign Solvent for Catalyst‐free One‐pot Multi‐component Synthesis of 1H‐Pyrozolo[1,2‐b]phthalazine‐5,10‐diones and 2H‐Indazolo[2,1‐b]phthalazine‐triones Under Controlled Microwaves Irradiation

A simple green and efficient one‐pot multi‐component synthesis of 1H‐pyrozolo[1,2‐b]phthalazine‐5,10‐diones and 2H‐indazolo[2,1‐b]phthalazine‐triones has been developed utilizing one‐pot multi‐component reaction of aromatic aldehydes, active methylene reagents, phthalic anhydride, and hydrazine hydrate or alternatively phthalhydrazide in glycerol without catalyst under controlled microwave heating. The current synthetic protocol offers several advantages such as excellent yields, high EcoScale and atom economy, simple working up reactants and products, and the absence of hazardous catalysts or solvents.

Polycyclic Aromatic Heterocycles with a Benzo[c][1,2]azaborinine Core

2‐Formylphenylboronic acid condenses with active methylene reagents like α‐amino esters, ketones, and lactams directly to give benzo‐fused 1‐hydroxy‐2,1‐azaborines in good yields within minutes under microwave‐accelerated conditions. The new stable boron heterocycles prepared to demonstrate this approach were characterized by NMR spectroscopy. Three members of a new diboron heteropentacyclic ring system, 5a,12a‐diaza‐5,12‐dibora‐5,12‐dihydroxypentacene‐6,13‐dione, were prepared, and one of these highly fluorescent compounds was characterized by X‐ray crystallography. Some key solid‐state structural features revealed by the X‐ray analysis provide a basis for explaining the limited solubility of these pentaheterocycles in common organic solvents.

A new direction in the alkylation of 5‐acetyl‐2‐amino‐6‐methyl‐4‐phenyl‐4H‐pyran‐3‐carbonitrile with active methylene reagents

In this paper, we report a new synthesis route to 4H‐pyran derivatives and a plausible reaction mechanism. The interaction of 5‐acetyl‐2‐amino‐6‐methyl‐4‐phenyl‐4H‐pyran‐3‐carbonitrile with different active methylene reagents gives rise to the cleavage and subsequent recyclization of the pyran ring to afford the corresponding 4H‐pyran derivatives.

-Oxo anilides in Heterocyclic Synthesis: Novel Synthesis of Pyridazinones, Pyrazolopyridazines, and Cinnolines

Compound 1 coupled smoothly with aromatic diazonium salts to yield the corresponding arylhydrazones 2a-d. Compounds 2a-d condensed with DMF-DMA in refluxing xylene to yield the pyridazinones 3a-d. Compounds 3a-d were also established based on its further reaction with some active methylene reagents and some nucleophilic reagents. So, reactions of 3a, b with malononitrile in refluxing ethanolic piperidine afforded arylidinemalononitrile 4a,b. The pyridazinone derivatives 3a, b reacted with hydrazine hydrate to afford the hydrazine derivatives 5a, b. When 3a,b were fused with hydrazine hydrate without solvent, the pyrazolo[4,3-c]-pyridazines 6a,b were obtained. Compounds 6a, b were also obtained when compounds 5a, b melt over melting point for short time. Condensation of 2a, b with ethyl cyanoacetate yield 7a, b. Similarly, reactions of 2a,b with 1 mole of malononitrile afforded the pyridazine derivatives 8a,b. While, when 2 moles of malononitrile reacted with 2a, b in the same experimental conditions to yield the cinnoline derivative (9a, b). Reactions of pyridazine 8a,b with 1 mole of malononitrile afforded 9. Compound 2b was reacted with a mixture of arylidinemalononitrile and acrylonitrile to yield product formulated as triazole moieties 12a, b. Similarly, compound 2b was reacted with a mixture of maleic anhydride and acrylonitrile in the same above experimental conditions to give 13. Also, reactions of 2b with hydroxylamine hydrochloride yield 14.

One-pot solvent-free synthesis of pyranonaphthoquinone-fused spirooxindoles catalyzed by SBA-IL

In this research article, ionic liquid modified SBA-15 mesoporous material (SBA-IL) as a recyclable, heterogeneous catalyst efficiently catalyzed the synthesis of pyranonaphthoquinone-fused spirooxindoles through the one-pot three-component reaction of isatin derivatives, activated methylene reagents, and 2-hydroxy-1,4-naphthoquinone. The reactions were performed under microwave irradiation and solvent-free conditions. The synthesized SBA-IL was characterized by SEM, FT-IR, nitrogen adsorption-desorption, and thermogravimetric analyses. Excellent chemical yields, short reaction times, mild reaction condition, easy workup procedures and reusability of catalyst are noteworthy advantages of this protocol.

Synthesis, Anticancer Screening and Molecular Docking Studies of New Heterocycles with Trimethoxyphenyl Scaffold as Combretastatin Analogues.

In this study, synthesis, molecular docking and anticancer screening of new series of substituted heterocycles with trimethoxy phenyl scaffold as Combretastatin analogues were described. Substituted pyridines were synthesized via the reaction of (E)-3-(dimethylamino)-1-(3,4,5- trimethoxyphenyl)prop-2-en-1-one (2) with active methylene reagents. Substituted pyrimidines were prepared by the reaction of the enaminone (2) with heterocyclic amines and 6-amino thiouracil. Furthermore, a series of pyrazoles substituted with trimethoxyphenyl scaffold were prepared by the reaction of the enaminone 2, with selected examples of hydrazonoyl halides. The cytotoxic effect of the newly compounds was evaluated against HePG-2, HCT-116, MCF-7 and PC3 cancer cell lines. Among the new products, compounds 2, 3, 7 and 10 were found to exhibit promising results as anticancer agents. The IC50 values of 2, 3 and 7 were 54.6, 77.4 and 47.4 on PC3 respectively. Also, compound 2 had IC50 28.06 on MCF7. Moreover, the selectivity index indicated that compounds 2 and 3 are safe.