N-1-Naphthyl-3-oxobutanamide in Heterocyclic Synthesis: A Facile Synthesis of Nicotinamide,Thieno[2,3-b]pyridine,and Bi- or Tricyclic Annulated Pyridine Derivatives Containing Naphthyl Moiety

N-1-Naphthyl-3-oxobutanamide (1) reacts with arylidinecyanothioacetamide 2a–c in ethanol/piperidine solution under reflux to yield the pyridine-2(1H)-thiones 6a–c. Compound 6a reacts with α-haloketones 7a–e to give the 6-thio-N-1-naphthyl-nicotinamides derivatives 8a–e, which cyclized to thieno[2,3-b]pyridine derivatives 9a–e. The reaction of compound 9a with hydrazine hydrate and formamide gives the thieno[2,3-b]pyridine carbohydrazide derivative 10 and pyridothienopyrimidine derivative 11, respectively. Reaction of 9a with benzoyl isothiocyanate gave thiourea derivative 12. Compound 12, upon treatment with alcoholic NaOH, gave pyridothienopyrimidine 13. Saponifications of 9a gave the amino acid 15, which affords 16 when refluxed in Ac₂O. Treatment of compound 16 with AcONH₄/AcOH gave 17. Diazotization and self-coupling of 9b gave the pyridothienotriazine 18. Also, diazotization of the ortho-aminohydrazide 10 give the corresponding azide 19, which was subjected to Curtius rearrangement in boiling xylene to give imidazothienopyridine 20. Reaction of 10 with either formic acid or triethylorthoformate and phenyl isothiocyanate gave the corresponding pyridothienotriazepines 22 and 23, respectively. The interaction of 10 with acetylacetone furnished the pyrazolyl derivative 24. The structures of the synthesized compounds were established from their analytical and spectral data.     

One-Pot Solvent-Involved Synthesis of 5-O-Substituted 5H-Chromeno[2,3-b]pyridines

Chromeno[2,3-b]pyridines are substances demanded in medicinal and material chemistry. PASE (pot, atom, and step economy) and in particular one-pot approaches are key green chemistry techniques that are applied for the synthesis of heterocyclic compounds. In this case, the PASE approach was extended with ‘component economy’, as solvent was used also as reactant (solvent-involved reaction). This approach was adopted for the one-pot synthesis of previously unknown O-substituted 5-alkoxy-5H-chromeno[2,3-b]pyridines via two-step transformation, namely the reaction of salicylaldehydes and malononitrile dimer, with the subsequent addition of alcohol. The mechanistic studies revealed the possibility of concurrent reaction. The studies aided in optimizing the reaction conditions for the best yields (77–93%). Thus, the one-pot reaction proceeds efficient and quickly, and the work-up procedure (only simple filtering) is very convenient. The structure of synthesized chromeno[2,3-b]pyridines was confirmed by 2D NMR spectroscopy.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Synthesis and Properties of Substituted Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines

We synthesized derivatives of a novel heterocyclic system, isoxazolo[3',4':4,5]thieno[2,3-b]pyridine by sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by -halomethyl ketones in alkaline medium, to form 3-aminothieno[2,3-b]pyridines; diazotization of the amino group followed by nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the diazonium salts; and thermolysis of the azides formed.     

噻吩并[2,3-b]吡啶化合物的合成及应用

噻吩并[2;3-b]吡啶;生物活性;医药;农药;合成     

Synthesis of certain pyrrolo[2,3-b]pyridine-5-carboxylic acid derivatives as potential antimicrobial agents

Summary A synthetic approach to new 1-benzyl-7-alkyl-2,3-dimethyl-4-oxopyrrolo[2,3-b]pyridine-5-carboxylic acids using 5,6-dimethyl-2,4-dioxopyrrolo[2,3-d][1,3]oxazine as the starting material is reported. The antimicrobial activity of these compound is reported.

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Synthese von Pyrrolo[2,3-b]pyridin-5-carbonsäure-Derivaten als potentielle antimikrobielle Substanzen

Zusammenfassung Die Synthese von neuen 1-Benzyl-7-alkyl-2,3-dimethyl-4-oxopyrrolo[2,3-b]pyridin-5-carbonsäuren durch Verwendung von 5,6-Dimethyl-2,4-dioxopyrrolo[2,3-d][1,3]oxazinen als Ausgangsmaterial wird beschrieben. Die antimikrobielle Aktivität dieser Substanzen wurde geprüft.

     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

Pyrazolo[3,4-b]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1H- and 2H-isomers. More than 300,000 1H-pyrazolo[3,4-b]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds.     

Synthesis,in-vitro antibacterial and anticancer screening of novel nicotinonitrile-coumarin hybrids utilizing piperazine citrate

Abstract

An efficient, low-cost, high yield% and eco-friendly synthetic procedure is designed for the synthesis of novel series of nicotinonitrile-coumarin hybrid molecules bearing several aryl and/or heteroaryl moieties. Our strategy includes the synthesis of a novel series of 2-hydroxybenzaldehydes, bearing nicotinonitrile moiety, followed by its Knoevenagel reaction with ethyl acetoacetate in the presence of an organo-base. The above reaction is studied in different reaction conditions. The optimized conditions are performing the reaction in ethanol at 80?°C in the presence of 10?mol% of piperazine citrate (1:1). The in-vitro antibacterial activities of the nicotinonitrile-coumarins were evaluated against different Gram-positive and negative bacterial strains. Moreover, the in-vitro cytotoxicity of nicotinonitrile-coumarins were estimated against different eukaryotic cell lines. Compounds 5a and 5b exhibited the most promising antibacterial agents among the novel series. The structures of novel series of the target nicotinonitrile-coumarin hybrid molecules were confirmed by considering their elemental analyses and spectral data.     

Synthesis of New 2-[(Substituted-pyrazolin-1-yl)carbonyl]-thieno[2,3-b]pyridine Derivatives

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate chalcones 2a-2d in the presence of acid catalyst produced the corresponding 3-amino-2-[(3,5-disubstituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d . 3-Amino-2-[(3-substituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 7a, 7b were also obtained by the cyclization reaction of carbohydrazide 1 with Mannich base derivatives 6a, 6b under basic condition.     

Synthesis and cytotoxicity of new 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid amides

Abstract

The synthesis and anticancer activity evaluation of new thiazolo[4,5-b]pyridine-5-carboxylic acid amides is described. The structures of the synthesized compounds were confirmed by spectroscopic data and a single crystal X-ray diffraction analysis for 2.4. The synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The most active 7-(4-fluorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)amide 2.2 and 7-(4-chlorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)amide 2.5 were screened for their cytotoxicity effects on C6 Rat glioma cells and U373 Human glioblastoma astrocytoma cells which revealed promising results comparable to temozolamide as reference control according MTT assay data.     

Synthesis and characterisation of thieno[3,2-b]thiophene-based linear shaped liquid crystals

A series of thieno[3,2-b]thiophene-based liquid crystalline molecules has been synthesised. To investigate the effects of alkyl substituent groups and structure of mesogenic cores, eight kinds of thieno[3,2-b]thiophene-based molecules containing different alkyl substituent groups and mesogenic cores have been synthesised. These molecules were characterised by differential scanning calorimetry, polarising optical microscopy, ultraviolet–visible absorption spectroscopy, fluorescence spectroscopy, cyclic voltammetry and polarised fluorescence spectroscopy. The results indicated that the thieno[3,2-b]thiophene-based donor-acceptor-donor (D-A-D) type molecules showed the presence of a smectic A phase. Changes in the length of alkyl substituents and mesogenic cores affected the phase transitions, optical and electrochemical properties of the molecules.     

Synthesis and structure of N-methylated azacalix[4]pyridines and azacalix[1]arene[3]pyridines

Reaction of azacalix[4]pyridine and azacalix[1]arene[3]pyridine with methyl iodide afforded N-methylated products selectively and highly efficiently. Crystal structures revealed that the modified electronic nature of the pyridines could change the conjugation between the bridging nitrogen and the neighbouring aromatics.     

1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

Synthesis of novel triazolothione,thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives and their antimicrobial activity

A series of novel triazolothione, thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives 9a–l, respectively, were prepared starting from 2 (1H) pyridone 3 through selective O/S-alkylation followed by Thorpe–Ziegler cyclization to form furo/thieno[2,3-b]pyridine derivatives 6. Compounds 6 on reaction with hydrazine hydrate resulted carbohydrazide derivatives 7 and further reacted with diverse substituted phenyl isothiocyanates to form phenyl hydrazine carbothiamide derivatives 8. Each compound 8 is independently reacted in presence of NaOH, H₂SO₄, and N₂H₄.H₂O to form triazolothione, thiadiazole, triazole-functionalized furo/thieno[2,3-b]pyridine derivatives 9a–l, respectively. All the products 9a–l were screened against Gram +ve, Gram –ve bacteria and fungal strains. Compounds 9c–h showed high activity against Bacillus subtilis microbial-type culture collection (MTCC) 121 at <8.0 micromolar concentration. Promising compounds further screened for minimum bactericidal concentration against B. subtilis MTCC 121 using ciprofloxacin as standard and found to show very good activity. These compounds also screened for biofilm inhibition activity against B. subtilis MTCC 121 using erythromycin as standard and confirmed the high activity.     

Synthesis,Reactions, and Characterization of 6-Amino-4-(Benzo[b]Thiophen-2-YL)-2-Thioxo-1, 2-Dihydropyridine-3, 5-Dicarbonitrile

Abstract

Benzothiophene -2- carbaldehyde 1 reacted with 2-cyanoethanethioamide 2 in 1:2 molar ratios to give the corresponding 6-amino-4-(benzo[b]thiophen-2-yl)-2-thioxo-1, 2-dihydropyridine-3,5-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents to afford the corresponding thieno[2,3-b]pyridine derivatives 11a,b, 14, 16, and 19. Also, compound 6 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 21. Compound 21 condensed with 4-(2-thienyl)benzaldehyde to afford pyrazolo[3,4-b]pyridine derivative 23. Structural elucidation of all the newly synthesized heterocyclic compounds was based on elemental analyses, IR, ¹H NMR, and mass spectra.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines

Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b–f and 4e. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABA_A) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c–f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.     

Phenyl isothiocyanate in heterocyclic synthesis: Novel synthesis of thiazoles,thieno[2,3-b]pyridine,thiophene and thieno[3,2-c]pyridazine derivatives

Summary The enamino nitriles1 and2 react with phenyl isothiocyanate followed by cyclization with -haloketones3 and10 to afford in each case the thiazole5, thiophene11 and the thieno[2,3-b]pyridine derivatives19 and21. Chemical and spectroscopic evidences for the structures of the new compounds are described.

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Phenylisothiocyanate in der Heterocyclensynthese: Neue Synthesen für Thiazol-, Thieno [2,3-b]pyridin-, Thiophen- und Thieno[3,2-c]pyridazin-Derivate

Zusammenfassung Die Enamin-nitrile1 und2 ergaben nach Reaktion mit Phenylisothiocyanaten und nachfolgender Cyclisierung mit -Halogenketonen3 und10 die entsprechenden Thiazole5, die Thiophene11 und die Thieno[2,3-b]pyridine19 und21. Chemische und spektroskopische Untersuchungen wurden als Strukturbeweise für die neuen Verbindungen herangezogen.