Synthesis,cytotoxicity, in-vitro antibacterial screening and in-silico study of novel thieno[2,3-b]pyridines as potential pim-1 inhibitors

Abstract

A novel series of thieno[2,3-b]pyridines was prepared via an one-step protocol in excellent yields. The protocol involved the reaction of pyridine-2(1H)-thiones with the appropriate halogen containing reagents in ethanolic sodium ethoxide solution under stirring at 80?°C for 2?h. The new thienopyridines were screened against different bacterial and fungal strains. Thieno[2,3-b]pyridine-2-carboxylate 9a showed the most effective antibacterial activities against each of Staphylococcus aureus and Escherichia coli with MIC/MBC values of 9.9/19.8 and 19.8/39.5?µM, respectively, when compared with Ciprofloxacin. 9a was the most effective compound against MRSA with inhibition zone of 16.2?±?0.6?mm, when compared with Gentamicin. Moreover, 9a exhibited the best cytotoxic activity against each of HEPG2 and MCF-7 cell lines with IC₅₀ values of 25.7 and 30.53?µM, respectively, when compared with Doxorubicin. The in-silico study was performed to predict the capability of new thienopyridines as potential inhibitors of pim-1 kinase.     

Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing quinoline ring and evaluation of their antimicrobial activity

Abstract

Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their antimicrobial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl 2-chloroacetate. The obtained ester compound (1) first reacted with hydrazine hydrate (2) then with phenyl isothiocyanate (3). Ring closure by KOH led to 3-mercapto-1,2,4-triazole derivative (4). Lastly, it reacted with 2-chloro-N-(substituted (benzo)/thiazole)acetamide derivatives to obtain the final compounds (5a–j). The structural elucidation of the compounds was performed by ¹H NMR and ¹³C NMR spectroscopy and high resolution mass spectrometry techniques and elemental analysis. The synthesized compounds were investigated for their antimicrobial activities against seven bacteria and four fungi. As a result of the activity studies, it was observed that compounds N-(6-nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5a) and N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5d) were the most active molecules. Also, the antifungal activity of the compounds was found to be higher than their antibacterial activity although lower than the standard drug’s potential. Additionally, the physicochemical properties of the compounds were calculated which were evaluated to be at a suitable range for oral administration.     

Convenient synthesis and anticancer evaluation of novel pyrazolyl-thiophene,thieno[3,2-b]pyridine,pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine derivatives

The newly synthesized 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was utilized as a precursor for the synthesis of pyrazolyl-thiophene derivative, which undergoes cyclization upon treatment with benzaldehyde derivatives to provide pyrazolo[3,4-d]thieno[3,2-b]pyridines. Basic treatment of pyrazolyl-thiophene derivative with phenyl isothiocyanate followed by subsequent addition of chloroacetone and/or ethyl bromoacetate yielded the thiazolylidene-pyrazolyl thiophenes. In addition, the building block 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was converted into the corresponding thieno[3,2-b]pyridine compounds through its reactions with (DMF-DMA) and/or heating in sodium ethoxide. Moreover, the reaction of 7-hydroxy-5-oxo-N-phenyl-2-(phenylamino)-4,5-dihydrothieno[3,2-b]pyridine-3-carboxamide with 2-arylidenemalononitrile produced the new annulated pyrano[2,3-d]thieno[3,2-b]pyridines. The prepared thiophene-based compounds were evaluated against HepG2, PC3, and MCF-7 cancer cells, and normal fibroblast cell (WI38). The pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine compounds substituted with chlorophenyl group presented promising cytotoxic activities against HepG2 cancer cell line without any human toxicity. Docking study for the synthesized thiophene compounds delivered valuable insights about the binding interactions with the crystal structure of NS5B enzyme with PDB ID (4TLR).     

Furopyridines. XIV. Synthesis of 2-aminoalkyl derivatives of furo[2,3-b]-, furo[3,2-b], furo[2,3-c]- and furo[3,2-c]pyridine

The preparation of 2-aminomethyl- 3a-d , 2-acetamidomethyl- 4a-d , 2-N,N-dimethylaminomethyl- 5a-d , 2-(1-hydroxy-2-nitroethyl)- 6a-d , 2-(1-hydroxyl-2-aminoethyl)- 7a-d and 2-(1-hydroxy-2-N,N-dimethylaminoethyl)- 8b-d derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine is described.     

6-取代-3-（3，4，5-三甲氧基苯基）-1，2，4-三唑[3,4-b][1,3,4]噻二唑的合成与生物活性

以3,4,5-三甲氧基苯甲酸为原料,通过4步反应得到4-氨基-5-(3,4,5-三甲氧基苯基)-3-巯基-1,2,4-三唑,再与取代芳酸反应,得到11个6-取代-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑衍生物5a～5k。其结构经IR,1H NMR,MS和元素分析确证。初步生物活性测试结果表明部分化合物有一定的杀菌活性。     

含双-三唑并噻二唑环的庚烷类衍生物的合成及抗菌活性

The aroylhydrazides were prepared by esterification and hydrazinolysis of corresponding aromatic carboxylic acids.The reaction of aroylhydrazides with CS2/KOH in absolute ethanol gave potassium aroyldithiocarbazates and then hydrazinolysis of potassium aroyldithiocarbazates with hydrazine hydrate afforded 3-aryl-4-amino-5-mercapto-1,2,4-triazoles(1a～1g).New seven compounds of bis[(3-aryl)-s-triazolo[3,4-b]-[1,3,4]thiadiazole derivatives(2a～2g) were synthesized in high yields by cyclization of nonanedioic ac...     

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.     

Synthesis and antiviral activity of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties

A series of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties were designed and synthesized. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR, Infrared, and elemental analysis. The results of bioactivity analysis showed that most of the target compounds exhibited moderate to good antiviral activity against tobacco mosaic virus at a concentration of 500 mg/L. Especially, among the title compounds, Y2, Y8, and Y10 possessed appreciable curative activity in vivo, with inhibition rates of 50.51, 52.08, and 54.62%, respectively, which were similar to that of Ningnanmycin (53.40%).     

Synthesis of Pyrazolo[3,4-b]- and Pyrido[2,3-b]-1,5-benzodiazepines

Abstract

3-Dimethylaminomethyleno-4-phenyl-1H-1,5-benzodiazepin-2-one (1) was synthesized and reacted with hydrazines, active nitriles, and amino-heterocyclic compounds to give fused heterocyclic compounds 2–14.     

Synthesis,characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety

The synthesis and antimicrobial activity of 2,4-thiazolidinedione derivatives 5a–g and 6a–g are described. The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analyses. All compounds were evaluated for their preliminary in vitro antibacterial and antifungal activity. The results revealed that most of the compounds showed high or moderate biological activity against tested microorganisms.     

Synthesis and Pharmacological Evaluation of Some Novel Imidazo[2,1-b][1,3,4]thiadiazole Derivatives

Synthesis of bis‐1,3‐{6′‐arylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl}‐1,2,2‐trimethylcyclopentane ( 3 ), bis‐1,3‐{thiadiazolo[2′,3′:2,1]imidazo[4,5‐b]quinoxalinyl}‐1,2,2‐trimethylcyclopentane ( 5 ) has been achieved by the reaction of bis‐(5′‐amino‐1′,3′,4′‐thiadiazolyl)‐1,2,2‐trimethylcyclopentane with α‐haloketones, 2,3‐dichloroquinoxaline respectively. Bromination of compound 3 furnished bis‐1,3‐{5′‐bromo‐6′‐arylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl}‐1,2,2‐trimethylcyclopentane ( 4 ). The structural assignment of these compounds was supported by IR, ¹H NMR and elemental analysis data. The antimicrobial, anti‐inflammatory and antifungal activities of some of the compounds have also been evaluated.     

Synthesis,anticancer activity and molecular docking studies of novel pyrido[1,2-a]pyrimidin-4-one derivatives

A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.     

Synthesis of pyrazolo[3,4-c]isoquinoline and pyrazolo[3,4-b]pyridine derivatives from azomethines and CH-acidic compounds

Summary Donor substituted arylidene aminopyrazoles1a–c and CH-acidic 1,3-dicarbonyl compounds2a–e give in ethanol in an addition/cyclization reaction pyrazolo[3,4-c]isoquinolines4a–i and pyrazolo[3,4-b]pyridine derivatives5a,b, respectively. Using ethyl cyanoacetate as CH-acidic component, cinnamate6 and the cyano substituted pyrazolo[3,4-b]pyridine7 are formed.

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Synthese von Pyrazolo[3,4-c]isochinolin- und Pyrazolo[3,4-b]pyridin-Derivaten aus Azomethinen und CH-aciden Verbindungen

Zusammenfassung Die Reaktion der donorsubstituierten Aryliden-aminopyrazole1a–c mit den CH-aciden 1,3-Dicarbonylverbindungen2a–e führt in einer Additions/Cyclisierungsreaktion zu den Pyrazolo[3,4-c]isochinolin-4a–i bzw. Pyrazolo[3,4-b]pyridin-Derivaten5a,b. Verwendet man Cyanessigester als CH-acide Komponente, werden der Zimtsäureester6 und das cyanosubstituierte Pyrazolo[3,4-b]pyridin7 gebildet.

     

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.

     

Synthesis and Antimicrobial Activity of Some Condensed [4‐(2,4,6‐Trimethylphenyl)‐1(2H)‐oxo‐phthalazin‐2‐yl]acetic Acid Hydrazide

Some new 1,2,4‐triazolo‐, 1,3,4‐oxadiazolo‐, 1,3,4‐thiadiazol‐, and pyrazolo‐2,4,6‐trimethylphenyl‐1(2H)‐oxo‐phthalazine derivatives were synthesized and identified by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The new compounds were synthesized with the objective of studying their antimicrobial activity.     

新型咪唑[2,1-b][1,3,4]噻二唑衍生物的合成及生物活性

合成了18个新型含苯并噁/噻唑啉酮结构的2,6-二取代咪唑[2,1-b][1,3,4]噻二唑衍生物5a~5i', 即2-[(2-苯并噁/噻唑啉酮-3-基)甲基]-6-芳基-咪唑[2,1-b][1,3,4]噻二唑. 利用红外光谱、 核磁共振和元素分析对化合物的结构进行了表征. β2-肾上腺素受体(β2-AR)拮抗剂钙流筛选结果表明, 部分目标化合物对β2-AR具有明显的拮抗作用, 其中化合物5c'的拮抗效果最高, 为70%. 这些化合物可作为潜在的β2-AR拮抗剂.     

Synthesis,crystal structure,and FET characteristics of thieno[2,3-b]thiophene-based bent-thienoacenes

Two novel bent-shaped thienoacenes, naphtho[2,3-b]naphtho[2′,3′:4,5]thieno[3,2-d]thiophene (bent-DNTT) and anthra[2,3-b]anthra[2′,3′:4,5]thieno[3,2-d]thiophene (bent-DATT) were synthesized from thieno[2,3-b]thiophene and their corresponding aromatic anhydrides by three steps: Friedel–Crafts acylation, acid-promoted cyclization, and reductive aromatization. The structural curvature improved the solubility of these thienoacenes in organic solvents. The bent-DNTT based FET device was fabricated by the spin-coating method. The device exhibited p-type characteristics with a mobility of 5.1 × 10^?5 cm² V^?1 s^?1. Its thin-film structure was fully characterized as an edge-on orientation with large intermolecular orbital coupling.     

Synthesis of bifunctional thieno[3,2-c]pyrazole,pyrazolothieno[2,3-d]pyrimidin derivatives and their antimicrobial activities

A simple and convenient route was performed for the synthesis of some new heterocyclic compounds based on thieno[3,2-c]pyrazole derivative for antimicrobial evaluation. The key intermediate, 5-amino-3-methyl-1-phenyl-1H-thieno[3,2-c]pyrazole-6-carbohydrazide 3, was prepared by Gewald’s synthesis of Ethyl 5-amino-3-methyl-1-phenyl-1H-thieno[3,2-c]pyrazole-6-carboxylate 2. This intermediate reacted with various reagents to afford different fused and polyfunctional substituted. The structures of these compounds were confirmed by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data. All the new synthesized compounds were screened for various microorganisms such as Aspergillus fumigatus; Geotrichum candidum; Syncephalastrum racemosum (Fungus); Candida albicans (Yeast fungus); Staphylococcus aureus; Bacillus subtilis (as Gram-positive bacteria); Pseudomonas aeruginosa and Escherichia coli (as Gram-negative bacteria) by the disc diffusion method. In general, the novel synthesized compounds possessed moderate to high antimicrobial activity against the previously mentioned microorganisms.