SYNTHESIS AND REACTIONS OF SOME NEW HETEROCYCLIC COMPOUNDS CONTAINING THE THIENYLTHIENO[2,3-B]PYRIDINE MOIETY

(4-Aryl-3-cyano-6-(2-thienyl)pyridin-2-ylthio)acethydrazides (5a–c), 3-amino-4-aryl-6-(2-thienyl)thieno[2,3-b]pyridine-2-carbohydrazides (6a–c) and 3-amino-4-phenyl-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylic acid (30) were prepared and employed as key intermediates in the synthesis of the title compounds.     

Pyridine-2(1H)-thione in Heterocyclic Synthesis: Synthesis of Some New Nicotinic Acid Ester,Thieno[2, 3-b]pyridine,Pyrido[3′, 2′: 4, 5]thieno [3, 2-d]pyrimidine,and Thiazolylpyrazolo[3, 4-b]pyridine Derivatives

Nicotinic acid esters 3a–c were prepared by the reaction of pyridine-2(1H)-thione derivative 1 with α-halo-reagents 2a–c. Compounds 3a–c underwent cyclization to the corresponding thieno[2, 3-b]pyridines 4a–c via boiling in ethanol/piperidine solution. Compounds 4a–c condensed with dimethylformamide-dimethylacetal (DMF-DMA) to afford 3-{[(N,N-dimethylamino)methylene]amino}thieno[2, 3-b]- pyridine derivatives 6a–c. Moreover, compounds 4a–c and 6a–c reacted with different reagents and afforded the pyrido[3′,2′:4, 5]thieno[3, 2-d]pyrimidine derivatives 10a–d, 11a–c, 12a,b, 14a,b, 17, and 19. In addition, pyrazolo[3, 4-b]pyridine derivative 20 (formed via the reaction of 1 with hydrazine hydrate) reacted with ethylisothiocyanate yielded the thiourea derivative 21. Compound 21 reacted with α-halocarbonyl compounds to give the 3-[(3H-thiazol-2-ylidene)amino]-1H-pyrazolo[3, 4-b]pyridine derivatives 23a–c, 25, and 27a,b.     

Cyanothioacetamide in Heterocyclic Chemistry: Synthesis of Thiopyran,Pyridinethione, Thienopyridine,Pyridothienotriazine and Pyridothienopyrimidine Derivatives

Abstract

Cyanothioacetamide (1) reacted with α- and β-naphthaldehyde 2a,b to afford the corresponding 3-naphthyl-2-thiocarboxamidopropenonitriles 3a,b. Compounds 3a,b structures could be elucidated via their reactions with acrylonitrile, ethyl acrylate (4a,b). N-arylmaleimides 6a-c and ethyl acetoacetate (8). The isolated products could be represented as the thiopyran, thiopyranopyrrolidine and pyridinethione derivatives 5a-d, 7a-f and 9a,b respectively. Pyridinethiones 9a,b had been used as the starting materials in the present study in addition to the next ones to synthesize several new thienopyridines, pyridothienotriazine and pyridothienopyrimidines 12a-f, 15a,b, 16b, 17–19a,b respectively through their reactions with the corresponding reagents.

All structures of the newly synthesized heterocyclic compounds were established on the basis of the data of IR, ¹H NMR and elemental analyses.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Simple Analogues of Acyclonucleosides: Synthesis of N‐Substituted Pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine Derivatives

The synthesis of N‐substituted pyridothienopyrimidines bearing ethoxymethyl, benzyloxymethyl, methylthiomethyl, benzoylmethyl, allyl, sec‐butyl, and 2‐acetyloxyethyl chains as a sugar mimic was described. The O‐substituted pyridothienopyrimidines were obtained during some reactions.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

One-pot synthesis of 4,6-diaryl-3-cyanopyridine-2(1H)-thiones and their transformation to substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3",2":4,5]thieno[3,2-d]pyrimidines

4,6-Diaryl-3-cyanopyridine-2(1H)-thiones were synthesized in one step by the reaction of elemental sulfur, malononitrile, and 2-aryl-1-aroylethylenes in the presence of excess triethylamine. The products were used in one-pot syntheses of substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3",2":4,5]thieno[3,2-d]pyrimidines.     

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW PYRIDO[3′,2′:4,5]THIENO[3,2-d]- PYRIMIDINE DERIVATIVES

5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides (1a, b) were reacted with aromatic aldehydes or with some cycloalkanones to give the corresponding tetrahydropyridothienopyrimidinone derivatives 2a–f and 4a–d . The reaction of compound 1b with urea and/or carbon disulfide has been carried out and their products were identified. Some representative compounds were screened in vitro for their antimicrobial activities.