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Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299385


An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors.

Alcaloides/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Inibidores Enzimáticos/farmacologia , Indóis/química , Biofilmes/efeitos dos fármacos , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Piridinas/química
Molecules ; 26(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199910


Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Molecules ; 26(2)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477568


This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin (benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

Cumarínicos/química , Compostos Heterocíclicos/síntese química , Hidrocarbonetos Aromáticos/síntese química , Pironas/química
Acta Pharm ; 62(2): 157-79, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22750815


A series of 1-(N-substituted-1H-indol-3-yl)-3-arylprop-2-ene-1-ones (2a, b-4a, b) were prepared and allowed to react with urea, thiourea or guanidine to give pyrimidine derivatives 5a, b-13a, b. Reaction of 2a, b-4a, b with ethyl acetoacetate in the presence of a base gave cyclohexanone derivatives 14a, b-16a, b. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 17a, b-19a, b. On the other hand, reaction of 2a, b-4a, b with some hydrazine derivatives, namely hydrazine hydrate, acetyl hydrazine, phenylhydrazine and benzylhydrazine hydrochloride, led to the formation of pyrazole derivatives 20a, b-31a, b. Moreover, reaction of 2a, b-4a, b with hydroxylamine hydrochloride gave isoxazole derivatives 32a, b-34a, b. The newly synthesized compounds were tested for their antimicrobial activity and showed that 4-(N-ethyl-1H-indol-3-yl)-6-(p-chlorophenyl)-pyrimidine-2-amine (11b) was the most active of all the test compounds towards Candida albicans compared to the reference drug cycloheximide. Eighteen new compounds, namely pyrimidin-2(1H)-ones 5a, b-7a, b, pyrimidin-2(1H)-thiones 8a, b-10a, b and pyrimidin-2-amines 11a, b-13a, b derivatives, were tested for their in vitro antiproliferative activity against HEPG2, MCF7 and HCT-116 cancer cell lines. 4-(N-ethyl-1H-indol-3-yl)-6-(p-methoxyphenyl)-pyrimidin-2-amine (11a) was found to be highly active with IC(50) of 0.7 µmol L⁻¹.

Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Indóis/síntese química , Indóis/farmacologia , Anti-Infecciosos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Cicloexanonas/síntese química , Cicloexanonas/química , Cicloexanonas/farmacologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Indóis/química , Concentração Inibidora 50 , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Neoplasias/tratamento farmacológico , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
Acta Pharm ; 62(1): 15-30, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22472446


Starting from N-substituted indole-3-carboxaldehydes (1a-g) a series of new 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles (3a-g and 4a-g) have been synthesized via the acid catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone, followed by the reaction with arylidene malononitriles. A series of new 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles (7a-g) have been prepared either via the base catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone to give 6a-g, followed by the reaction with malononitrile or by the reaction of N-substituted-3-indolylidene malononitriles (5a-g) with 3-amino-5-pyrazolone. According to the obtained results, the newly synthesized compounds possess significant anti-inflammatory, analgesic and anticonvulsant activities. The anticonvulsant potency of certain tested compounds was more pronounced than both anti-inflammatory and analgesic activities. Moreover, most of the newly synthesized compounds possess potential antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa.

Nitrilas/síntese química , Nitrilas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Benzoquinonas , Carragenina , Química Farmacêutica , Modelos Animais de Doenças , Estimulação Elétrica , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Feminino , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Camundongos , Estrutura Molecular , Dor/induzido quimicamente , Dor/prevenção & controle , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Ratos , Convulsões/etiologia , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Tecnologia Farmacêutica/métodos
Acta Pharm ; 60(1): 55-71, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20228041


Starting from 1-benzyl- (2a) and 1-benzoyl-3-bromoacetyl indoles (2b) new heterocyclic, 2-thioxoimidazolidine (4a, b), imidazolidine-2,4-dione (5a, b), pyrano(2,3-d)imida-zole (8a, b and 9a, b), 2-substituted quinoxaline (11a, b-17a, b) and triazolo(4,3-a)quinoxaline derivatives (18a, b and 19a, b) were synthesized and evaluated for their antimicrobial and anticancer activities. Antimicrobial activity screening performed with concentrations of 0.88, 0.44 and 0.22 microg mm(-2) showed that 3-(1-substituted indol-3-yl)quinoxalin-2(1H)ones (11a, b) and 2-(4-methyl piperazin-1-yl)-3-(1-substituted indol-3-yl) quinoxalines (15a, b) were the most active of all the tested compounds towards P. aeruginosa, B. cereus and S. aureus compared to the reference drugs cefotaxime and piperacillin, while 2-chloro-3-(1-substituted indol-3-yl)quinoxalines (12a, b) were the most active against C. albicans compared to the reference drug nystatin. On the other hand, 2-chloro-3-(1-benzyl indol-3-yl) quinoxaline 12a display potent efficacy against ovarian cancer xenografts in nude mice with tumor growth suppression of 100.0 +/- 0.3 %.

Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Indóis/síntese química , Animais , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Benzoatos/síntese química , Benzoatos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Indóis/farmacologia , Camundongos , Camundongos Nus , Testes de Sensibilidade Microbiana/métodos