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1.
Front Chem ; 12: 1419242, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38911996

RESUMO

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 µg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 µg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11 µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

2.
Arch Pharm (Weinheim) ; 354(1): e2000180, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32959443

RESUMO

A new series of nitric oxide-donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c-e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Doadores de Óxido Nítrico/farmacologia , Oximas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Bactérias/efeitos dos fármacos , Ciprofloxacina/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade
3.
ACS Med Chem Lett ; 10(5): 726-731, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31097990

RESUMO

Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR.

4.
Eur J Med Chem ; 146: 79-92, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29396364

RESUMO

Two structurally novel series of histone deacetylase inhibitors (HDACIs) involving two potential surface recognition moieties; 3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione (in series I) and 1-(3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide (in series II) were designed, synthesized, and evaluated for their anti-proliferative activities, HDAC inhibitory activities, and their binding modes to HDAC protein. Compounds 5f and 10e showed comparable HDAC inhibitory activity to SAHA. Series II have been also demonstrated as potential HDAC-tubulin dual inhibitors, promoted with structural similarities between (1-(3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide) nucleus, of series II, and Combretastatin A4. The tubulin inhibitory activities of series II members, together with their docking into colchicine binding site of ß-tubulin were performed. Compound 9a showed remarkable cytotoxicity. Hybrid 10e behaved as potent HDAC-tubulin dual inhibitor. It showed better tubulin inhibition than CA4 as well as its effectiveness against HDAC.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Tubulina (Proteína)/metabolismo
5.
J Med Chem ; 59(5): 1869-79, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26878150

RESUMO

A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 µM, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC50's ranging from 0.9 to 1.5 µM. The CC50 value obtained in a cytotoxicity assay for compound 9 was >100 µM, corresponding to a therapeutic index (CC50/EC50) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Benzotiazóis/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Piridonas/farmacologia , Precursores de RNA/metabolismo , RNA Viral/metabolismo , Replicação Viral/efeitos dos fármacos , Processamento Alternativo/genética , Fármacos Anti-HIV/química , Benzotiazóis/síntese química , Benzotiazóis/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Humanos , Integrases/metabolismo , Estrutura Molecular , Peptídeo Hidrolases/metabolismo , Piridonas/síntese química , Piridonas/química , Precursores de RNA/genética , RNA Viral/genética , Receptores CXCR5/antagonistas & inibidores , Relação Estrutura-Atividade
6.
Arch Pharm (Weinheim) ; 339(1): 32-40, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16411174

RESUMO

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.


Assuntos
Anti-Inflamatórios/síntese química , Triazóis/síntese química , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/prevenção & controle , Dose Letal Mediana , Masculino , Ratos , Ratos Wistar , Semicarbazidas/síntese química , Semicarbazidas/farmacologia , Semicarbazidas/toxicidade , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/toxicidade
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