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1.
Bioorg Chem ; 75: 317-331, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29080496

RESUMO

A library of 4,6-dihydroxypyrimidine diones (1-35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC50 values between 22.6±1.14-117.4±0.73µM, in comparison to standard, thiourea (IC50=21.2±1.3µM). Kinetics studies on the most active compounds 2-7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants Ki. Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with Ki values in the range of 7.91±0.024-13.03±0.013µM, whereas, compounds 4-6, and 17 were found to be non-competitive inhibitors with Ki values in the range of 9.28±0.019-13.05±0.023µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria.


Assuntos
Pirimidinonas/química , Urease/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Pirimidinonas/metabolismo , Relação Estrutura-Atividade , Tiobarbitúricos/química , Urease/metabolismo
2.
Bioorg Med Chem ; 24(16): 3387-95, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27374882

RESUMO

A library of benzimidazole derivatives 1-20 were synthesized, and studied for their α-chymotrypsin (α-CT) inhibitory activity in vitro. Kinetics and molecular docking studies were performed to identify the type of inhibition. Compound 1 was found to be a good inhibitor of α-chymotrypsin enzyme (IC50=14.8±0.1µM, Ki=16.4µM), when compared with standard chymostatin (IC50=5.7±0.13µM). Compounds 2-8, 15, 17, and 18 showed significant inhibitory activities. All the inhibitors were found to be competitive inhibitors, except compound 17, which was a mixed type inhibitor. The substituents (R) in para and ortho positions of phenyl ring B, apparently played a key role in the inhibitory potential of the series. Compounds 1-20 were also studied for their cytotoxicity profile by using 3T3 mouse fibroblast cells and compounds 3, 5, 6, 8, 12-14, 16, 17, 19, and 20 were found to be cytotoxic. Molecular docking was performed on the most active members of the series in comparison to the standard compound, chymostatin, to identify the most likely binding modes. The compounds reported here can serve as templates for further studies for new inhibitors of α-chymotrypsin and other chymotrypsin-like serine proteases enzymes.


Assuntos
Benzimidazóis/farmacologia , Quimotripsina/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Células 3T3 , Animais , Benzimidazóis/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores Enzimáticos/química , Técnicas In Vitro , Cinética , Camundongos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
3.
Bioorg Med Chem ; 23(23): 7417-21, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26552899

RESUMO

Twenty-five derivatives of 2-arylquinazolin-4(3H)-ones (1-25) were evaluated for their yeast (Saccharomyces cerevisiae) α-glucosidase inhibitory activities. All synthetic compounds, except 1 and 6, were found to be several hundred fold more active (IC50 values in the range of 0.3±0.01-117.9±1.76µM), than the standard drug, acarbose (IC50=840±1.73µM). The enzyme kinetic studies on the most active compounds 12, 4, 19, and 13 were performed for the determination of their modes of inhibition and dissociation constants Ki. Study of the modes of inhibition of compounds 12, and 4 were also performed using molecular modeling techniques. In brief, current study identifies a novel class of α-glucosidase inhibitors which can be further studied for the treatment of hyperglycemia and obesity.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Quinazolinonas/farmacologia , Acarbose/farmacologia , Sítio Alostérico , Domínio Catalítico , Ensaios Enzimáticos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Cinética , Simulação de Acoplamento Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade , alfa-Glucosidases/química
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