Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
ACS Chem Neurosci ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961126

RESUMO

Naegleria fowleri and Balamuthia mandrillaris are protist pathogens that infect the central nervous system, causing primary amoebic meningoencephalitis and granulomatous amoebic encephalitis with mortality rates of over 95%. Quinazolinones and their derivatives possess a wide spectrum of biological properties, but their antiamoebic effects against brain-eating amoebae have never been tested before. In this study, we synthesized a variety of 34 novel arylquinazolinones derivatives (Q1-Q34) by altering both quinazolinone core and aryl substituents. To study the antiamoebic activity of these synthetic arylquinazolinones, amoebicidal and amoebistatic assays were performed against N. fowleri and B. mandrillaris. Moreover, amoebae-mediated host cells cytotopathogenicity and cytotoxicity assays were performed against human keratinocytes cells in vitro. The results revealed that selected arylquinazolinones derivatives decreased the viability of B. mandrillaris and N. fowleri significantly (P < 0.05) and reduced cytopathogenicity of both parasites. Furthermore, these compounds were also found to be least cytotoxic against HaCat cells. Considering that nanoparticle-based materials possess potent in vitro activity against brain-eating amoebae, we conjugated quinazolinones derivatives with silver nanoparticles and showed that activities of the drugs were enhanced successfully after conjugation. The current study suggests that quinazolinones alone as well as conjugated with silver nanoparticles may serve as potent therapeutics against brain-eating amoebae.

2.
PLoS One ; 15(1): e0227549, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986186

RESUMO

Over-expression of thymidine phosphorylase (TP) plays a key role in many pathological complications, including angiogenesis which leads to cancer cells proliferation. Thus in search of new anticancer agents, a series of 4-hydroxybenzohydrazides (1-29) was synthesized, and evaluated for in vitro thymidine phosphorylase inhibitory activity. Twenty compounds 1-3, 6-14, 16, 19, 22-24, and 27-29 showed potent to weak TP inhibitory activities with IC50 values in the range of 6.8 to 229.5 µM, in comparison to the standards i.e. tipiracil (IC50 = 0.014 ± 0.002 µM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 µM). Kinetic studies on selected inhibitors 3, 9, 14, 22, 27, and 29 revealed uncompetitive and non-competitive modes of inhibition. Molecular docking studies of these inhibitors indicated that they were able to interact with the amino acid residues present in allosteric site of TP, including Asp391, Arg388, and Leu389. Antiproliferative (cytotoxic) activities of active compounds were also evaluated against mouse fibroblast (3T3) and prostate cancer (PC3) cell lines. Compounds 1, 2, 19, and 22-24 exhibited anti-proliferative activities against PC3 cells with IC50 values between 6.5 to 10.5 µM, while they were largely non-cytotoxic to 3T3 (mouse fibroblast) cells proliferation. Present study thus identifies a new class of dual inhibitors of TP and cancer cell proliferation, which deserves to be further investigated for anti-cancer drug development.

3.
Eur J Med Chem ; 182: 111575, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415900

RESUMO

We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 µg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Quinazolinonas/farmacologia , Amebicidas/síntese química , Amebicidas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
4.
Bioorg Chem ; 79: 201-211, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29772470

RESUMO

5-Aryl-1H-tetrazoles (1-24) were synthesized and screened for their xanthine oxidase (XO) inhibitory activity using allopurinol as standard inhibitor (IC50 = 2.0 ±â€¯0.01 µM). Six compounds 3, 4, 5, 9, 21, and 24 exhibited significant to weak activities with IC50 values in the range of 7.4-174.2 µM. Active compounds were further subjected to kinetic and molecular docking studies to deduce their modes of inhibition, and to study their interactions with the protein (XO) at atomic level, respectively. Interestingly, all these compounds showed a competitive mode of inhibition. Docking studies identified several important interactions between the ligand and the receptor protein (XO). Some of these interactions were similar to that exhibited by clinical inhibitors of XO (allopurinol, and febuxostat). This study identifies 5-aryl-1H-tetrazoles as a new class of xanthine oxidase inhibitors, which deserves to be further, investigated for the treatment of hyperuricemia and gout.


Assuntos
Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Tetrazóis/farmacologia , Xantina Oxidase/antagonistas & inibidores , Alopurinol/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Xantina Oxidase/metabolismo
5.
Bioorg Chem ; 69: 37-47, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27669119

RESUMO

Coumarin sulfonates 4-43 were synthesized by reacting 3-hydroxy coumarin 1, 4-hydroxy coumarin 2and6-hydroxy coumarin 3 with different substituted sulfonyl chlorides and subjected to evaluate for their in vitro immunomodulatory potential. The compounds were investigated for their effect on oxidative burst activity of zymosan stimulated whole blood phagocytes using a luminol enhanced chemiluminescence technique. Ibuprofen was used as standard drug (IC50=54.2±9.2µM). Eleven compounds 6 (IC50=46.60±14.6µM), 8 (IC50=11.50±6.5µM), 15 (IC50=21.40±12.2µM), 19 (IC50=5.75±0.86µM), 22 (IC50=10.27±1.06µM), 23 (IC50=33.09±5.61µM), 24 (IC50=4.93±0.58µM), 25 (IC50=21.96±14.74µM), 29 (IC50=12.47±9.2µM), 35 (IC50=20.20±13.4µM) and 37 (IC50=14.47±5.02µM) out of forty demonstrated their potential suppressive effect on production of reactive oxygen species (ROS) as compared to ibuprofen. All the synthetic derivatives 4-43 were characterized by different available spectroscopic techniques such as 1H NMR, 13C NMR, EIMS and HRMS. CHN analysis was also performed.


Assuntos
Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Espécies Reativas de Oxigênio/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Agaricales/enzimologia , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química
6.
Bioorg Chem ; 66: 117-23, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27149363

RESUMO

Twenty derivatives of 5-aryl-2-(6'-nitrobenzofuran-2'-yl)-1,3,4-oxadiazoles (1-20) were synthesized and evaluated for their α-glucosidase inhibitory activities. Compounds containing hydroxyl and halogens (1-6, and 8-18) were found to be five to seventy folds more active with IC50 values in the range of 12.75±0.10-162.05±1.65µM, in comparison with the standard drug, acarbose (IC50=856.45±5.60µM). Current study explores the α-glucosidase inhibition of a hybrid class of compounds of oxadiazole and benzofurans. These findings may invite researchers to work in the area of treatment of hyperglycemia. Docking studies showed that most compounds are interacting with important amino acids Glu 276, Asp 214 and Phe 177 through hydrogen bonds and arene-arene interaction.


Assuntos
Benzofuranos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Oxidiazóis/farmacologia , alfa-Glucosidases/metabolismo , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
7.
Bioorg Chem ; 65: 100-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26894559

RESUMO

Benzimidazole analogs 1-27 were synthesized, characterized by EI-MS and (1)HNMR and their α-glucosidase inhibitory activities were found out experimentally. Compound 25, 19, 10 and 20 have best inhibitory activities with IC50 values 5.30±0.10, 16.10±0.10, 25.36±0.14 and 29.75±0.19 respectively against α-glucosidase. Compound 6 and 12 has no inhibitory activity against α-glucosidase enzyme among the series. Further studies showed that the compounds are not showing any cytotoxicity effect. The docking studies of the compounds as well as the experimental activities of the compounds correlated well. From the molecular docking studies, it was observed that the top ranked conformation of all the compounds fit well in the active site of the homology model of α-glucosidase.


Assuntos
Benzimidazóis/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/toxicidade , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Células 3T3-L1 , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Camundongos , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 108: 13-20, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26619389

RESUMO

4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against Leishmania major promastigotes in vitro with IC50 values = 1.87-61.48 µM. Among the twenty four synthetic derivatives, 4-[4'-(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2'-methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with IC50 values 1.87 ± 0.31 and 4.37 ± 0.02 µM, respectively, more active than the standard drug, pentamidine (IC50 = 5.09 ± 0.09 µM). Compound 16 (IC50 = 6.53 ± 0.21 µM) displayed an activity comparable to the standard. Compounds 15 (IC50 = 9.04 ± 0.03 µM), 18 (IC50 = 12.28 ± 0.18 µM), 14 (IC50 = 19.87 ± 0.22 µM), and 5 (IC50 = 24.03 ± 2.71 µM) also showed good activities.


Assuntos
Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose/parasitologia , Doenças Negligenciadas/parasitologia , Quinazolinas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Humanos , Leishmaniose/tratamento farmacológico , Estrutura Molecular , Doenças Negligenciadas/tratamento farmacológico , Testes de Sensibilidade Parasitária , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
9.
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
10.
Bioorg Chem ; 63: 142-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26547232

RESUMO

Thymidine phosphorylase (TP) over expression plays an important role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. In this regard, a series of twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 were evaluated for thymidine phosphorylase inhibitory activity. Six compounds 5, 6, 20, 2, 23, and 3 were found to be active against thymidine phosphorylase enzyme with IC50 values in the range of 42.9-294.6µM. 7-Deazaxanthine (IC50=41.0±1.63µM) was used as a standard inhibitor. Compound 5 showed a significant activity (IC50=42.9±1.0µM), comparable to the standard. The enzyme kinetic studies on the most active compounds 5, 6, and 20 were performed for the determination of their modes of inhibition, and dissociation constants Ki. All active compounds were found to be largely non-cytotoxic against the mouse fibroblast 3T3 cell line. This study identifies a novel class of thymidine phosphorylase inhibitors which may be further investigated as leads to develop therapeutic agents.


Assuntos
Inibidores Enzimáticos/farmacologia , Quinazolinonas/farmacologia , Timidina Fosforilase/antagonistas & inibidores , Células 3T3 , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Fibroblastos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Timidina Fosforilase/metabolismo
11.
Bioorg Chem ; 63: 24-35, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26398141

RESUMO

2-Indolcarbohydrazones 1-28 were synthesized and evaluated for their α-glucosidase inhibitory potential. A varying degree of inhibitory potential with IC50 values in the range of 2.3±0.11-226.4±6.8µM was observed while comparing these outcomes with the standard acarbose (IC50=906.0±6.3µM). The stereochemistry of ten (10) randomly selected compounds (1, 3, 6, 8, 12, 18, 19, 23, 25 and 28) was predicted by Density Functional Theory (DFT). The stability of E isomer was deduced by comparing the calculated and experimental vibration modes of νCO, νNC and νCH (CH in NCH-R). It was observed that except compound 18, all other compounds were deduced to have E configuration while molecular modeling studies revealed the key interactions between enzyme and synthesized compounds.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrazonas/farmacologia , Indóis/farmacologia , Teoria Quântica , alfa-Glucosidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Hidrazonas/síntese química , Hidrazonas/química , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Saccharomyces cerevisiae/enzimologia , Estereoisomerismo , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 23(15): 4155-62, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26183542

RESUMO

Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 µM. The IC50 values were being compared to the standard acarbose (IC50=856.45 ± 5.60 µM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50=2.64 ± 0.05 µM), which has trihydroxy substitution at C-2', C-4', and C-5' on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50=856.45 ± 5.60 µM). Compound 23 (IC50=34.64 ± 0.35 µM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2' to C-4' (6) and C-3' (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.


Assuntos
Inibidores de Glicosídeo Hidrolases/síntese química , Oxidiazóis/química , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Glicosídeo Hidrolases/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
13.
Med Chem ; 11(4): 336-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25470505

RESUMO

A library of twenty-five derivatives of 2-substituted quinazolin-4(3H)-ones 1-25 was synthesized and evaluated against phosphodiesterase-I (PDE) and carbonic anhydrase-II (CA). Compounds 17 (IC50 = 210.7 ± 2.62 µM), 16 (IC50 = 301.6 ± 1.18 µM), and 13 (IC50 = 458.13 ± 3.60 µM), selectively exhibited PDE inhibition while compounds 22 (IC50 = 61.33 ± 2.38 µM), 1 (IC50 = 108.30 ± 0.93 µM), and 21 (IC50 = 191.93 ± 2.72 µM), discriminatingly exhibited CA inhibition as compared to standards EDTA (IC50 = 277.69 ± 2.52 µM) and acetazolamide (IC50 = 0.12 ± 0.03 µM), for PDE and CA inhibitions, respectively. However, compound 15 was found to be active against both enzymes with the IC50 values 344.33 ± 4.32 µM and 20.94 ± 0.58 µM, for PDE and CA inhibitions, respectively. Remaining compounds were found to be inactive against both the enzymes. Structure-activity relationship studies are discussed herein.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Fosfodiesterase I/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Quinazolinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Acetazolamida/química , Animais , Anidrase Carbônica II/química , Anidrase Carbônica II/isolamento & purificação , Inibidores da Anidrase Carbônica/química , Desenho de Drogas , Ácido Edético/química , Ensaios Enzimáticos , Estrutura Molecular , Fosfodiesterase I/química , Fosfodiesterase I/isolamento & purificação , Inibidores de Fosfodiesterase/química , Quinazolinonas/química , Bibliotecas de Moléculas Pequenas/química , Serpentes/metabolismo , Soluções , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 22(22): 6509-14, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25440732

RESUMO

A series of Schiff base triazoles 1­25 was synthesized and evaluated for their nucleotide pyrophosphatase/phosphodiesterase-1 inhibitory activities. Among twenty-five compounds, three compounds 10 (IC50 = 132.20 ± 2.89 lM), 13 (IC50 = 152.83 ± 2.39 lM), and 22 (IC50 = 251.0 ± 6.64 lM) were identified as potent inhibitors with superior activities than the standard EDTA (IC50 = 277.69 ± 2.52 lM). The newly identified inhibitors may open a new avenue for the development of treatment of phosphodiesterase-I related disorders. These compounds were also evaluated for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitory potential and were found to be inactive. The compounds showed non-toxic effect towards PC3 cell lines.


Assuntos
Inibidores Enzimáticos/síntese química , Pirofosfatases/antagonistas & inibidores , Bases de Schiff/química , Triazóis/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácido Edético/química , Ácido Edético/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/toxicidade , Humanos , Ligação Proteica , Pirofosfatases/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/toxicidade
15.
Bioorg Med Chem ; 22(19): 5454-65, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25151088

RESUMO

Oxadiazoles and thiadiazoles 1-37 were synthesized and evaluated for the first time for their α-glucosidase inhibitory activities. As a result, fifteen of them 1, 4, 5, 7, 8, 13, 17, 23, 25, 30, 32, 33, 35, 36 and 37 were identified as potent inhibitors of the enzyme. Kinetic studies of the most active compounds (oxadiazoles 1, 23 and 25, and thiadiazoles 35 and 37) were carried out to determine their mode of inhibition and dissociation constants Ki. The most potent compound of the oxadiazole series (compound 23) was found to be a non-competitive inhibitor (Ki=4.36±0.017 µM), while most potent thiadiazole 35 was identified as a competitive inhibitor (Ki=6.0±0.059 µM). The selectivity and toxicity of these compounds were also studied by evaluating their potential against other enzymes, such as carbonic anhydrase-II and phosphodiesterase-I. Cytotoxicity was evaluated against rat fibroblast 3T3 cell line. Interestingly, these compounds were found to be inactive against other enzymes, exhibiting their selectivity towards α-glucosidase. Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. α-Glucosidase inhibitors can also be used as anti-obesity and anti-viral drugs. Our study identifies two novel series of potent α-glucosidase inhibitors for further investigation.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Oxidiazóis/farmacologia , Tiadiazóis/farmacologia , alfa-Glucosidases/metabolismo , Células 3T3 , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Fosfodiesterase I/antagonistas & inibidores , Fosfodiesterase I/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
16.
Bioorg Med Chem ; 22(13): 3449-54, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24844756

RESUMO

2-Arylquinazolin-4(3H)-ones 1-25 were synthesized by reacting anthranilamide with various benzaldehydes using CuCl2·2H2O as a catalyst in ethanol under reflux. Synthetic 2-arylquinazolin-4(3H)-ones 1-25 were evaluated for their ß-glucuronidase inhibitory potential. A trend of inhibition IC50 against the enzyme in the range of 0.6-198.2µM, was observed and compared with the standard d-saccharic acid 1,4-lactone (IC50=45.75±2.16µM). Compounds 13, 19, 4, 12, 14, 22, 23, 25, 15, 8, 17, 11, 21, 1, 3, 18, 9, 2, and 24 with the IC50 values within the range of 0.6-44.0µM, indicated that the compounds have superior activity than the standard. The compounds showed no cytotoxic effects against PC-3 cells. A structure-activity relationship is established.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucuronidase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Estrutura Molecular , Relação Estrutura-Atividade
17.
Med Chem ; 10(8): 778-82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24611780

RESUMO

Twenty-three (23) derivatives of coumarin (5-27) were synthesized and screened for their in vitro ß- glucuronidase (E. coli) inhibitory activities. Only three compounds, 7,8-dihydroxy-4-methyl-2H-chromen-2-one (9) (IC50 = 52.39 ± 1.85 µM), 3-chloro-6-hexyl-7-hydroxy-4-methyl-2H-chromen-2-one (18) (IC50 = 60.50 ± 0.87 µM), and 3,6- dichloro-7-hydroxy-4-methyl-2H-chromen-2-one (15) (IC50 = 380.26 ± 0.92 µM) displayed activities against ß- glucuronidase as compared to standard D-saccharic acid 1,4-lactone (IC50 = 45.75 ± 2.16 µM). The results indicated that the activity of the synthetic coumarins depends upon the substituents present on the coumarin skeleton.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Cumarínicos/síntese química , Inibidores Enzimáticos/síntese química , Glucuronidase/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/isolamento & purificação , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Escherichia coli/química , Escherichia coli/enzimologia , Ácido Glucárico/química , Glucuronidase/química , Glucuronidase/isolamento & purificação , Cinética , Lactonas/química , Estrutura Molecular , Relação Estrutura-Atividade
18.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 1): o75, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476456

RESUMO

The title mol-ecule, C10H10N4O2, is almost planar and adopts an E configuration of the azomethine [C=N = 1.298 (2) Å] double bond. The benzene ring is attached to an essentially planar (r.m.s. deviation = 0.0226 Å) amidine moiety (N=CN/Me2), the dihedral angle between the two mean planes being 18.42 (11)°. The cyano group lies in the plane of the benzene ring [the C and N atoms deviating by 0.030 (3) and 0.040 (3) Å, respectively], while the nitro group makes a dihedral angle 5.8 (3)° with the benzene ring. There are two distinct inter-molecular hydrogen bonds, C-H⋯O and C-H⋯N, that stabilize the crystal structure; the former inter-actions result in centrosymmetric dimers about inversion centers resulting in ten-membered rings, while the later give rise to chains of mol-ecules running parallel to the b axis.

19.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 1): o8, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476461

RESUMO

In the title mol-ecule, C16H14N4O4, the quinazoline ring is substanti-ally planar (r.m.s. deviation = 0.0129 Å) and forms a dihedral angle of 2.73 (8)° with the benzene ring. The conformation of the mol-ecule is stabilized by an intra-molecular C-H⋯N hydrogen bond. In the crystal, mol-ecules are linked into chains running parallel to the b axis by C-H⋯O hydrogen bonds. In addition, π-π stacking is observed between dimethoxy-substituted and nitro-substituted benzene rings, with centroid-centroid distances in the range 3.6438 (10)-3.7148 (10) Å.

20.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 10): o2920, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23125710

RESUMO

In the title compound, C(11)H(8)O(3), the benzopyran-4-one or chromone ring system is almost planar, with a maximum deviation of 0.045 (2) Å. The crystal structure is stablized by π-π inter-actions between the benzene and pyran rings of inversion-related mol-ecules stacked along the b axis, with a centroid-centroid distance of 3.5463 (12) Å

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA