RESUMO
An amino-assisted [3 + 2] cycloaddition strategy of nitrile imines with o-aminotrifluoroacetophenones has been explored, thus providing functionalized 1,3,4-oxadiazolines bearing CF3-quaternary centers in good to excellent yields in the presence of K2CO3 under mild conditions. The amino groups located at the ortho-position of trifluoroacetophenone might play a crucial role in the present cyclization. The MTT assay shows that the 1,3,4-oxadiazoline derivatives could be potential candidates for the treatment of head and neck cancers.
RESUMO
Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized. Aldose reductase inhibitory activities of the novel compounds were characterized by IC50 values ranging from 0.015 to 31.497 µM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3-benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.
Assuntos
Ácido Acético , Aldeído Redutase , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento MolecularRESUMO
A series of 9H-purin-6-amine derivatives as aldose reductase (ALR) inhibitors were designed and synthesized. Most of these derivatives, having a C6-substituted benzylamine side chain and N9 carboxylic acid on the core structure, were found to be potent and selective ALR inhibitors, with submicromolar IC50 values against ALR2. Particularly, compound 4e was the most active with an IC50 value of 0.038 µM, and it was also proved to be endowed with excellent inhibitory selectivity. The structure-activity relationship and molecular docking studies highlighted the importance of the carboxylic acid head group along with different halogen substituents on the C6 benzylamine side chain of the 9H-purin-6-amine scaffold for the construction of strong and selective ALR inhibitors.
Assuntos
Complicações do Diabetes , Diabetes Mellitus , Aldeído Redutase , Aminas , Benzilaminas , Ácidos Carboxílicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
AKR1B1 (Aldose reductase) has been used as therapeutic intervention target for treatment of diabetic complications over 50 years, and more recently for inflammation and cancer. However, most developed small molecule inhibitors have the defect of low bioactivity. To address this limitation, novel series of 3,4-dihydroquinolin-2(1H)-one derivatives as dual inhibitor targeting AKR1B1/ROS (Reactive Oxygen Species) were designed and synthesized. Most of these derivatives were found to be potent and selective against AKR1B1, and compound 8a was the most active with an IC50 value of 0.035 µM. Moreover, some prepared derivatives showed strong anti-ROS activity, and among them the phenolic 3,5-dihydroxyl compound 8b was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox at a concentration of 100 µM. Thus the results suggested a success in the construction of potent dual inhibitor for the therapeutic intervention target of AKR1B1/ROS.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Complicações do Diabetes/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Quinolonas/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Aldeído Redutase/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Complicações do Diabetes/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Cardiac glycosides (CGs) have been used to treat cancer for hundreds of years. However, the narrow therapeutic window and system toxicity have hindered their wide clinical applications. Herein, the small molecule prodrug strategy and nanotechnology were integrated into one drug delivery system with enhanced therapeutic effect. Using periplocymarin (PPM) as a target agent, we designed a novel redox-responsive prodrug conjugated with linoleic acid (PPM-ss-LA), which was capable of self-assembling independent of exogenous excipients. This prodrug could co-assemble with DSPE2k to form PEGylated prodrug nanoparticles (PPM-ss-LA/DSPE2k-NPs) with enhanced colloidal stability and blood circulation. Compared with free PPM, PPM-ss-LA/DSPE2k-NPs retained high anti-proliferative activity and showed increased cell uptake and therapeutic efficacy. Furthermore, the PPM-ss-LA/DSPE2k-NPs acquired a greatly enhancement of 50% lethal dose (LD50) in mice and reduced system toxicity compared with the free drug. Overall, the on-demand release of nanoprodrug delivery system could improve the therapeutic window and anticancer efficacy of CGs.
Assuntos
Glicosídeos Cardíacos/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Tecnologia Farmacêutica/métodos , Animais , Glicosídeos Cardíacos/administração & dosagem , Glicosídeos Cardíacos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Glutationa/química , Dose Letal Mediana , Ácido Linoleico/química , Camundongos , Oxirredução , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Pró-FármacosRESUMO
Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them 13d was the most active (IC50 = 0.107 µM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/síntese química , Descoberta de Drogas/métodos , Inibidores Enzimáticos/síntese química , Quinoxalinas/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/química , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC50 values ranging from 0.059 to 6.825µM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid (6b) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Fenóis/química , Quinoxalinas/química , Aldeído Redutase/metabolismo , Antioxidantes/química , Sítios de Ligação , Domínio Catalítico , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ligação Proteica , Quinoxalinas/síntese química , Quinoxalinas/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of pyrido[2,3-b]pyrazin-3(4H)-one based derivatives were designed as inhibitors of aldose reductase (ALR2), the enzyme which plays a key role in the development of diabetes complications as well as in the oxidative stress processes associated with diabetes and other pathologies. Most of the derivatives, having a substituted C2 aromatic group and a N4 acetic acid group on the core structure, were found to be potent and selective aldose reductase inhibitors with submicromolar IC50 values, and 9c was the most active with IC50 value 0.009 µM. Particularly, a number of the designed compounds bearing phenolic hydroxyl substituted C2-styryl side chain showed excellent not only in ALR2 inhibition but also in antioxidant, and among these 11i was proved to be the top one with an antioxidant ability even comparable to that of the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies highlighted the importance of phenolic hydroxyl substituents and vinyl spacer in C2 side chain of the scaffold for the construction of efficient and multifunctional ALR2 inhibitors.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Aldeído Redutase/química , Compostos de Bifenilo/química , Domínio Catalítico , Desenho de Fármacos , Simulação de Acoplamento Molecular , Picratos/químicaRESUMO
Diabetes mellitus is a major threat to global public health that requires long-term medical attention. In view of the potentially devastating effects of diabetes on ocular health, it highlights the urgent need of therapeutic drugs for the prevention and treatment of the diabetic complications. The patent described in this evaluation (WO2015026380A1) claimed a topical composition for treating diabetic cataracts both in animals and human beings. The composition containing a therapeutic amount of the 2R-methyl sorbinil, one of aldose reductase inhibitors, delivered to the dog's eye can exert a preventive, inhibitory, or prophylactic effect on diabetic cataracts in a statistically significant portion of the population being studied. Thus methods and strategies using new formulations of known inhibitors are promising for future use in the treatment of diabetic complications.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Catarata/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Administração Oftálmica , Animais , Catarata/etiologia , Catarata/veterinária , Complicações do Diabetes/patologia , Complicações do Diabetes/veterinária , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazolidinas/administração & dosagem , Imidazolidinas/farmacologia , Imidazolidinas/uso terapêutico , Patentes como AssuntoRESUMO
A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.982 µM. The most active compound 2-(3-(4-hydroxyphenoxy)-6-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (4c) also had an excellent selectivity. In addition, a number of compounds showed strong antioxidant activity and the phenolic 3,5-dihydroxyl compound 4f with 7-chloro in the quinoxalinone core was most active in scavenging the DPPH radical and suppressing lipid peroxidation.