RESUMO
The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.
Assuntos
Antibacterianos , Linezolida , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Animais , Linezolida/farmacologia , Relação Estrutura-Atividade , Células CACO-2 , Camundongos , Estrutura Molecular , Relação Dose-Resposta a Droga , Staphylococcus aureus/efeitos dos fármacos , Ratos , Farmacorresistência Bacteriana/efeitos dos fármacos , Masculino , Enterococcus faecalis/efeitos dos fármacos , Oxazolidinonas/farmacologia , Oxazolidinonas/química , Oxazolidinonas/síntese química , Ratos Sprague-DawleyRESUMO
HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Pirimidinas , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Humanos , Relação Estrutura-Atividade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Estrutura Molecular , Ratos , Relação Dose-Resposta a Droga , Masculino , Simulação de Acoplamento Molecular , Ratos Sprague-DawleyRESUMO
In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3â¯nM and 60.8â¯nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50â¯=â¯17.3â¯nM, MDA-MB-361 IC50â¯=â¯8.4â¯nM, and MV4-11 IC50â¯=â¯5.4â¯nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLintâ¯=â¯21.3⯵L·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-tâ¯=â¯657â¯ng·h·mL-1, oral bioavailability of 21.4â¯%) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.
Assuntos
Antineoplásicos , Neoplasias , Inibidores de Proteínas Quinases , Animais , Ratos , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição , Proteínas que Contêm Bromodomínio/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Quinase 1 Polo-Like/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
A facile tandem [2 + 2] cycloaddition and Nazarov reaction has been developed. The combination of In(OTf)3 and benzoic acid was found to synergistically promote the coupling of alkynes and acetals to form 2,3-disubstituted indanones in excellent yield and diastereoselectivity.
Assuntos
Acetais/química , Alcinos/química , Indanos/síntese química , Ácido Benzoico/química , Catálise , Ciclização , Reação de Cicloadição , Indanos/química , Mesilatos/química , Estrutura Molecular , EstereoisomerismoRESUMO
We describe herein a viable binary acid strategy for the catalytic Nazarov reaction of aryl vinyl ketones. Simply combining a Lewis acid and a Brønsted acid led to a dramatic enhancement of the catalytic activity in the Nazarov reaction of aryl vinyl ß-ketoesters. The obtained optimal binary acid catalyst In(OTf)(3)/diphenyl phosphoric acid (DPP) can be applied to a range of aryl vinyl ketones with good activity. A trend of reactivity has also been summarized on the basis of mapping of the substituents.
Assuntos
Cetonas/síntese química , Ácidos de Lewis/química , Compostos Organofosforados/química , Compostos de Vinila/síntese química , Catálise , Ciclização , Cetonas/química , Estrutura Molecular , Estereoisomerismo , Compostos de Vinila/químicaRESUMO
A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 99%) with very good diastereo- (up to >20:1 dr) and enantioselectivities (up to 97% ee).
RESUMO
The current article reports an organocatalytic strategy for the asymmetric catalysis of chiral oxindoles bearing 3-position all-carbon quaternary stereocenters. Accordingly, highly enantioselective Michael addition reactions of 3-substituted oxindoles to terminal alkenes have been developed by utilizing a bifunctional tertiary-amine thiourea catalyst. The reactions accommodate a number of Michael donor compounds (different substituted 3-aryl or methyl oxindoles), and Michael acceptor compounds (vinyl ketones and vinyl sulfones) to give the desired oxindole products with moderate to excellent yields (up to 99%) and moderate to excellent enantioselectivities (up to 91% ee).