RÉSUMÉ
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.
Sujet(s)
Antibactériens , Linézolide , Tests de sensibilité microbienne , Antibactériens/pharmacologie , Antibactériens/composition chimique , Antibactériens/synthèse chimique , Humains , Animaux , Linézolide/pharmacologie , Relation structure-activité , Cellules Caco-2 , Souris , Structure moléculaire , Relation dose-effet des médicaments , Staphylococcus aureus/effets des médicaments et des substances chimiques , Rats , Résistance bactérienne aux médicaments/effets des médicaments et des substances chimiques , Mâle , Enterococcus faecalis/effets des médicaments et des substances chimiques , Oxazolidinones/pharmacologie , Oxazolidinones/composition chimique , Oxazolidinones/synthèse chimique , Rat Sprague-DawleyRÉSUMÉ
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.
Sujet(s)
Conception de médicament , Inhibiteurs de protéines kinases , Protein-Serine-Threonine Kinases , Pyrimidines , Pyrimidines/pharmacologie , Pyrimidines/composition chimique , Pyrimidines/synthèse chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Humains , Relation structure-activité , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protein-Serine-Threonine Kinases/métabolisme , Animaux , Structure moléculaire , Rats , Relation dose-effet des médicaments , Mâle , Simulation de docking moléculaire , Rat Sprague-DawleyRÉSUMÉ
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.