RESUMEN
The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC50=2.99 and 2.19nM, respectively). Inhibitory activity of 21 was found to be slightly better than PF-8380 (IC50=2.80nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, 21 displayed higher potency (IC50=14.99nM) than the first clinical ATX inhibitor, GLPG1690 (IC50=242.00nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of 21 was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket.
Asunto(s)
Diseño de Fármacos , Simulación del Acoplamiento Molecular , Hidrolasas Diéster Fosfóricas/metabolismo , Tiazoles/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
LCB01-0648 is a novel oxazolidinone compound that shows potent antibacterial activities against most Gram-positive cocci, including the multi-drug resistant Staphylococcusaureus. In this study, in vivo activity of LCB01-0699, a LCB01-0648 prodrug, against S.aureus was evaluated in comparison with that of Linezolid. The results of the systemic infection study demonstrated that LCB01-0699 was more potent than Linezolid against methicillin-susceptible and -resistant S. aureus strains. The in vivo efficacy of LCB01-0699 against methicillin-susceptible and -resistant S. aureus strains in a skin infection model showed more potent activity than Linezolid. LCB01-0699 shows potent in vivo activity against methicillin-susceptible and -resistant S. aureus strains, suggesting that LCB01-0699 would be a novel candidate for the treatment of these infectious diseases caused by S. aureus.
Asunto(s)
Antibacterianos/farmacología , Profármacos/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Femenino , Ratones , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/química , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Profármacos/química , Profármacos/farmacocinética , Profármacos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiologíaRESUMEN
Oxazolidinones are a novel class of synthetic antibacterial agents that inhibit bacterial protein synthesis. Here, we synthesized and tested a series of oxazolidinone compounds containing cyclic amidrazone. Among these compounds, we further investigated the antibacterial activities of LCB01-0648 against drug-susceptible or resistant Gram-positive cocci in comparison with those of six reference compounds. LCB01-0648 showed the most potent antimicrobial activities against clinically isolated Gram-positive bacteria. Against the methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS) isolates, LCB01-0648 showed the lowest MIC90s (0.5 mg/L) among the tested compounds. In addition, LCB01-0648 had the lowest minimum inhibitory concentrations (MICs) against the four linezolid-resistant S. aureus (LRSA) strains (range 2-4 mg/L). The results of the time-kill studies demonstrated that LCB01-0648 at a concentration 8× the (MIC) showed bactericidal activity against methicillin-susceptible Staphylococcus aureus MSSA or MRSA, but showed a bacteriostatic effect against LRSA. These results indicate that LCB01-0648 could be a good antibacterial candidate against multidrug-resistant (MDR) Gram-positive cocci.
Asunto(s)
Antibacterianos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Fúngica/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Oxazolidinonas/farmacologíaRESUMEN
LCB01-0371 is a new oxazolidinone with cyclic amidrazone. In vitro activity of LCB01-0371 against 624 clinical isolates was evaluated and compared with those of linezolid, vancomycin, and other antibiotics. LCB01-0371 showed good activity against Gram-positive pathogens. In vivo activity of LCB01-0371 against systemic infections in mice was also evaluated. LCB01-0371 was more active than linezolid against these systemic infections. LCB01-0371 showed bacteriostatic activity against Staphylococcus aureus.
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Oxazolidinonas/farmacología , Acetamidas/farmacología , Acetamidas/uso terapéutico , Animales , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Bacterias Grampositivas/efectos de los fármacos , Linezolid , Masculino , Ratones , Ratones Endogámicos ICR , Oxazolidinonas/uso terapéutico , Staphylococcus aureus/efectos de los fármacos , Vancomicina/farmacología , Vancomicina/uso terapéuticoRESUMEN
Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50â¯=â¯1.23â¯nM, FS-3 and 2.18â¯nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.