ABSTRACT
We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then screened in vitro against panel of susceptible and resistant Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis (Mtb). Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against the tested bacteria. Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis. Selected compound 10b showed good human microsomal stability and CYP-profile, and showed low activity against hERG channel.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Acetamides/metabolism , Acetamides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/metabolism , Bacterial Infections/drug therapy , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Mycobacterium tuberculosis/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/metabolism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacology , Tuberculosis/drug therapyABSTRACT
AIM: The aim of the present study was to evaluate the DNA hypermethylation profiles of 14 genes known to be associated with tumor behavior and their clinical significance in cervical cancer. METHOD: The clinical features of 82 patients with stage IB cervical cancer were analyzed in terms of DNA hypermethylation of 14 genes (hMLH1, p16, COX-2, CDH1, APC, DAPK, MGMT, p14, RASSF1A, RUNX3, TIMP3, FHIT, THBS1, and HLTF). RESULTS: Of 14 genes investigated, only hypermethylation of COX-2 showed significant association with poor disease-free survival (P = 0.001). To further investigate an alteration in COX-2 expression by DNA hypermethylation, immunohistochemistry for COX-2 protein was performed in the cervical cancer tissues. We found no significant association between hypermethylation and expression patterns of the COX-2 gene. CONCLUSIONS: The present results suggest that DNA hypermethylation of the COX-2 gene may be a potential prognostic marker in early stage cervical cancer, the underlying mechanism of which is independent of gene silencing.
