ABSTRACT
Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.
Subject(s)
Adenosine/chemistry , Anti-Bacterial Agents/chemical synthesis , DNA Ligases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , NAD/chemistry , Adenine/chemistry , Administration, Oral , Animals , Anti-Bacterial Agents/chemistry , Biological Availability , Chromatography, Liquid/methods , DNA Ligases/chemistry , Dogs , Drug Design , Drug Evaluation, Preclinical/methods , Fluorine/chemistry , Inhibitory Concentration 50 , Mass Spectrometry/methods , Models, Chemical , RatsABSTRACT
Optimization of adenosine analog inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. Antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus was improved by modification of the 2-position substituent on the adenine ring and 3'- and 5'-substituents on the ribose. Compounds with logD values 1.5-2.5 maximized potency and maintained drug-like physical properties.
