Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity.

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.