Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity.
Stokes SS, Huynh H, Gowravaram M, Albert R, Cavero-Tomas M, Chen B, Harang J, Loch JT, Lu M, Mullen GB, Zhao S, Liu CF, Mills SD.
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.