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 log D values 1.5-2.5 maximized potency and maintained drug-like physical properties. (C) 2011 Elsevier Ltd. All rights reserved.