title: Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity.
abstract: 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.
authors: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. suzanne.stokes@astrazeneca.com
authors: Suzanne S
authors: SS
authors: Stokes
authors: Hoan
authors: H
authors: Huynh
authors: Madhusudhan
authors: M
authors: Gowravaram
authors: Robert
authors: R
authors: Albert
authors: Marta
authors: M
authors: Cavero-Tomas
authors: Brendan
authors: B
authors: Chen
authors: Jenna
authors: J
authors: Harang
authors: James T
authors: JT
authors: Loch
authors: Min
authors: M
authors: Lu
authors: George B
authors: GB
authors: Mullen
authors: Shannon
authors: S
authors: Zhao
authors: Ce-Feng
authors: CF
authors: Liu
authors: Scott D
authors: SD
authors: Mills
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009243:NAD / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009243:NAD; D011088:DNA Ligases; D000241:Adenosine