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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Adenosine / analogs & derivatives
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Adenosine / chemical synthesis
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Adenosine / pharmacology
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Crystallography, X-Ray
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DNA Ligases / antagonists & inhibitors*
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DNA Ligases / metabolism
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Microbial Sensitivity Tests
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NAD / metabolism
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Protein Structure, Tertiary
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Staphylococcus aureus / drug effects
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Streptococcus pneumoniae / drug effects
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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NAD
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DNA Ligases
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Adenosine