Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 28, Issue 10, Pages 1903-1910Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.03.085
Keywords
Bacterial resistance; Fluoroquinolone; DNA gyrase; Topoisomerase
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Funding
- National Institutes of Health (NIH) [R01 AI87671]
- NIH Predoctoral Training Program in Pharmacological Sciences [GM067795]
- American Foundation for Pharmaceutical Education Predoctoral Fellowship Program
- American Chemical Society Division of Medicinal Chemistry Fellowship
- University of Iowa Center for Biocatalysis and Bio-processing
- NIH [GM008365]
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Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-l position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-l position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-l position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-l position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II. (C) 2018 Elsevier Ltd. All rights reserved.
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