Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase

Tyrell R. Towle, Chaitanya A. Kulkarni, Lisa M. Oppegard, Bridget P. Williams, Taylor A. Picha, Hiroshi Hiasa, Robert J. Kerns

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 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-1 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-1 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.

Original languageEnglish (US)
Pages (from-to)1903-1910
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number10
DOIs
StatePublished - Jun 1 2018

Keywords

  • Bacterial resistance
  • DNA gyrase
  • Fluoroquinolone
  • Topoisomerase

Fingerprint Dive into the research topics of 'Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase'. Together they form a unique fingerprint.

  • Cite this