Design, synthesis and structure-activity relationships of novel 15-membered macrolides: Quinolone/quinoline-containing sidechains tethered to the C-6 position of azithromycin acylides

Bing Zhi Fan, Hiroshi Hiasa, Wei Lv, Scott Brody, Zhao Yong Yang, Courtney Aldrich, Mark Cushman, Jian Hua Liang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.

Original languageEnglish (US)
Article number112222
JournalEuropean Journal of Medicinal Chemistry
Volume193
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
This work is financially supported by the National Natural Science Foundation of China ( 81673335 ; 21878022 ) and National Key Research and Development Program of China ( 2018YFA0901800 ). This work during Liang’s visiting University of Minnesota is supported by China Scholarship Council . This work is also partially supported by the National Natural Science Foundation of China ( 81761128016 ; 8187131584 ). The authors thank to Prof. Yun Li at Peking University for their antibacterial assays. The authors also appreciate the spectral data supporting from the Analysis & Testing Center, Beijing Institute of Technology .

Keywords

  • Dual modes of action
  • Hybrid
  • Macrolide
  • Quinolone
  • Ribosome
  • Topoisomerase

PubMed: MeSH publication types

  • Journal Article

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