Synthesis and biological evaluation of semi-synthetic albocycline analogs

  • Bioorg Med Chem Lett. 2020 Nov 1;30(21):127509. doi: 10.1016/j.bmcl.2020.127509.
Samer S Daher  1 ,  Kevin P Franklin  1 ,  Tyler Scherzi  2 ,  Paul M Dunman  2 ,  Rodrigo B Andrade  3
Affiliations
  • 1. Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • 2. Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
  • 3. Department of Chemistry, Temple University, Philadelphia, PA 19122, United States. Electronic address: [email protected].
PMID: 32827630 DOI: 10.1016/j.bmcl.2020.127509
Abstract

Albocycline (ALB) is a unique macrolactone natural product with potent, narrow-spectrum activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate (VISA), and vancomycin-resistant S. aureus (VRSA) strains (MIC = 0.5-1.0 μg/mL). Described herein is the synthesis and evaluation of a novel series analogs derived from albocycline by functionalization at three specific sites: the C2-C3 enone, the tertiary carbinol at C4, and the allylic C16 methyl group. Exploration of the structure-activity relationships (SAR) by means of minimum inhibitory concentration assays (MICs) revealed that C4 ester analog 6 was twice as potent as ALB, which represents a class of lead compound that can be further studied to address multi-drug resistant pathogens.

Keywords
Albocycline; Antibiotic; MIC; SAR.
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