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. Epub 2020 Aug 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Dose-Response Relationship, Drug
  • Lactones / chemical synthesis
  • Lactones / chemistry
  • Lactones / pharmacology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Staphylococcus aureus / drug effects*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Biological Products
  • Lactones
  • albocycline