Synthesis and biological evaluation of semi-synthetic albocycline analogs. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Daher, Samer S.; Franklin, Kevin P.; Scherzi, Tyler; Dunman, Paul M.; Andrade, Rodrigo B.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: MRSA methicillin-resistant Staphylococcus aureus -- VISA vancomycin-intermediate Staphylococcus aureus -- VRSA vancomycin-resistant Staphylococcus aureus -- SAR structure-activity relationship -- MIC Minimum Inhibitory Concentration -- NPs natural products -- ALB albocycline -- ABPP affinity-based protein profiling -- TBAI tetrabutylammonium iodide -- NBS N-bromosuccinimide -- DPPA diphenyl phosphoryl azide; Albocycline -- MIC -- SAR -- Antibiotic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127509
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.