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. 2020 Nov 1;30(21):127509.
doi: 10.1016/j.bmcl.2020.127509. Epub 2020 Aug 19.

Synthesis and biological evaluation of semi-synthetic albocycline analogs

Affiliations

Synthesis and biological evaluation of semi-synthetic albocycline analogs

Samer S Daher et al. Bioorg Med Chem Lett. .

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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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Structures of albocycline (ALB, 1) and vancomycin (2).
Figure 2.
Figure 2.
Studying antibiotic activity across albocycline and its analogs.
Scheme 1.
Scheme 1.
Functionalization of ALB at the C4 carbinol position by acylation to access ester analog 6 or by alkylation to access ether analog 7.
Scheme 2.
Scheme 2.
Allylic functionalization at C16 with NBS or SeO2 to generate regioisomeric bromides 8 and 8’ or allylic alcohol 9, respectively.
Scheme 3.
Scheme 3.
Allylic functionalization at C16 to generate aldehyde 10 and ether 11
Scheme 4.
Scheme 4.
Allylic functionalization at C16 to generate azides 13 and 14 from isolable phosphonate intermediate 12.
Scheme 5.
Scheme 5.
Synthesis of P-amino-sulfide adduct 15 (dr = 2:1) of ALB.

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