Design, synthesis, and structure–activity relationship studies of the anaephene antibiotics. (21st June 2021)

• Record Type: Journal Article
• Authors: Kukla, David L.; Canchola, Juan; Rosenthal, Joseph D.; Mills, Jonathan J.
• Is Part Of: Chemical biology & drug design. Volume 98:Number 2(2021)
• Page Start: 295
• Page End: 304
• Publication Date: 2021-06-21
• Subjects: antibiotics -- methicillin‐resistant Staphylococcus aureus -- natural products -- Staphylococcus aureus -- synthesis; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13903
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: The natural products, anaephenes A (1 ) and B (2 ), were found to have antimicrobial activity against methicillin‐resistant Staphylococcus aureus (MRSA). In this report, we expanded on our previous synthetic efforts by preparing a library of eighteen analogues in order to understand the structure–activity relationships (SAR) of this interesting class of natural products. These analogues were selected to explore the biological impact of structural variations in the alkyl chain and on the phenol moiety. Last, we further assessed the biological activity of anaephene B (2 ) and two additional analogues against other clinically relevant bacterial strains and the hemolytic activity of each and determined that these compounds act via a bactericidal mechanism. These studies led to the identification of compound 7, which was 4‐fold more potent than the natural product (2 ) against MRSA (2 vs. 8 μg/ml) and a 2‐hydroxypyridine analogue (18 ) which demonstrated equal potency compared with the natural product (2 ), albeit with a significant reduction in hemolytic activity (<1% vs. 80% at 100 μM). Abstract : Eighteen analogues of the anaephene natural products were designed and synthesized. The antibacterial activity was evaluated against several clinically relevant strains of bacteria. This led to the development of analogues with improved potency and drug‐like properties.