Design, synthesis, and structure-activity relationship studies of the anaephene antibiotics.

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).

Synthesis of the Cyanobacterial Antibiotics Anaephenes A and B.

The first syntheses of the antibacterial natural products anaephenes A (1) and B (2) are reported. Both natural products were synthesized in five linear steps from commercially available tert-butyl(3-iodophenoxy)dimethylsilane. Key steps for the synthesis included a Sonogashira cross-coupling and a Julia-Kocienski olefination to selectively construct the E-alkene present in the natural products. This synthetic route allowed the identities and antimicrobial activities of anaephenes A (1) and B (2) to be confirmed. Additionally, these compounds displayed antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 16 and 8 µg/mL, respectively.