Motualevic acids and analogs: Synthesis and antimicrobial structure–activity relationships

Abstract

Synthesis of the marine natural products motualevic acids A, E, and analogs in which modifications have been made to the ω-brominated lipid (E)-14,14-dibromotetra-deca-2,13-dienoic acid or amino acid unit are reported, together with antimicrobial activities against Staphylococcus aureus, methicillin-resistant S. aureus, Enterococcus faecium, and vancomycinresistant Enterococcus.Starting with Fleming's discovery of penicillin in the 1920's, the discovery and development of new antibiotics was marked by unmatched success in the area of drug discovery and remained at the fore for decades.1 Numerous classes of antibacterial agents were discovered from Nature, and many of those are in clinical use today. The expansion of antibiotic research reached its peak by the middle of the last century, then paused for four decades before approval of oxazolidinone linezolid in 20002 and the lipopeptide daptomycin in 2003.3 Nonetheless, a variety of infectious diseases persist as true global health burdens,4 and infections associated with drug resistant organisms5 such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. (VRE) continue to rise. To help alleviate this problem, development of new antibiotics that function with unique mechanisms of action and can escape the resistance mechanisms used by drug resistant bacteria are needed. Combined studies involving discovery and synthesis of new antimicrobial natural products can be valuable in this area.7Recently we reported the isolation, structure elucidation and antibacterial properties of motualevic acids A-E (1a-c and 8, for example) from the marine sponge Siliquariaspongia sp.7 These compounds contain an unusual ω-brominated lipid (E)-14,14-dibromotetradeca-2,13-dienoic acid, where motualevic acids A-D are its glycyl conjugates and motualevic acid E the free acid (Figure 1). Antimicrobial assays revealed that motualevic acid A (1a) inhibited the growth of S. aureus (SA) and MRSA at low micromolar concentrations, while motualevic acid E (8) showed greatly diminished activity, effective against SA only at much higher concentrations (50 µg/disk). Interestingly, the naturally occurring amides 1b and 1c and the Z isomer of 1a also exhibited greatly diminished antimicrobial activity providing some insight into the structure-activity relationships for this series. To obtain a more general picture of the chemical features necessary for antimicrobial activity, we have synthesized motualevic acids A and E together ©2010 caroleb@mail.nih.gov, tel (301)594-5187. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the jou...

Marine natural products

“…477 The synthesis of motualevic acids A and E (Siliquariaspongia sp.) 478 has been achieved by the original investigators 479 at the same time as an independent synthesis of all five acids A-E. 480 Two polyunsaturated aminoketones 399 and 400 have been isolated from a Haliclona sp. (Weizhou Is., Guangxi, China).…”