Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure–Activity Relationships

• DOI: 10.1002/anie.201606657
• Publication Date: 2016-09-16T11:24:33Z
• Authors: Silvia A. Albu; Kalinka Koteva; Andrew M. King; Salma Al‐Karmi; Gerard D. Wright; Alfredo Capretta
• Keywords: Aspartic Acid; Acinetobacter; Dose-Response Relationship, Drug; Molecular Structure; Microbial Sensitivity Tests; Amides; 01 natural sciences; beta-Lactamases; Anti-Bacterial Agents; 0104 chemical sciences; Structure-Activity Relationship; Enterobacteriaceae; Pseudomonas; Enzyme Inhibitors

AbstractThe fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo‐β‐lactamases NDM‐1 and VIM‐2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM‐1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.