Total and Semi‐Syntheses of Antimicrobial Thuggacin Derivatives |
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| Authors: | Dr Jana Franke Dr Martin Bock Dr Richard Dehn Dr Jörg Fohrer Dr Santosh B Mhaske Dr Antonella Migliorini Dr Argyrios A Kanakis Dr Rolf Jansen Dr Jennifer Herrmann Prof Dr Rolf Müller Prof Dr Andreas Kirschning |
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| Institution: | 1. Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universit?t Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49)?511‐762‐3011;2. Division of Organic Chemistry, CSIR‐National Chemical Laboratory, Pune 411 008 (India);3. Helmholtz Centre for Infection Research (HZI), Microbial Drugs (MWIS), Inhoffenstra?e 7, 38124 Braunschweig (Germany);4. Helmholtz‐Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Microbial Natural Products (MINS) and Saarland University, Campus Building C2.3, 66123 Saarbrücken (Germany) |
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| Abstract: | The total and semi‐synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A–C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi‐synthetic O‐methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17–C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties. |
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| Keywords: | antibiotics lactones natural products synthesis design total synthesis |
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