Semisynthesis of Platensimycin Derivatives with Antibiotic Activities in Mice via Suzuki-Miyaura Cross-Coupling Reactions

  • J Med Chem. 2018 Dec 27;61(24):11341-11348. doi: 10.1021/acs.jmedchem.8b01580.
Youchao Deng  1 ,  Meng Su  1 ,  Dingding Kang  1 ,  Xingyun Liu  1 ,  Zhongqing Wen  1 ,  Yuling Li  1 ,  Lin Qiu  1 ,  Ben Shen ,  Yanwen Duan  1  2  3 ,  Yong Huang  1  3
Affiliations
  • 1. Xiangya International Academy of Translational Medicine at Central South University , Changsha , Hunan 410013 , China.
  • 2. Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery , Changsha , Hunan 410011 , China.
  • 3. National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery , Changsha , Hunan 410011 , China.
PMID: 30461269 DOI: 10.1021/acs.jmedchem.8b01580
Abstract

Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved Antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of Antibiotics.