2. Academic Validation
  3. Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria

Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria

  • Eur J Med Chem. 2018 Apr 25:150:771-782. doi: 10.1016/j.ejmech.2018.03.031.
Yonghua Liu 1,  Xinxin Hu 2,  Yanbin Wu 2,  Weixing Zhang 2,  Xiaofang Chen 2,  Xuefu You 3,  Laixing Hu 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing, 100050, China. Electronic address: [email protected].
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing, 100050, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing, 100050, China. Electronic address: [email protected].
PMID: 29604581 DOI: 10.1016/j.ejmech.2018.03.031
Abstract

A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro Antibacterial activity against a range of Gram-positive and Gram-negative Bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum Antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 μg/mL. Slightly more potent Antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable Antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 μg/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective Antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED50values of 2.62 mg/kg.

Keywords

Antibacterial; Broad-spectrum; Diamidine; Gram-negative bacteria; Indole; MRSA; NDM-1.

Figures