Synthesis, biological evaluation and molecular docking analysis of 2-phenyl-benzofuran-3-carboxamide derivatives as potential inhibitors of Staphylococcus aureus Sortase A

Wan He, Yong Zhang, Jian Bao, Xinxian Deng, Jennifer Batara, Shawn Casey, Qiuyuan Guo, Faqin Jiang*, Lei Fu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


In Gram-positive bacteria, Sortase A (Srt A) is a critical cysteine transpeptidase that is responsible for recognizing and assembling surface virulence proteins through the recognition of a LPXTG (leucine, proline, X, threonine, and glycine, where X is any amino acid) signal. Mutants lacking genes for Srt A attenuate infections without affecting microbial viability. Here a series of 2-phenyl-benzofuran-3-carboxamide derivatives were synthesized and identified as potent Srt A inhibitors. Activity assays revealed that multiple compounds exhibited excellent inhibitory activity against Srt A compared with known Sortase A inhibitor pHMB (IC50 = 130 μM). Structural activity relationships (SARs) demonstrated that the amide group at 3-position was essential for inhibitory activity. Replacement of the hydroxyl group at the 2-phenyl position of benzofuran with other substitutions such as a methoxyl, halogen or nitro group reduced the enzyme inhibitory activity in most cases. The compound Ia-22 was found to be the most potent inhibitor against the enzyme with an IC50value of 30.8 μM. Molecular docking studies showed Ia-22 shared similar binding pattern with substrate LPXTG in the binding pocket of Srt A (PDB: 2KID) including i-butyl stretching, L-shape pattern kinking, and H-bond interaction with Srt A functional site residues Cys184, Trp194 and Arg197.

Original languageEnglish
Pages (from-to)1341-1351
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number4
Publication statusPublished - 2017
Externally publishedYes


  • Benzofuran
  • Inhibitor
  • Sortase A
  • Staphylococcus aureus

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