Synthesis, biological evaluation and molecular docking of 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives as potential Staphylococcus aureus Sortase A inhibitors

• Potent Staphylococcus aureus Sortase A inhibitors were designed and synthesized.
• Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM).
• The structural activity relationship (SAR) and molecular docking studies were revealed.

A series of novel 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against Staphylococcus aureus Sortase A with known Sortase A inhibitor pHMB as positive compound (IC50 = 130 μM). Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM). Structure–activity relationship studies demonstrated that substitution at 7-position and 2-position of benzoxazole had great influence on the activities. Specifically, the substituent at 7-position is indispensable for inhibitory activity. The molecular docking studies revealed the i-butyl amide group went towards the β6/β7 loop-β8 substructure of the protein and the benzoxazole core lied in a hydrophobic pocket composed of Ala118, Val166, Val168, Val169 and Ile182, shaping the whole molecule into a L-shape mode to be recognized by Sortase A.

Thirty-one 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives were designed and synthesized as potentially potent Staphylococcus aureus Sortase A inhibitors. Most compounds exhibited excellent inhibitory activity (IC50 = 19.8–184.2 μM). The structural activity relationship (SAR) of these compounds demonstrated that substitution at 7-position and 2-position of benzoxazole has great influence on the inhibitory activities. The molecular docking studies revealed the i-butyl amide group and the benzoxazole core shaped the whole molecule into a L-shape mode to be recognized by Sortase A.Figure optionsDownload as PowerPoint slide