•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.

A series of 3-substituted-imine-6-hydroxy-benzofuran derivatives were chemically synthesized and biologically evaluated as antibacterial and antifungal agents against Candida albicans, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Most compounds showed a selective antibacterial activity to gram-positive bacteria and four compounds revealed great antibacterial activities against methicillin-resistant Staphylococcus aureus comparing to the positive control (Ceftazidime) with MIC80 = 12.5–25 μg/mL. Structure-activity relationship studies demonstrated that the free hydroxy group at the C-6 position is essential to the antibacterial activity, and the aromatic imine fragment at the C-3 position also greatly increases antibacterial activity.

Thirty-two 2-substituted ethenesulfonic acid ester derivatives were designed, synthesized, and evaluated for their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-Cell protein tyrosine phosphatase (TCPTP). Preliminary structure–activity relationship studies demonstrated that the substitution at the aromatic center and the length of linker between the hydrophobic tail and aromatic center markedly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. Specifically, compounds 43 and 36 revealed excellent inhibitory activity to PTP1B with IC50 = 1.3 μM and 1.5 μM, respectively, and marked 10- and 20-fold selectivity over TCPTP. Cytotoxicity data showed low cytotoxicity for COS-7 cell with IC50 values >100 μM for most synthesized chemicals.Graphical abstractWe confirmed that the substitution at the aromatic center and the length of linker markedly affected the inhibitory activity against PTP1B and its selectivity over TCPTP.Highlights► Thirty-two 2-substituted ethenesulfonic acid ester derivatives were prepared. ► Most compounds exhibited excellent inhibitory activities against PTP1B with IC50 values of 1.3–15.1 μM. ► The substitution at the aromatic center and the length of linker markedly affected the inhibitory activity against PTP1B. ► Most chemicals have low cytotoxicity for COS-7 cell with IC50 values >100 μM. ► Compounds 43 and 36 marked 10- and 20-fold selectivity over TCPTP respectively.

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 IC50 value 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.