title: Synthesis, biological evaluation and molecular docking analysis of 2-phenyl-benzofuran-3-carboxamide derivatives as potential inhibitors of Staphylococcus aureus Sortase A.
abstract: 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=130μM). 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 30.8μM. 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.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Wan
authors.initials: W
authors.lastname: He
authors.affiliation: School of Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Bao
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Xinxian
authors.initials: X
authors.lastname: Deng
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Batara
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Shawn
authors.initials: S
authors.lastname: Casey
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
authors.forename: Qiuyuan
authors.initials: Q
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China. Electronic address: jfq2008@sjtu.edu.cn.
authors.forename: Faqin
authors.initials: F
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China. Electronic address: leifu@sjtu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D015853:Cysteine Proteinase Inhibitors; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: Benzofuran; Inhibitor; Sortase A; Staphylococcus aureus