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

Yong Zhang; Jian Bao; Xin-Xian Deng; Wan He; Jia-Jun Fan; Fa-Qin Jiang; Lei Fu

doi:10.1016/j.bmcl.2016.06.074

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

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4081-5. doi: 10.1016/j.bmcl.2016.06.074. Epub 2016 Jun 25.

Authors

Yong Zhang¹, Jian Bao², Xin-Xian Deng², Wan He², Jia-Jun Fan², Fa-Qin Jiang³, Lei Fu⁴

Affiliations

¹ School of Life Science and Biotechnology, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
² School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China.
³ School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China. Electronic address: [email protected].
⁴ School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China. Electronic address: [email protected].

PMID: 27400889
DOI: 10.1016/j.bmcl.2016.06.074

Abstract

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=130μM). Most compounds exhibited excellent inhibitory activity (IC50=19.8-184.2μM). 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.

Keywords: Anti-infective; Benzo[d]oxazole; Sortase A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry*
Amides / metabolism
Amides / pharmacology
Aminoacyltransferases / antagonists & inhibitors*
Aminoacyltransferases / metabolism
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Binding Sites
Cysteine Endopeptidases / metabolism
Inhibitory Concentration 50
Molecular Docking Simulation
Oxazoles / chemistry
Protein Binding
Protein Structure, Tertiary
Staphylococcus aureus / enzymology*
Static Electricity
Structure-Activity Relationship

Substances

Amides
Anti-Bacterial Agents
Bacterial Proteins
Oxazoles
Aminoacyltransferases
sortase A
Cysteine Endopeptidases