title: Improved small-molecule macroarray platform for the rapid synthesis and discovery of antibacterial chalcones.
abstract: Bacterial resistance to current antibiotics is a major global health threat. Consequently, there is an urgent need for the identification of new antibacterial agents. We are applying the small-molecule macroarray platform to rapidly synthesize and screen compounds for activity against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report the synthesis of a 1,3-diphenyl-2-propen-1-one (chalcone) macroarray using a Rink-amide linker-derivatized cellulose support. The Rink linker allowed for the incorporation of a broader array of library building blocks relative to our previous syntheses because milder reaction conditions could be utilized; significantly higher compound loadings were also achieved (~80% vs ~15%). Analysis of the 174-member chalcone macroarray in off-support antibacterial screening assays revealed three chalcones with minimum inhibitory concentration (MIC) values against MRSA comparable to currently used antibacterial drugs and low hemolytic activities. These results serve to further showcase and extend the utility of the small molecule macroarray for antibacterial discovery.
authors.affiliation: Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706-1322, United States.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stringer
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Bowman
authors.forename: Bernard
authors.initials: B
authors.lastname: Weisblum
authors.forename: Helen E
authors.initials: HE
authors.lastname: Blackwell
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D055624:Methicillin-Resistant Staphylococcus aureus; D046228:Microarray Analysis; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D047188:Chalcones