title: Combinatorial synthesis and in vitro evaluation of a biaryl hydroxyketone library as antivirulence agents against MRSA.
abstract: Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA), the most widespread bacterial pathogen. Structure-activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (1) and aryloxy acetonitriles (2) as synthons. A Lewis-acid-activated Friedel-Crafts' acylation step involving a nitrile functionality of 2 by ZnCl2, followed by nucleophilic attack by 1 was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, 4f-12, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound.
authors.affiliation: Department of Biochemistry, and ‡Department of Chemistry, Case Western Reserve University , Millis Science Center, Rm 216, 2074 Adelbert Road, Cleveland Ohio 44106, United States.
authors.forename: Guanping
authors.initials: G
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Kuo
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
authors.forename: Rajesh
authors.initials: R
authors.lastname: Viswanathan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D019151:Peptide Library; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D007659:Ketones; D019151:Peptide Library