Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

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.