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 <i>Staphylococcus aureus</i> (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 (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> 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, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

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 <i>Staphylococcus aureus</i> (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 (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> 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, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

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 <i>Staphylococcus aureus</i> (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 (<b>1</b>) and aryloxy acetonitriles (<b>2</b>) as synthons. A Lewis-acid-activated Friedel–Crafts’ acylation step involving a nitrile functionality of <b>2</b> by ZnCl₂, followed by nucleophilic attack by <b>1</b> 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, <b>4f-12</b>, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound

Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice

A polyethylene glycol (PEG) retinylamine (Ret-NH₂) conjugate PEG-GFL-NH-Ret with a glycine-phenylalanine-leucine (GFL) spacer was synthesized for controlled oral delivery of Ret-NH₂ to treat retinal degenerative diseases, including Stargardt disease (STGD) and age-related macular degeneration (AMD). The peptide spacer was introduced for sustained release of the drug by digestive enzymes in the gastrointestinal tract. The pharmacokinetics experiments showed that the PEG conjugate could control the sustained drug release after oral administration and had much lower nonspecific liver drug accumulation than the free drug in wild-type female C57BL mice. In the mean time, the conjugate maintained the same concentration of Ret-NH₂ in the eye as the free drug. Also, PEG-GFL-NH-Ret at a Ret-NH₂ equivalent dose of 25 mg/kg produced complete protection of <i>Abca4</i>^–/–<i>Rdh8</i>^–/– mouse retinas against light-induced retinal degeneration for 3 days after oral administration, as revealed by OCT retina imaging, whereas free Ret-NH₂ did not provide any protection under identical conditions. The polymer conjugate PEG-GFL-NH-Ret has great potential for controlled delivery of Ret-NH₂ to the eye for effective protection against retinal degenerative diseases