Novel spiro[chromanone-2,4'-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation

Abstract

Bacterial survival depends on membrane lipid homeostasis that enables to regulate lipid composition to adapt and optimize their growth in diverse environments. Therefore, the development of inhibitors that interfere with the bacterial fatty acid synthesis process is considered to be a promising tactic. In this study, 58 novel spirochromanone derivatives were prepared and their structure-activity relationship (SAR) was investigated. The bioassay results showed that all most of the compounds showed excellent biological activities, exampled by compounds B₁₄, C₁, B₁₅, and B₁₃, which had outstanding inhibitory activities toward various pathogenic bacteria with EC₅₀ values of 0.78 μg/mL ∼3.48 μg/mL. Preliminary antibacterial behavior was studied by a series of biochemical assays including, but not limited to, fluorescence imaging patterns, GC-MS analysis, TEM images, and fluorescence titration experiments. Notably, compound B₁₄ decreased the lipid content of the cell membrane, and increased cell membrane permeability, thereby destroying the integrity of the bacterial cell membrane. Further qRT-PCR results indicated that compound B₁₄ interfered with the mRNA expression levels of fatty acid synthesis process-related genes including ACC, ACP, and Fab family genes. Herein, we highlight the promising bactericidal skeleton based on the spiro[chromanone-2,4'-piperidine]-4-one as a potential inhibitor of fatty acid synthesis.

Keywords: Antibacterial activity; Bacterial fatty acid synthesis process; Membrane lipid homeostasis; Spirochromanone derivatives.