Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents

Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.

Automated summary

The issue of antimicrobial resistance and the lack of new antibiotics for treating multidrug-resistant bacteria present a significant challenge in public health. Research on the structure-activity relationships of the C5-acylaminomethyl moiety of the oxazolidinone antibiotic linezolid has provided valuable insights into the development of new antibiotics. The study suggests that modifications at this specific position are crucial for the function of antibiotics in this class.