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.
Bibliographical noteFunding Information: Funding was received from King’s College London (project AC11460), PHE Pipeline (project 109502) and Grant-in Aid project (Project 109506). SJ is funded by Grants from Emergent Biosolutions (RE13292), National Biofilm Innovation Centre (POC2-091) and BBSRC (BB/T007737/1).
Open Access: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd.
Citation: Christos Matsingos, Taha Al-Adhami, Shirin Jamshidi, Charlotte Hind, Melanie Clifford, J. Mark Sutton, Khondaker Miraz Rahman, Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents, Bioorganic & Medicinal Chemistry, Volume 49, 2021, 116397, ISSN 0968-0896,
- Antimicrobial resistance
- C5-aminomethyl derivatives
- Oxazolidinone antibiotics
- Structure-activity relationship