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.

Novel Linezolid analogues with antiparasitic activity against Hymenolepis nana.

The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of l-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidinones 1 and 2, and coupling with 4-(4-bromophenyl)morpholine (3) to obtain N,N-dibenzylamino Linezolid analogues 4 and 5. A hydrogenolysis reaction over 4 and 5 resulted in amino-free Linezolid analogues 6 and 7, which were acetylated to reach diasteromeric Linezolid analogues 8 and 9. The six Linezolid analogues 4-9 show in vitro antiparasitic activity against Hymenolepis nana cestode, but not against several bacterial strains. Interestingly, compounds 6, 7 and 9 exhibit high potency, having shorter paralysis and death times after exposure (6-10 and 18-21 min, respectively), shorter than those found with antihelmintic compound Praziquantel (20 and 30 min) at 20 mg/mL. In addition, a cytocompatibility assay of 6-9 with human cells (ARPE-19 cells) demonstrate a non-cytotoxic effect at 0.4 mM. These results show the pharmacological potential of the newly reported Linezolid-type analogues as antiparasitic agents against Hymenolepis nana.

Design, synthesis and evaluation of the antibacterial activity of new Linezolid dipeptide-type analogues.

Worldwide studies towards development of new drugs with a lower rate in emergence of bacterial resistance have been conducted. The molecular docking analysis gives a possibility to predict the activity of new compounds before to perform their synthesis. In this work, the molecular docking analysis of 64 Linezolid dipeptide-type analogues was performed to predict their activity. The most negative scores correspond to six Fmoc-protected analogues (9as, 9bs, 9bu, 10as, 10ax and 10ay) where Fmoc group interacts in PTC for Linezolid. Twenty-six different Fmoc-protected Linezolid dipeptide-type analogues 9(as-bz) and 10(as-bz) were synthesized and tested in antimicrobial experiments. Compounds 9as, 9ay, 9ax, 10as, 10ay and 9bu show significant activity against group A Streptococcus clinical isolated. Analogue 10ay also display high activity against ATCC 25923 Staphylococcus aureus strain and MRSA-3, MRSA-4 and MRSA-5 clinical isolates, with MIC values lower than Linezolid. The highest activity against multidrug-resistant clinical isolates of Mycobacterium tuberculosis was exhibited by 9bu. Finally, a cytotoxicity assay with ARPE-19 human cells revealed a non-cytotoxic effect of 9bu and 10ay at 50 and 25 µM, respectively.

Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity.

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.

Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification.

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h-1 .

Synthesis and antibacterial bioactivities of cationic deacetyl linezolid amphiphiles.

Bacterial infections cause various life-threatening diseases and have become a serious public health problem due to the emergence of drug-resistant strains. Thus, novel antibiotics with excellent antibacterial activity and low cytotoxicity are urgently needed. Here, three series of novel cationic deacetyl linezolid amphiphiles bearing one lipophilic alkyl chain and one non-peptidic amide bond were synthesized and tested for antimicrobial activities. Several compounds showed excellent antibacterial activity toward drug-sensitive bacteria such as gram-negative bacteria Escherichia coli (E. coli), Salmonella enterica (S. enterica) and gram-positive Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis). Moreover, these amphiphilic molecules also exhibited strong activity against drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC (Klebsiella pneumoniae carbapenemase) and NDM-1 (New Delhi metallo-ß-lactamase 1) producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MICs (minimum inhibitory concentrations) of the best compound 6e, ranged from 2 to 16 µg/mL and linezolid ranged from 2 to >64 µg/mL against these strains. Therefore, 6e is a broad-spectrum antimicrobial compound that may be a suitable lead as an antibiotic. The molecule 6e were found to function primarily by permeabilization and depolarization of bacterial membranes. Importantly, bacterial resistance against compound 6e was difficult to induce, and 6e was stable under plasma conditions and showed suitable activity in mammalian plasma. Thus, these compounds can be further developed into a potential new class of broad-spectrum antibiotics.

Synthesis of Linezolid Metabolites PNU-142300 and PNU-142586 toward the Exploration of Metabolite-Related Events.

Linezolid (1) is an oxazolidinone antibiotic that is partially metabolized in vivo via ring cleavage of its morpholine moiety to mainly form two metabolites, PNU-142300 (2) and PNU-142586 (3). It is supposed that accumulation of 2 and 3 in patients with renal insufficiency may cause thrombocytopenia, one of the adverse effects of linezolid. However, the poor availability of 2 and 3 has hindered further investigation of the clinical significance of the accumulation of these metabolites. In this paper, we synthesized metabolites 2 and 3 via a common synthetic intermediate, 4; this will encourage further exploration of events related to these metabolites and lead to improved clinical use of linezolid.

Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry.

In this work, for the first time we report complementary structural and spectral studies of linezolid and its synthetic precursors (R)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methanol and (R)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methyl azide employing solid-state nuclear magnetic resonance (SS NMR) spectroscopy and electron ionization mass spectrometry. Each technique provides unique and specific set of information. Through high-resolution SS NMR using (13) C, (15) N, and (19) F as structural probes, we revealed dynamic molecular disorder in the crystal lattice for polymorphs II and III of linezolid, never reported before. Utilizing variable temperature (13) C cross-polarization magic-angle spinning technique, we proved that the disorder has a local character. Only morpholine residue of linezolid is under fast regime exchange at room temperature. This process slows down at a lower temperature and stopped at 213 K. The mass spectrometry revealed that chemical modification at oxazolidinone end of linezolid has a significant influence on fragmentation pathways of studied drug and its synthetic precursors. In particular, the compound that has azide group at the methyl substituent in the position C5 of the oxazolidinone ring is characterized by the most complicated fragmentation pattern, probably caused by thermal decomposition, which was taking place before ionization.