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

• Published in: Bioorganic chemistry 2020-01, Vol.95, p.103483, Article 103483
• Main Authors: García-Olaiz, G.D., Alcántar-Zavala, Eleazar, Ochoa-Terán, Adrián, Cabrera, Alberto, Muñiz-Salazar, Raquel, Montes-Ávila, Julio, Salazar-Medina, Alex J., Alday, Efrain, Velazquez, Carlos, Medina-Franco, José L., Laniado-Laborín, Rafael
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Dipeptide-type; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Docking; Dose-Response Relationship, Drug; Drug Design; Humans; Linezolid - chemical synthesis; Linezolid - chemistry; Linezolid - pharmacology; Linezolid analogues; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis - drug effects; Organic synthesis; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103483

[Display omitted] •A stereoselective synthesis of 26-Linezolid dipeptide-type analogous was performed.•Docking analysis shows the coupling of Linezolid dipeptide-type analogues in PTC.•Linezolid analogues display antibacterial activity against clinical isolates.•Linezolid dipeptide-type analogous preserve the cellular integrity of ARPE-19 cells. 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.