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

Abstract 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. The 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.