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Synthesis and biological activities of novel pleuromutilin derivatives with a substituted thiadiazole moiety as potent drug-resistant bacteria inhibitors.

Abstract：

:A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Shang R,Pu X,Xu X,Xin Z,Zhang C,Guo W,Liu Y,Liang J

doi

10.1021/jm500374c

subject

Has Abstract

pub_date

2014-07-10 00:00:00

pages

5664-78

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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