Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with a Substituted Thiadiazole Moiety as Potent Drug-Resistant Bacteria Inhibitors

• Published in: Journal of medicinal chemistry Vol. 57; no. 13; pp. 5664 - 5678
• Main Authors: Shang, Ruofeng, Pu, Xiuying, Xu, Ximing, Xin, Zhijun, Zhang, Chao, Guo, Wenzhu, Liu, Yu, Liang, Jianping
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.07.2014; Amer Chemical Soc
• Subjects: Animals; Bacteria - drug effects; Chemistry, Medicinal; Diterpenes - chemical synthesis; Diterpenes - pharmacokinetics; Diterpenes - pharmacology; Escherichia coli - drug effects; Life Sciences & Biomedicine; Methicillin Resistance - drug effects; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Models, Molecular; Molecular Docking Simulation; Pharmacology & Pharmacy; Pleuromutilins; Polycyclic Compounds; Rats; Science & Technology; Staphylococcus epidermidis - drug effects; Structure-Activity Relationship; Thermodynamics; Thiadiazoles - chemical synthesis; Thiadiazoles - pharmacokinetics; Thiadiazoles - pharmacology; FIT; CHEMISTRY; AGENTS; ANTIBACTERIAL ACTIVITY; BINDING; VALNEMULIN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500374c

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 (ΔG b, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.