Synthesis and biological evaluation of new pleuromutilin derivatives as antibacterial agents.

Ruo-Feng Shang,Si-Jie Liu,Xi-Ming Xu,Guan-Hua Wang,Jian-Ping Liang,Yu Liu,Chao Zhang,Yun-Peng Yi

doi:10.3390/molecules191119050

Abstract

Several pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant S. aureus, methicillin-resistant S. epidermidis, S. aureus, S. epidermidis, E. coli, and B. cereus were tested by the agar dilution method and Oxford cup assay. All the screened compounds displayed potent activity. Compound 6d was the most active antibacterial agent because of its lowest MIC value and largest inhibition zone. Docking experiments were performed to understand the possible mode of the interactions between the derivatives and 50S ribosomal subunit. Moreover, the absorption, distribution, metabolism, excretion and toxicity properties of the synthesized compounds were analyzed after prediction using the Advanced Chemistry Development/Percepta Platform available online.

Highlights

The natural compound pleuromutilin (Figure 1) was first discovered and isolated in a crystalline form from Pleurotus mutilus and P. passeckerianus in 1951 [1]
Pleuromutilin derivatives 5a–c and 6a–d were synthesised from the lead compound
The reactions were performed at room temperature in the presence of 1-ethyl-3-(3-dimethyllaminopropyl) carbodiimide hydrochloride (EDCI) and

Summary

Introduction

The natural compound pleuromutilin (Figure 1) was first discovered and isolated in a crystalline form from Pleurotus mutilus and P. passeckerianus in 1951 [1]. Pleuromutilin is a diterpene, constituted of a rather rigid 5-6-8 tricyclic carbon skeleton with eight stereogenic centers [2,3] and a glycolic acid chain at C-14 which was considered as the main molecular modification point [4]. Pleuromutilin has a modest antibacterial activity, the modifications of the C-14 position have led to three drugs: tiamulin, valnemulin, and retapamulin (Figure 1). Tiamulin and valnemulin are used in veterinary medicine for pigs and poultry. Retapamulin was approved as a topical antimicrobial agent for the treatment of human skin infections in 2007 by FDA [5,6]. Extensive efforts were made to formulate BC-3781, BC-3205 and BC-7013 (Figure 1) for human use [7,8] after the success of retapamulin

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Results

Conclusion