Pleuromutilins were discovered as natural-product antibiotics in 1950. The modifications of pleuromutilin lead to the successful development of veterinary medicines such as tiamulin and valnemulin. Retapamulin became the first pleuromutilin approved for use in human skin infections. Recent advances have led to the synthesis of pleuromutilins that combine potent antibacterial activity with favorable pharmaceutical properties, and three new pleuromutilins, BC-3781, BC-3205 and BC-7013, have entered clinical trials. In this review, the key pleuromutilin derivatives, as well as related novel derivatives during 2009-2013, and its antibacterial activities, are presented. Moreover, the antibacterial and resistance mechanism are discussed.

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.

A series of pleuromutilin derivatives were synthesized by two synthetic procedures under mild reaction conditions and characterized by Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), and High Resolution Mass Spectrometer (HRMS). Most of the derivatives with heterocyclic groups at the C-14 side of pleuromutilin exhibited excellent in vitro antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, 3a, 3b, and 3f, displayed modest antibacterial activities. Compound 3a, the most active antibacterial agent, displayed rapid bactericidal activity and affected bacterial growth in the same manner as that of tiamulin fumarate. Moreover, molecular docking studies of 3a and lefamulin provided similar information about the interactions between the compounds and 50S ribosomal subunit. The results of the study show that pyrimidine rings should be considered in the drug design of pleuromutilin derivatives.