Synthesis and Biological Activity Evaluation of Novel Heterocyclic Pleuromutilin Derivatives

Abstract

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 <i>Staphylococcus aureus</i>, methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), methicillin-resistant <i>Staphylococcus epidermidis</i> (MRSE), and vancomycin-resistant <i>Enterococcus</i> (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, <b>3a</b>, <b>3b</b>, and <b>3f</b>, displayed modest antibacterial activities. Compound <b>3a</b>, 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 <b>3a</b> 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.