Synthesis and Pharmacological Evaluation of Novel Pleuromutilin Derivatives with Substituted Benzimidazole Moieties

Abstract

A series of novel pleuromutilin derivatives with substituted benzimidazole moieties were designed and synthesized from pleuromutilin and 5-amino-2-mercaptobenzimidazole through sequential reactions. All the newly synthesized compounds were characterized by IR, NMR, and HRMS. Each of the derivatives was evaluated in vitro for their antibacterial activity against <i>Escherichia coli</i> (<i>E. coli</i>) and five Gram (+) inoculums. 14-<i>O</i>-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (<b>3</b>) was the most active compound and showed highest antibacterial activities. Furthermore, we evaluated the inhibition activities of compound <b>3</b> on short-term <i>S. aureus</i> and MRSA growth and cytochrome P450 (CYP). The bioassay results indicate that compound <b>3</b> could be considered potential antibacterial agents but with intermediate inhibition of CYP3A4.