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 Escherichia coli (E. coli) and five Gram (+) inoculums. 14-O-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (3) was the most active compound and showed highest antibacterial activities. Furthermore, we evaluated the inhibition activities of compound 3 on short-term S. aureus and MRSA growth and cytochrome P450 (CYP). The bioassay results indicate that compound 3 could be considered potential antibacterial agents but with intermediate inhibition of CYP3A4.
Highlights
The emergence of multidrug-resistant bacteria has led to the reduction or loss of the curative effects of many available drugs and remains a global human threat with the potential for catastrophic consequences in the future [1]
We describe the design, synthesis, and antibacterial studies for a novel pleuromutilin derivatives with a substituted benzimidazole moiety
Novel antibacterial pleuromutilin derivatives were synthesized by introduction of the substituted benzimidazole moieties to its C22 side
Summary
The emergence of multidrug-resistant bacteria has led to the reduction or loss of the curative effects of many available drugs and remains a global human threat with the potential for catastrophic consequences in the future [1]. The natural compound pleuromutilin (Figure 1) was first discovered and isolated in a crystalline form from cultures of two species of basidiomycetes, Pleurotus mutilus and P. passeckerianus in 1951 [3]. This compound has a modest antibacterial activity [4]. Modification of the C-14 position of pleuromutilin may improve its biological activity and has led to three drugs: tiamulin, valnemulin, and retapamulin (Figure 1) [5,6,7]
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