Synthesis, biological activities, and docking study of novel chalcone‐pleuromutilin derivatives

Abstract

The issue of antibiotic resistance is becoming progressively serious these days, and the feasible solution to address it is to develop and discover novel antibiotics. The diterpene natural pleuromutilin is a prominent candidate for its special mode of action by inhibiting protein synthesis. In this study, a series of novel pleuromutilin derivatives with chalcone moiety was designed and synthesized, and their antibacterial activities were assessed in vitro. As suggested from the results, most of compounds exhibited potent activities against two methicillin‐resistant Staphylococcus aureus (MRSA) ATCC 33591 and 43300. The further modification of the chalcone structure, aza‐cyclic derivatives were afforded and then assessed, and potent activities against the tested strains were reported. The preliminary docking studies were conducted to explore the interactions between target molecules and binding site.

Cprp—An Unusual, Repetitive Protein Which Impacts Pleuromutilin Biosynthesis in the Basidiomycete Clitopilus passeckerianus

“…These compounds are all derived from a tricyclic diterpene natural product called pleuromutilin, which is produced by Clitopilus passeckerianus and related basidiomycete fungi (Hartley et al, 2009 ). Tiamulin and valnemulin ( Figure 1 ) have been used in veterinary medicine for many years (Poulsen et al, 2001 ), but an increasing need for new antibiotics—largely due to the emergence of antibiotic resistant strains in community situations—has led to a surge in the development of pleuromutilin derivatives specifically for human use (Brooks et al, 2001 ; Bacqué et al, 2002 ; Springer et al, 2003 ; Hirokawa et al, 2009 ; Wang et al, 2012 ; Shang et al, 2013 , 2014 ; Gao et al, 2017 ; Mu et al, 2017 ; Jin et al, 2019 ; Fan et al, 2020 ; Xie et al, 2020 ; Zhang et al, 2020 ). To date, two pleuromutilin antibiotics, retapamulin and lefamulin ( Figure 1 ), have approval for use in human therapeutics (Butler, 2008 ; Lodise et al, 2020 ), and the development of further derivatives is ongoing, with the extended spectrum pleuromutilins (ESPs) showing promise against the difficult to treat Gram-negative bacteria (Paukner et al, 2013a , b , 2015a , b ; Wicha et al, 2015 ; Thirring et al, 2017 ).…”