Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage

Abstract

Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 lg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate p-p stacking between molecules and surrounding residues.

Biosynthesis and regulation of terpenoids from basidiomycetes: exploration of new research

“…Basidiomycetes are rich sources of terpenes with extensive pharmacological activities, such as the antidepressant effect of Armillaria mellea (Zhang et al 2021a , b , c ), the anticancer and anti-inflammatory activity of Antrodia camphorata (Wang et al 2019a , b ), the antitumour and immunoregulatory effects of L. rhinocerotis , and the antitumour, anti-inflammatory and antiallergic effects of Agaricus blazei , H. erinaceus and Grifola frontosa (Lau et al 2015 ). However, genetic manipulation of basidiomycetes is known to be difficult and immature.…”

“…Basidiomycetes, particularly their sporocarps, contain abundant natural products (Tian et al 2020 ). For example, pleuromutilin, a diterpenoid natural product, shows moderate activities against gram-positive bacteria and mycoplasmas (Zhang et al 2021a , b , c ). Due to its low cytotoxicity in mammals and low environmental impact, pleuromutilin has been gradually developed into a commercial antibiotic.…”

“…The primary active components of G. lucidum are polysaccharides and G. lucidum triterpenes (GLTs), which have immune regulation and antitumour effects (Tian et al 2021 ; Shao et al 2020 ; Do et al 2021 ; Zhang et al 2021a , b , c ; Bharadwaj et al 2019 ). G. lucidum is the fungus with the most triterpenoids, and more than 250 triterpenoid compounds have been identified from this species.…”

Acute, subacute oral toxicity and Ames test of Py-mulin: an antibacterial drug candidate

“…The modification of the pleuromutilin glycolic ester, especially the presence of thioether group, has been shown to give derivatives with improved antibacterial activities [ 14 , 15 ], and thus has led to four drugs: tiamulin, valnemulin, retapamulin and lefamulin [ 16 – 20 ]. Tiamulin and valnemulin were approved as veterinary antibiotics for swine dysentery, enzootic pneumonia and chronic respiratory disease in poultry [ 16 , 17 , 21 ]. Retapamulin was for human topical skin infections [ 19 ].…”

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

“…In 2008, Muhi-eldeen et al, synthesized a hybrid compound with 1,3,4-oxadiazole moiety and pyrrolidine connected with propargylic moiety showed antibacterial activity against Staphylococcus aureus and E. coli [ 14 ]. On the other hand, the coupling of piperazine with heterocyclic compounds enhanced the biological activities like anticancer [ 15 – 16 ], antibacterial [ 17 ], antimalarial [ 18 ], anti-inflammatory [ 19 ], and lead to a promising scaffold for the treatment of Alzheimer’s disease [ 20 ]. Our previous work showed that a combination between cholic acid and heterocyclic scaffolds improved the antibacterial property ( Figure 1 ) [ 21 ].…”