Screening and Characterisation of Antimicrobial Properties of Semisynthetic Betulin Derivatives

Abstract

Betulin (lup-20(29)-ene-3β, 28-diol) is a naturally occurring triterpene, which is found in substantial amounts from the outer bark of birch trees. A library of 51 structurally diverse semisynthetic betulin derivatives was screened against five bacterial strains, Enterobacter aerogenes, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus and a fungal strain Candida albicans, using broth microdilution assays. Primary antimicrobial screening at 50 µM concentration led to the identification of five compounds showing antimicrobial properties (inhibition of growth by >70% against one or more microbial strains). According to the dose-response results, 28-O-(N-acetylanthraniloyl)betulin (compound 5) was the most active, showing MIC90 of 6.25 µM against two Gram-positive bacteria, E. faecalis and S. aureus. However, the activity of this compound was affected by albumin binding, which was demonstrated by the loss of activity in a host-pathogen co-culture assay as well as in the antibacterial assay in the presence of increased concentration of albumin. Furthermore, the effects on mammalian cells were evaluated by cytotoxicity assessment on hepatocyte cell culture after 24 h exposure to the compounds. Betulinic aldehyde (18), betulin-28-oxime (31) and hetero cycloadduct with acetoxy groups at carbon atoms 3 and 28 and ethyl substituent at the triazolo ring (43) displayed cytotoxicity towards hepatocytes, with IC50 values of 47, 25 and 16 µM, respectively. The IC50 value for 28-O-(N-acetylanthraniloyl)betulin (5) was 56 µM. The current study presents an insight into using betulin scaffold for developing derivatives with antibacterial potential, and furthermore the necessity of in-depth analysis of found actives through selectivity profiling and follow-up studies including in silico ADMET predictions.

Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential

“…However, another study confirmed the inhibitory activity of BA isolated from Forsythia suspensa VAHL towards the urease enzyme of H. pylori (Shin et al 2009). Despite these contradictions, some derivatives of BE were reported to exhibit antibacterial activity, which seems like a promise for future applications (Chue et al 2011;Haque et al 2014).…”

Ameliorative effect of betulin from Betula platyphylla bark on scopolamine-induced amnesic mice

“…The difference in the cognitive-enhancing activity of these two pentacyclic triterpenes, despite their structural similarity, might be related, in part, to their different distribution constants. 25,26) In this study, we show for the first time the memoryenhancing potential of betulin. Although more in vivo studies are needed to elucidate the mechanism of mammalian metabolites of betulin, we suggest that betulin has potential as a candidate as cognitive-enhancing therapeutic agent to attenuate the progression of AD.…”

C-28 Esters of Triterpenoid Acids Bearing Tris(hydroxymethyl)aminomethane: Synthesis and Anticancer/Antimicrobial Activity

“…Considering these results, we assume that dihydrobetulinic acid and compound 2 are able to trigger the programmed cell death, including apoptotic mechanisms and cell cycle arrest in the S phase. Previously, it was shown that triterpene acids, either in a pure state or as parts of plant extracts, exhibit moderate bacteriostatic activity, mainly against Gram-positive bacteria [17][18][19]. The minimum inhibitory concentrations (MICs) of ursolic and oleanolic acids against various Staphylococcus aureus strains, including the methicillin-resistant (MRSA) strain, were in the range from 8 to 64 μg/mL, while betulinic acid was less active against these strains [20].…”