66
3 Single Molecule Non-cleavable Multiply Active Antibacterials
the polypharmacology of natural poducts by Ho et al. (2018), and Wang et al. (2017b)
have detailed the effects of berberine metabolism on its in vivo pharmacological
profile. A summary of berberine metabolites, and berberine/berberrubine physicochemical properties, plus the clinical use of berberine are also covered in the review
by Caliceti et al. (2016).
As a result of its polypharmacology coupled with a versatile chemistry, research
on berberine and derivatives continues to expand including in the antibacterial area.
Implications for the design of potential multi-targeting agents based on berberine
derivatives are explored further in this chapter.
It is also of interest to note that berberine has been shown to display anti-biofilm
activity (Borges et al. 2015; Aswathanarayan and Vittal 2018). From in vitro, and in
vivo (Caenorhabditis elegans), studies berberine inhibited biofilm formation (Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium) and had antiinfective properties with the Salmonella sp. at sub-MIC levels (Aswathanarayan
and Vittal 2018). Also Sun et al. (2019) have shown that berberine at half its MIC
concentration level can compromise biofilm formation through inhibition of the
quorum sensing system in antibacterial-resistant Escherichia coli. This inhibition
was effected through the downregulation of the expression of genes related to the
quorum sensing system.
3.2.3.2 Versatile Chemistry of Berberine
Berberine has a rich and versatile chemistry which includes electrophilic substitution,
nucleophilic addition and substituent group changes. Further versatility ensues after
ready conversion to dihydroberberine (Fig. 3.9b) with its embedded enamine functionality and also further reduction to tetrahydroberberine (Fig. 3.9c). These reduced
structures avoid issues which may flow from having a quaternary ammonium group
present for instance with adequate oral absorption for in vivo activity, assuming the
reduced structures have similar bioactivity. Dihydro derivatives are antibacterially
active (Zhang et al. 2018), but dihydroberberine itself is not as active as berberine
against Stahylococcus aureus in vitro (Rodrigues et al. 2018).
The C8 position in berberine readily undergoes nucleophilic addition reactions with a range of carbon-centred and other nucleophiles (Nechepurenko et al.
2010). Examples include the formation of 8-acetonyldihydroberberine and 8allyldihydroberberine by such nucleophilic additions. Reaction with potassium
hydroxide and subsequent oxidation (presumably in the presence of air) affords
8-oxoberberine which can then be converted to the 8-chloro derivative by reaction
with phosphorus oxychloride (Cheng et al. 2010). The 8-chloro derivative in turn is
a very useful one for the introduction of other substituents for example 8,8-dialkyl
groups (Cheng et al. 2010).
At the C9 position the methoxy substituent can be demethylated simply by thermolysis of berberine chloride to give the 9-hydroxy derivative (berberrubine) in good
yield. This phenolic group, although weakly nucleophilic due to significant electron
3 Single Molecule Non-cleavable Multiply Active Antibacterials
the polypharmacology of natural poducts by Ho et al. (2018), and Wang et al. (2017b)
have detailed the effects of berberine metabolism on its in vivo pharmacological
profile. A summary of berberine metabolites, and berberine/berberrubine physicochemical properties, plus the clinical use of berberine are also covered in the review
by Caliceti et al. (2016).
As a result of its polypharmacology coupled with a versatile chemistry, research
on berberine and derivatives continues to expand including in the antibacterial area.
Implications for the design of potential multi-targeting agents based on berberine
derivatives are explored further in this chapter.
It is also of interest to note that berberine has been shown to display anti-biofilm
activity (Borges et al. 2015; Aswathanarayan and Vittal 2018). From in vitro, and in
vivo (Caenorhabditis elegans), studies berberine inhibited biofilm formation (Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium) and had antiinfective properties with the Salmonella sp. at sub-MIC levels (Aswathanarayan
and Vittal 2018). Also Sun et al. (2019) have shown that berberine at half its MIC
concentration level can compromise biofilm formation through inhibition of the
quorum sensing system in antibacterial-resistant Escherichia coli. This inhibition
was effected through the downregulation of the expression of genes related to the
quorum sensing system.
3.2.3.2 Versatile Chemistry of Berberine
Berberine has a rich and versatile chemistry which includes electrophilic substitution,
nucleophilic addition and substituent group changes. Further versatility ensues after
ready conversion to dihydroberberine (Fig. 3.9b) with its embedded enamine functionality and also further reduction to tetrahydroberberine (Fig. 3.9c). These reduced
structures avoid issues which may flow from having a quaternary ammonium group
present for instance with adequate oral absorption for in vivo activity, assuming the
reduced structures have similar bioactivity. Dihydro derivatives are antibacterially
active (Zhang et al. 2018), but dihydroberberine itself is not as active as berberine
against Stahylococcus aureus in vitro (Rodrigues et al. 2018).
The C8 position in berberine readily undergoes nucleophilic addition reactions with a range of carbon-centred and other nucleophiles (Nechepurenko et al.
2010). Examples include the formation of 8-acetonyldihydroberberine and 8allyldihydroberberine by such nucleophilic additions. Reaction with potassium
hydroxide and subsequent oxidation (presumably in the presence of air) affords
8-oxoberberine which can then be converted to the 8-chloro derivative by reaction
with phosphorus oxychloride (Cheng et al. 2010). The 8-chloro derivative in turn is
a very useful one for the introduction of other substituents for example 8,8-dialkyl
groups (Cheng et al. 2010).
At the C9 position the methoxy substituent can be demethylated simply by thermolysis of berberine chloride to give the 9-hydroxy derivative (berberrubine) in good
yield. This phenolic group, although weakly nucleophilic due to significant electron