68
3 Single Molecule Non-cleavable Multiply Active Antibacterials
Incorporation of more than one substituent attached to the berberine core can be
achieved by sequential application of the regioselective reactions mentioned above.
A good recent review of a range of such berberine analogues, plus some interesting
new chemistry for mono substituent variations, is summarised in Wang et al. (2015).
Included in this review is a discussion of 13-alkyl- and various 9- or 13-alkoxy
(long chain) berberine derivatives as well as disubstituted analogues, together with
some antibacterial activity data. Such disubstituted berberines are readily accessible
synthetically and some have reduced human fibroblast cell toxicity with very good
in vitro activity against drug resistant strains of Staphylococcus aureus (Wang et al.
2017a).
In addition to the sites mentioned for the attachment of substituents, the fused
methylenedioxy group in berberine can be selectively ring opened giving access
to a 2,3-diol or catechol derivative (demethyleneberberine) on reaction with boron
tribromide and aqueous workup (Roselli et al. 2016) and these groups in turn could
then serve as anchor points for other groups, although regioselectivity issues may be
a problem if different groups are involved. The methylenedioxy group can also be
cleaved by hydrogenolysis to afford the o-methoxyphenolic system.
Apart from introducing other functional groups, the reaction products from
cleavage of the methylenedioxy groups also constitute a manipulation of the berberine
heterocyclic framework with the 5-membered ring being removed from the berberine
5, 6, 6, 6, 6 fused ring network. Framework manipulation of the berberine skeleton
and reduced derivatives has been widely researched over a number of years and one
example of this is the transformation skeletally to the 5, 6, 7, 5, 6 series as reported
by Zhou and Tong (2016).
3.2.3.3 How to Devise New Structures
While de novo design or fragment-based design are important approaches to attaining
multi-targeting compounds, an equally important opportunity involves starting with
a known relatively complex structure (rather than simpler ones as in the fragmentbased design approach) and using it to plan and develop new structures with different
pharmacophoric groupings. To illustrate some of the principles involved with this
alternative approach, application to the alkaloid berberine as a structurally advanced
starting point is discussed in this sub-section.
The first general design steps normally involve maintaining the core framework
and varying attached groups. Within the ‘flatland’ sphere of berberine there are
sites or opportunities for substituent variation and for the introduction of other
rings, including spiro systems, to increase topological complexity and other sites for
displaying different functional groups with different relative spatial arrangements. A
challenge though, and this applies to other medicinal agent design, is how to modify
the skeleton expeditiously. Normally, to do this a synthesis from scratch is required,
but with berberine as indicated in the section above, functional groups or group units
can be introduced and/or interchanged with compact syntheses and moderate to good
yields.
3 Single Molecule Non-cleavable Multiply Active Antibacterials
Incorporation of more than one substituent attached to the berberine core can be
achieved by sequential application of the regioselective reactions mentioned above.
A good recent review of a range of such berberine analogues, plus some interesting
new chemistry for mono substituent variations, is summarised in Wang et al. (2015).
Included in this review is a discussion of 13-alkyl- and various 9- or 13-alkoxy
(long chain) berberine derivatives as well as disubstituted analogues, together with
some antibacterial activity data. Such disubstituted berberines are readily accessible
synthetically and some have reduced human fibroblast cell toxicity with very good
in vitro activity against drug resistant strains of Staphylococcus aureus (Wang et al.
2017a).
In addition to the sites mentioned for the attachment of substituents, the fused
methylenedioxy group in berberine can be selectively ring opened giving access
to a 2,3-diol or catechol derivative (demethyleneberberine) on reaction with boron
tribromide and aqueous workup (Roselli et al. 2016) and these groups in turn could
then serve as anchor points for other groups, although regioselectivity issues may be
a problem if different groups are involved. The methylenedioxy group can also be
cleaved by hydrogenolysis to afford the o-methoxyphenolic system.
Apart from introducing other functional groups, the reaction products from
cleavage of the methylenedioxy groups also constitute a manipulation of the berberine
heterocyclic framework with the 5-membered ring being removed from the berberine
5, 6, 6, 6, 6 fused ring network. Framework manipulation of the berberine skeleton
and reduced derivatives has been widely researched over a number of years and one
example of this is the transformation skeletally to the 5, 6, 7, 5, 6 series as reported
by Zhou and Tong (2016).
3.2.3.3 How to Devise New Structures
While de novo design or fragment-based design are important approaches to attaining
multi-targeting compounds, an equally important opportunity involves starting with
a known relatively complex structure (rather than simpler ones as in the fragmentbased design approach) and using it to plan and develop new structures with different
pharmacophoric groupings. To illustrate some of the principles involved with this
alternative approach, application to the alkaloid berberine as a structurally advanced
starting point is discussed in this sub-section.
The first general design steps normally involve maintaining the core framework
and varying attached groups. Within the ‘flatland’ sphere of berberine there are
sites or opportunities for substituent variation and for the introduction of other
rings, including spiro systems, to increase topological complexity and other sites for
displaying different functional groups with different relative spatial arrangements. A
challenge though, and this applies to other medicinal agent design, is how to modify
the skeleton expeditiously. Normally, to do this a synthesis from scratch is required,
but with berberine as indicated in the section above, functional groups or group units
can be introduced and/or interchanged with compact syntheses and moderate to good
yields.