74
3 Single Molecule Non-cleavable Multiply Active Antibacterials
One potential concern with this ring construction approach to new structures is
that molecular weights can be increased significantly when starting from a multiatom natural product system which may then negatively impact on physicochemical
properties for oral bioavailability.
Exploring biologically relevant chemical structural space is a developing area of
research. Various approaches are being taken including fragment based ones with
later linking of the fragments in diversity-oriented strategies or what is referred
to as the top down synthetic approach in which more complex intermediates are
accessed and converted into natural product-resembling structural scaffolds. The
approach outlined from berberine above in a sense is an extension of this approach,
but one starting with a structurally versatile bio-active natural product or readily
available derivatives and then exploring other known or hypothetical skeletons from
this starting point. Some other recent advances in a related area involve mapping
of the amine-carboxylic acid coupling system with enumeration of the hypothetical
transformations that are possible (Mahjour et al. 2020). Further developments here
will be of interest as they are heading towards a fully mathematical description of
transformations and the properties of their products which could highlight and predict
previously unconsidered transformations of potential benefit in drug discovery.
Further framework manipulation of the berberine skeleton involving ring
construction of an additional 6-membered carbocyclic ring can be achieved by orthoand peri-fusion on to the basic skeleton. This involved reduction of berberine to dihydroberberine and then attack by the resultant enamine on glyoxal followed by water
loss and tautomerisation to reform the berberine skeleton with a 13-formylmethyl
group. Cyclisation to give what is referred to as cycloberberine can then be achieved
by intramolecular acid-catalysed electrophilic substitution on the adjacent electronrich aromatic ring (Yang et al. 2019). Some cycloberberine derivatives with an 8hydroxy group (the 9-position in berberine itself) show potent antibacterial activity
due, at least in part, to the binding to the hydrophobic binding pocket in topoisomerase
IV (Yang et al. 2019).
3.2.3.4 Dual Action Berberine-Based Hybrids
There has been a significant amount of work done on derivatives of berberine in a
search for increased antibacterial activity compared with berberine (Nechepurenko
et al. 2010; Iwasa et al. 1998) including in the dual action sector, where some intentionally dual-action designed berberine-based hybids have been made and assessed.
Berberine is a substrate for the NorA pump which severely comprises its antibacterial activity, for example in Staphylococcus aureus so compounds have been made
which contain structural elements based on a NorA efflux pump inhibitor attached
to a berberine core. Some examples based on berberine (Fig. 3.12c) include 13substituted derivatives incorporating methylene (Fig. 3.12a) (Bremner and Kelso
2010b; Tomkiewicz et al. 2010; Ball et al. 2006) or oxymethylene (Fig. 3.12b)
(Samosorn et al. 2009) linker groups plus terminal structural elements of the potent
NorA bacterial efflux pump inhibitor INF55 (5-nitro-2-phenyl-1H-indole). These
3 Single Molecule Non-cleavable Multiply Active Antibacterials
One potential concern with this ring construction approach to new structures is
that molecular weights can be increased significantly when starting from a multiatom natural product system which may then negatively impact on physicochemical
properties for oral bioavailability.
Exploring biologically relevant chemical structural space is a developing area of
research. Various approaches are being taken including fragment based ones with
later linking of the fragments in diversity-oriented strategies or what is referred
to as the top down synthetic approach in which more complex intermediates are
accessed and converted into natural product-resembling structural scaffolds. The
approach outlined from berberine above in a sense is an extension of this approach,
but one starting with a structurally versatile bio-active natural product or readily
available derivatives and then exploring other known or hypothetical skeletons from
this starting point. Some other recent advances in a related area involve mapping
of the amine-carboxylic acid coupling system with enumeration of the hypothetical
transformations that are possible (Mahjour et al. 2020). Further developments here
will be of interest as they are heading towards a fully mathematical description of
transformations and the properties of their products which could highlight and predict
previously unconsidered transformations of potential benefit in drug discovery.
Further framework manipulation of the berberine skeleton involving ring
construction of an additional 6-membered carbocyclic ring can be achieved by orthoand peri-fusion on to the basic skeleton. This involved reduction of berberine to dihydroberberine and then attack by the resultant enamine on glyoxal followed by water
loss and tautomerisation to reform the berberine skeleton with a 13-formylmethyl
group. Cyclisation to give what is referred to as cycloberberine can then be achieved
by intramolecular acid-catalysed electrophilic substitution on the adjacent electronrich aromatic ring (Yang et al. 2019). Some cycloberberine derivatives with an 8hydroxy group (the 9-position in berberine itself) show potent antibacterial activity
due, at least in part, to the binding to the hydrophobic binding pocket in topoisomerase
IV (Yang et al. 2019).
3.2.3.4 Dual Action Berberine-Based Hybrids
There has been a significant amount of work done on derivatives of berberine in a
search for increased antibacterial activity compared with berberine (Nechepurenko
et al. 2010; Iwasa et al. 1998) including in the dual action sector, where some intentionally dual-action designed berberine-based hybids have been made and assessed.
Berberine is a substrate for the NorA pump which severely comprises its antibacterial activity, for example in Staphylococcus aureus so compounds have been made
which contain structural elements based on a NorA efflux pump inhibitor attached
to a berberine core. Some examples based on berberine (Fig. 3.12c) include 13substituted derivatives incorporating methylene (Fig. 3.12a) (Bremner and Kelso
2010b; Tomkiewicz et al. 2010; Ball et al. 2006) or oxymethylene (Fig. 3.12b)
(Samosorn et al. 2009) linker groups plus terminal structural elements of the potent
NorA bacterial efflux pump inhibitor INF55 (5-nitro-2-phenyl-1H-indole). These