3.3 Triple Action Antibacterial Hybrid Agents
95
sequential Meisenheimer and reductive cleavage chemistry to afford other structural
variations in the product. The Meisenheimer rearrangement should favour formation
of a C1–O bond in this case and hence the positioning of the hydroxyl group after
N–O bond cleavage.
Ring construction reactions from the tropane scaffold to give more rigid compact
structures are also possible. For example, on basic hydrolysis of the ester side chain in
scopolamine, intramolecular nucleophilic attack on the epoxide group occurs readily
to give the tricyclic derivative oscine (Fig. 3.21c, R=CH 3 ). With this rigid skelton one
has a tertiary hydroxyl substituent, and an ether oxygen and amino nitrogen as part of
the ring system and pharmacophoric groups could be subsequently attached via this
nitrogen or from the hydroxyl group. Additional possibilities for attachment of groups
would be provided from the aza analogue (Fig. 3.21d, R=CH 3 ) of oscine, and derivatives, if this could be synthesised. A homologous system is known (DeCorte et al.
2018) but the 5-membered ring analogue does not appear to have been reported. Rigid
polycyclic scaffolds in drug design, including multi-mechanism chimeras (Bansal
and Silakari 2014; Van der Schyf and Geldenhuys 2009), are of continuing research
interest.
Berberine and congeners
The biologically active, antibacterial quaternary alkaloid berberine (Figs. 3.9a and
3.12c) also provides much scope for the design of potential triple action agents of
type i. It is available relatively cheaply commercially, and possesses a number of
sites for structural tailoring and introduction of different groups. There are a number
of reaction sites on the berberine skeleton and some of the key ones have been
summarized in Sect. 3.2.3.2. Reactions at these sites provide good opportunities for
the introduction of functional or structural moieties. For example substituent groups
can be introduced at C13 in berberine, after conversion to dihydroberberine or 8substituted dihydroberberines and subsequent re-conversion to the quaternary salt
structure (Bremner and Kelso 2010). Also electrophilic substitution on berberine
itself or on derivatives (for example berberrubine) enables the direct introduction
of substituents at C12. With berberrubine this substitution occurred via a Mannichtype reaction (Li et al. 2014b; Mistry et al. 2017). Using these reactions, at each of
these positions substituents incorporating different biological target motifs, A, or C
(as in Fig. 3.22a or b), for example, could be introduced. The heterocyclic skeleton
in the retained berberine core may act as a recognition element in itself (shown
as B in Fig. 3.22a) for DNA binding (Jin et al. 2010) or inhibition of assembly
of the protein FtsZ, a key protein for bacterial cell division (Boberek et al. 2010;
Domadia et al. 2008). Domadia et al. (2008) include in their paper modelling studies
on berberine interacting with FtsZ and from their results the inclusion of different
small pharmacophores in the 9-OR group would seem possible, while maintaining
FtsZ binding. Boberek et al. (2010) also indicate that this binding may be of greater
importance than DNA binding in the antibacterial activity of berberine on the basis
of genetic evidence in Escherichia coli. Various compounds show inhibitory activity
against FtsZ including 3-methoxybenzamide (3-MBA) analogues (Stokes et al. 2013)
95
sequential Meisenheimer and reductive cleavage chemistry to afford other structural
variations in the product. The Meisenheimer rearrangement should favour formation
of a C1–O bond in this case and hence the positioning of the hydroxyl group after
N–O bond cleavage.
Ring construction reactions from the tropane scaffold to give more rigid compact
structures are also possible. For example, on basic hydrolysis of the ester side chain in
scopolamine, intramolecular nucleophilic attack on the epoxide group occurs readily
to give the tricyclic derivative oscine (Fig. 3.21c, R=CH 3 ). With this rigid skelton one
has a tertiary hydroxyl substituent, and an ether oxygen and amino nitrogen as part of
the ring system and pharmacophoric groups could be subsequently attached via this
nitrogen or from the hydroxyl group. Additional possibilities for attachment of groups
would be provided from the aza analogue (Fig. 3.21d, R=CH 3 ) of oscine, and derivatives, if this could be synthesised. A homologous system is known (DeCorte et al.
2018) but the 5-membered ring analogue does not appear to have been reported. Rigid
polycyclic scaffolds in drug design, including multi-mechanism chimeras (Bansal
and Silakari 2014; Van der Schyf and Geldenhuys 2009), are of continuing research
interest.
Berberine and congeners
The biologically active, antibacterial quaternary alkaloid berberine (Figs. 3.9a and
3.12c) also provides much scope for the design of potential triple action agents of
type i. It is available relatively cheaply commercially, and possesses a number of
sites for structural tailoring and introduction of different groups. There are a number
of reaction sites on the berberine skeleton and some of the key ones have been
summarized in Sect. 3.2.3.2. Reactions at these sites provide good opportunities for
the introduction of functional or structural moieties. For example substituent groups
can be introduced at C13 in berberine, after conversion to dihydroberberine or 8substituted dihydroberberines and subsequent re-conversion to the quaternary salt
structure (Bremner and Kelso 2010). Also electrophilic substitution on berberine
itself or on derivatives (for example berberrubine) enables the direct introduction
of substituents at C12. With berberrubine this substitution occurred via a Mannichtype reaction (Li et al. 2014b; Mistry et al. 2017). Using these reactions, at each of
these positions substituents incorporating different biological target motifs, A, or C
(as in Fig. 3.22a or b), for example, could be introduced. The heterocyclic skeleton
in the retained berberine core may act as a recognition element in itself (shown
as B in Fig. 3.22a) for DNA binding (Jin et al. 2010) or inhibition of assembly
of the protein FtsZ, a key protein for bacterial cell division (Boberek et al. 2010;
Domadia et al. 2008). Domadia et al. (2008) include in their paper modelling studies
on berberine interacting with FtsZ and from their results the inclusion of different
small pharmacophores in the 9-OR group would seem possible, while maintaining
FtsZ binding. Boberek et al. (2010) also indicate that this binding may be of greater
importance than DNA binding in the antibacterial activity of berberine on the basis
of genetic evidence in Escherichia coli. Various compounds show inhibitory activity
against FtsZ including 3-methoxybenzamide (3-MBA) analogues (Stokes et al. 2013)