3.2 Designing for Mainly Dual Activity
71
to these systems or suggest new approaches to target systems and thus aid in the
exploration of further biological properties including antibacterial ones for multiactive antibacterial hybrid design. Such multi-ring systems could be bond linked.
atom linked (spiro systems), bond fused, bond bridged, stable/isolable complexes
with rings, quasi rings formed through non-covalent interactions, and mechanical
bond linked systems such as catenanes, rotaxanes with more than one ring, pseudorotaxanes (Xue et al. 2015) and pseudo-catenanes. In the context of mechanical
bond systems, it is of interest to note that nature uses antibacterial threaded-peptides
like capistruin and probably, microcin J25, to inhibit bacterial RNA polymerase
(Kuznedelov et al. 2011), and perhaps more such natural antibacterial systems will
be found in the future.
It is profitable to explore this ring taxonomy theme further with berberine as the
springboard for expansion into new chemical space while preserving capabilities for
inclusion of pharmacophoric or functional group entities.
As noted in Sect. 3.2.3.2, 13-hydroxyberberine as the phenolbetaine is amenable
to O-alkylation of the 13-oxy functionality (Samosorn et al. 2009) affording access to
potential new derivatives incorporating terminal primary amino group functionality
to facilitate permeation in Gram-negative bacterial pathogens. In addition, structural
features to target inhibition of bacterial efflux pump activity could also be built in to
an 8-alkoxy substituent leading to a hybrid which might overcome the pump efflux
resistance mechanism while maintaining overall features similar to those in berberine
and thus the ability to target the DNA and protein sites with which berberine interacts (Olleik et al. 2020). While 13-hydroxyberberine is a more potent antibacterial
than berberine it has greater liver cell toxicity. However some other 13-arylalkoxy
derivatives of berberine showed good antibacterial activity with very much reduced
toxicity. Olleik et al. (2020) showed that these derivatives did not seem to fragment
bacterial DNA but did interact with the bacterial FtsZ protein.
Thought experiments are important in helping to explore new structural space and
coming up with new structural possibilities. With these experiments one imagines
bond forming and/or bond making changes and then assesses the structural consequences of these changes. This can be illustrated for example with the reduced
tetrahydroberberine core structure (shown for simplicity in Scheme 3.1 without
the methoxy substituents or the fused methylenedioxy ring). Through such thought
experiments one can visualise systematic bond breaking around the ring nitrogen as
well as C–C bond breaking, followed by bond making or re-making, without necessarily knowing how to get there synthetically in the first instance. The emphasis
should be initially on hypothetical structural changes. Later functional group manipulations or modifications with the addition or deletion of atoms and subsequent reactions can be incorporated leading to other skeletons. Commensurate with this, the
simplified tetrahydroprotoberberine skeleton might be envisaged to provide access
to benz-fused tropanes for example with substituent variations as illustrated in
Scheme 3.1 by (I) and (II). This can be a powerful approach to new drug design
in which envisioning experiments are used initially to arrive at the new structure,
which can then be assessed for likely properties from database comparisons and from
computed pharmacologically relevant physical properties. Then synthetic approaches
71
to these systems or suggest new approaches to target systems and thus aid in the
exploration of further biological properties including antibacterial ones for multiactive antibacterial hybrid design. Such multi-ring systems could be bond linked.
atom linked (spiro systems), bond fused, bond bridged, stable/isolable complexes
with rings, quasi rings formed through non-covalent interactions, and mechanical
bond linked systems such as catenanes, rotaxanes with more than one ring, pseudorotaxanes (Xue et al. 2015) and pseudo-catenanes. In the context of mechanical
bond systems, it is of interest to note that nature uses antibacterial threaded-peptides
like capistruin and probably, microcin J25, to inhibit bacterial RNA polymerase
(Kuznedelov et al. 2011), and perhaps more such natural antibacterial systems will
be found in the future.
It is profitable to explore this ring taxonomy theme further with berberine as the
springboard for expansion into new chemical space while preserving capabilities for
inclusion of pharmacophoric or functional group entities.
As noted in Sect. 3.2.3.2, 13-hydroxyberberine as the phenolbetaine is amenable
to O-alkylation of the 13-oxy functionality (Samosorn et al. 2009) affording access to
potential new derivatives incorporating terminal primary amino group functionality
to facilitate permeation in Gram-negative bacterial pathogens. In addition, structural
features to target inhibition of bacterial efflux pump activity could also be built in to
an 8-alkoxy substituent leading to a hybrid which might overcome the pump efflux
resistance mechanism while maintaining overall features similar to those in berberine
and thus the ability to target the DNA and protein sites with which berberine interacts (Olleik et al. 2020). While 13-hydroxyberberine is a more potent antibacterial
than berberine it has greater liver cell toxicity. However some other 13-arylalkoxy
derivatives of berberine showed good antibacterial activity with very much reduced
toxicity. Olleik et al. (2020) showed that these derivatives did not seem to fragment
bacterial DNA but did interact with the bacterial FtsZ protein.
Thought experiments are important in helping to explore new structural space and
coming up with new structural possibilities. With these experiments one imagines
bond forming and/or bond making changes and then assesses the structural consequences of these changes. This can be illustrated for example with the reduced
tetrahydroberberine core structure (shown for simplicity in Scheme 3.1 without
the methoxy substituents or the fused methylenedioxy ring). Through such thought
experiments one can visualise systematic bond breaking around the ring nitrogen as
well as C–C bond breaking, followed by bond making or re-making, without necessarily knowing how to get there synthetically in the first instance. The emphasis
should be initially on hypothetical structural changes. Later functional group manipulations or modifications with the addition or deletion of atoms and subsequent reactions can be incorporated leading to other skeletons. Commensurate with this, the
simplified tetrahydroprotoberberine skeleton might be envisaged to provide access
to benz-fused tropanes for example with substituent variations as illustrated in
Scheme 3.1 by (I) and (II). This can be a powerful approach to new drug design
in which envisioning experiments are used initially to arrive at the new structure,
which can then be assessed for likely properties from database comparisons and from
computed pharmacologically relevant physical properties. Then synthetic approaches