92
3 Single Molecule Non-cleavable Multiply Active Antibacterials
groups with their associated recognition elements. Advantages that might accrue from
spiropeptidic designs include positioning control of functionality and resistance to
enzymatic attack on the core plus compactness, rigidity or partial flexibility, and
different chiral elements. Many spirocyclic antibacterials are known in nature, one
example being pseurotin A from Aspergillus fumigatus, which has some moderate
antibacterial activity against Gram-negative and Gram-positive bacteria. Pseurotin
A has a chiral partially peptidic 5,5-spiro system with an oxygen heteratom in one
ring in place of an NH (Mehedi et al. 2010).
In the hybrid design process it is good to have a basic starting skeletal structure
with versatile functional groups incorporating say three pharmacophoric elements.
In this book where examples are suggested, normally, although not only, two basic
skeletal types are used, one being based on the tropanoid skeleton initially and the
other on the berberine skeleton and related variations. In essence this will illustrate
approaches starting from a more globular sp
3 -atom rich structure in the first case,
and a flatter structure with aromatic fused rings in the second.
With the tropane derivatives, many opportunities present for the ready incorporation of three different pharmacophoric units in substituents attached to bicyclic and
tricyclic templates with a high proportion of saturated carbon atoms.
On the other hand, with the berberine-based systems, one has access to flatter
molecules. While a common sentiment in drug design is to move away from flatter
structures to improve the possibilities for clinical success, flatland can still be interesting both chemically and pharmacologically but structural hills and valleys should
also be explored. In an interesting report by Monteleone et al. (2017) an analysis
was done on how molecular connectivity can predefine polypharmacology or not,
looking at the classification of active molecules although not specifically antibacterials. Drugs with a higher number of double bonds and fused aromatic rings tended
to be active on more than four targets while one target selectivity was more evident
with higher numbers of sp
3 carbons and aliphatic rings. This suggests for multi-active
hybrid design that the possibility for incorporation of more tetrahedral carbon sites
in flatter molecules might still be a productive line of study. Higher levels of skeletal
sp
3 -atoms do allow for a greater diversity of sites in chemical space to be explored
as noted in Morgentin et al. (2018). This paper also includes a good discussion of
scaffold level analysis, as well as predictions of increased drug success. A more mathematical general analysis of this is covered in Lovering et al. (2009). Monteleone
et al. (2017) also concur with this, together with the presence of aliphatic rings and
chirality, although antibacterials were not specifically analysed in their work.
The presence of nitrogen is also significant in clinical bioactives and an analysis of U.S. FDA approved drugs published in 2014 revealed that 59% of unique
small molecule drugs contained a nitogen heterocycle (Vitaku et al. 2014). Such
heterocycles included fused and bridged systems and medium ring or macrocyclic
compounds, which we propose, further underscores the relevance of looking at
nitrogen-containing tropane and berberine analogues in the context of new hybrid
designs.
3 Single Molecule Non-cleavable Multiply Active Antibacterials
groups with their associated recognition elements. Advantages that might accrue from
spiropeptidic designs include positioning control of functionality and resistance to
enzymatic attack on the core plus compactness, rigidity or partial flexibility, and
different chiral elements. Many spirocyclic antibacterials are known in nature, one
example being pseurotin A from Aspergillus fumigatus, which has some moderate
antibacterial activity against Gram-negative and Gram-positive bacteria. Pseurotin
A has a chiral partially peptidic 5,5-spiro system with an oxygen heteratom in one
ring in place of an NH (Mehedi et al. 2010).
In the hybrid design process it is good to have a basic starting skeletal structure
with versatile functional groups incorporating say three pharmacophoric elements.
In this book where examples are suggested, normally, although not only, two basic
skeletal types are used, one being based on the tropanoid skeleton initially and the
other on the berberine skeleton and related variations. In essence this will illustrate
approaches starting from a more globular sp
3 -atom rich structure in the first case,
and a flatter structure with aromatic fused rings in the second.
With the tropane derivatives, many opportunities present for the ready incorporation of three different pharmacophoric units in substituents attached to bicyclic and
tricyclic templates with a high proportion of saturated carbon atoms.
On the other hand, with the berberine-based systems, one has access to flatter
molecules. While a common sentiment in drug design is to move away from flatter
structures to improve the possibilities for clinical success, flatland can still be interesting both chemically and pharmacologically but structural hills and valleys should
also be explored. In an interesting report by Monteleone et al. (2017) an analysis
was done on how molecular connectivity can predefine polypharmacology or not,
looking at the classification of active molecules although not specifically antibacterials. Drugs with a higher number of double bonds and fused aromatic rings tended
to be active on more than four targets while one target selectivity was more evident
with higher numbers of sp
3 carbons and aliphatic rings. This suggests for multi-active
hybrid design that the possibility for incorporation of more tetrahedral carbon sites
in flatter molecules might still be a productive line of study. Higher levels of skeletal
sp
3 -atoms do allow for a greater diversity of sites in chemical space to be explored
as noted in Morgentin et al. (2018). This paper also includes a good discussion of
scaffold level analysis, as well as predictions of increased drug success. A more mathematical general analysis of this is covered in Lovering et al. (2009). Monteleone
et al. (2017) also concur with this, together with the presence of aliphatic rings and
chirality, although antibacterials were not specifically analysed in their work.
The presence of nitrogen is also significant in clinical bioactives and an analysis of U.S. FDA approved drugs published in 2014 revealed that 59% of unique
small molecule drugs contained a nitogen heterocycle (Vitaku et al. 2014). Such
heterocycles included fused and bridged systems and medium ring or macrocyclic
compounds, which we propose, further underscores the relevance of looking at
nitrogen-containing tropane and berberine analogues in the context of new hybrid
designs.