3.3 Triple Action Antibacterial Hybrid Agents
79
do not involve linking groups but the cyclic molecular units may be joined via a
spiro centre or by sharing a common bond in a fused arrangement. The spiro linkage
arrangement offers further interesting structural possibilities though incorporation
of other elements in place of carbon at the spiro centre including nitogen, silicon,
or boron each conferring different properties on the hybrid. With nitrogen it would
carry a positive charge being quaternary, while with boron as a tetrahedral spiro
atom it would have a formal negative charge. The use of silicon in place of carbon in
potential drugs is an area of general interest (Ramesh and Reddy 2018) as are drugs
incorporating tri- or tetravalent boron groups, and some boron-based antibacterials
are discussed further in this book.
The last general classification (Fig. 3.13) involves an overlapping of the cyclic
molecular units to give a chimeric structure.
In the representative models in Fig. 3.13, the 6-membered ring is maintained
for inclusion of the pharmacophoric groups for clarity but clearly this ring size
could be varied. In addition, extension of the models to include quasi 6-membered
rings through strong non-covalent interactions would provide a powerful means to
expand the skeletal design repertoire. For example with a 6,6-fused sytem the central
‘bond’ might not necessarily involve a classical covalent bond but might result from
a transannular HN….C=O interaction involving the nitrogen lone pair electrons and
the π*–carbonyl group antibonding orbital.
Quasi-rings in antibacterial hybrid design
The use of quasi-rings resulting from non-covalent interactions to preference conformations in molecules has considerable scope in antibacterial design. Sometimes the
term ‘pseudo’ (Greek) is used, but it is preferable to use ‘quasi’ (Latin) being more
accurately reflective of the meaning of the word as ‘resembling’ or ‘seemingly’ in
this context rather than ‘false’ for ‘pseudo’. Such rings, include, for example, those
formed from strong single (or more than one single) intramolecular non-covalent
interaction(s) as replacements for actual covalent bonds while still containing other
functionality. This functionality may either be attached to atoms at the non-covalent
interaction sites or be located separately, for the required interactions with the biological target sites. Viewed from another perspective such interactions can be considered
in terms of biasing conformational preferences and hence substituent spatial placements. A review by Beno et al. (2015) includes applications of this type of interaction
in drug design with sulfur-based interactions.
Differences in geometries, atom separations and electrostatic potentials need to
be considered in these interactions. Access to single molecule quasi-cyclic, quasispirocyclic, or quasi-bridged systems should be possible with the appropriate noncovalent interactions as well as combination systems which incorporate a molecular
component with one or more quasi bonding motifs together with covalent bonds.
The quasi-ring forming intramolecular non-covalent interactions can also be classified in terms of transannular (forming two quasi rings) and non-transannular or
annular (quasi-single-ring forming) interactions. Generally these interactions result
from electrostatic attraction or from some orbital interaction and partial electron
distribution. A well established transannular interaction is evident with the alkaloid
79
do not involve linking groups but the cyclic molecular units may be joined via a
spiro centre or by sharing a common bond in a fused arrangement. The spiro linkage
arrangement offers further interesting structural possibilities though incorporation
of other elements in place of carbon at the spiro centre including nitogen, silicon,
or boron each conferring different properties on the hybrid. With nitrogen it would
carry a positive charge being quaternary, while with boron as a tetrahedral spiro
atom it would have a formal negative charge. The use of silicon in place of carbon in
potential drugs is an area of general interest (Ramesh and Reddy 2018) as are drugs
incorporating tri- or tetravalent boron groups, and some boron-based antibacterials
are discussed further in this book.
The last general classification (Fig. 3.13) involves an overlapping of the cyclic
molecular units to give a chimeric structure.
In the representative models in Fig. 3.13, the 6-membered ring is maintained
for inclusion of the pharmacophoric groups for clarity but clearly this ring size
could be varied. In addition, extension of the models to include quasi 6-membered
rings through strong non-covalent interactions would provide a powerful means to
expand the skeletal design repertoire. For example with a 6,6-fused sytem the central
‘bond’ might not necessarily involve a classical covalent bond but might result from
a transannular HN….C=O interaction involving the nitrogen lone pair electrons and
the π*–carbonyl group antibonding orbital.
Quasi-rings in antibacterial hybrid design
The use of quasi-rings resulting from non-covalent interactions to preference conformations in molecules has considerable scope in antibacterial design. Sometimes the
term ‘pseudo’ (Greek) is used, but it is preferable to use ‘quasi’ (Latin) being more
accurately reflective of the meaning of the word as ‘resembling’ or ‘seemingly’ in
this context rather than ‘false’ for ‘pseudo’. Such rings, include, for example, those
formed from strong single (or more than one single) intramolecular non-covalent
interaction(s) as replacements for actual covalent bonds while still containing other
functionality. This functionality may either be attached to atoms at the non-covalent
interaction sites or be located separately, for the required interactions with the biological target sites. Viewed from another perspective such interactions can be considered
in terms of biasing conformational preferences and hence substituent spatial placements. A review by Beno et al. (2015) includes applications of this type of interaction
in drug design with sulfur-based interactions.
Differences in geometries, atom separations and electrostatic potentials need to
be considered in these interactions. Access to single molecule quasi-cyclic, quasispirocyclic, or quasi-bridged systems should be possible with the appropriate noncovalent interactions as well as combination systems which incorporate a molecular
component with one or more quasi bonding motifs together with covalent bonds.
The quasi-ring forming intramolecular non-covalent interactions can also be classified in terms of transannular (forming two quasi rings) and non-transannular or
annular (quasi-single-ring forming) interactions. Generally these interactions result
from electrostatic attraction or from some orbital interaction and partial electron
distribution. A well established transannular interaction is evident with the alkaloid