3.3 Triple Action Antibacterial Hybrid Agents
81
nitrogen and the carbonyl group embedded in the ring. This n to π* interaction was
in fact indicated from DFT calculations to be accessible in the trans imine system in
a favoured pinched conformation (Fig. 3.14b). In these high level DFT calculations,
the structures were optimised in vacuo using the M062X functional and the 6–311++
g (2d, 2p) basis set. The pinched conformation for the trans imine was 3.61 kcal/mol
more stable (in vacuo) than a wide conformation in which the imine nitrogen was
well away from the carbonyl group. The optimised geometry conformation for the cis
imine (Fig. 3.14c) was also a little higher in energy than the trans pinched conformer
and no N–CO transannular interaction was observed in the former conformation
(Griffith and Bremner unpublished results).
There are a number of potential advantages of quasi bonds over covalent bonds
in the antibacterial design (and wider drug design) area. More compact or feasible
syntheses of these non-covalent bond based ring systems may be apparent. Also
they may open up possibilities for new chemistry and different synthetic routes.
In addition, the restraint on otherwise rotatable bonds could give better control of
exo-pharmacophoric group positioning or access to different positions and hence
different binding sites on the biological targets. Such transannular or simply annular
interactions also offer scope for the introduction of new skeletal atoms and new
functional groups together with modified electrostatic potential energy distributions.
In addition, with non-bonded but interacting structural components, different or
better pharmacokinetic characteristics in the molecule might be possible. These interactions would need to be maintained, however, in aqueous solution and on binding
to the respective targets. Possibly, though, it may be advantageous for them to be
overcome at the point of binding resulting in something like a quasi-prodrug situation
and the intentional incorporation of such interactions in prodrug antibacterial design
is worth considering further.
Annular non-bonded interactions have been shown to be important in the
methylcarbapenem type antibiotics where an intramolecular non-covalent bonded
S….
− OOC (classified as a 1,5-type with a quasi 5-membered ring formed) was
indicated involving S in a thioether substituent and the carboxylate group O on the
adjacent substituent (Nagao 2013; Nagao et al. 2001). Further annular non-bonded
interactions of S with other atoms such as N or halogens have also been investigated
by the Nagao group (Nagao 2013).
The annular interaction to form a quasi ring may also involve hydrogen bonding.
An example of this from the anti-cancer drug area is the quasi-cyclization involving
intramolecular hydrogen bonding of a pyrimidine substituted NH with a pyridine
ring N to form a quasi-6 membered ring in new Mer kinase inhibitors (Zhang et al.
2013). This quasi ring replaced a pyrazole ring in a known Mer inhibitor (UNC1062)
and further optimization produced a potent new series of inhibitors. Scope exists for
further use of this quasi ring replacement strategy in the antibacterial intentional
hybrid design area.
Another interesting aspect of non-covalent interactions is that they can also assist
in, or drive, further covalent bond forming transformations as noted in the review of
lactone macrolide—based antibacterials (Janas and Przybylski 2019).
81
nitrogen and the carbonyl group embedded in the ring. This n to π* interaction was
in fact indicated from DFT calculations to be accessible in the trans imine system in
a favoured pinched conformation (Fig. 3.14b). In these high level DFT calculations,
the structures were optimised in vacuo using the M062X functional and the 6–311++
g (2d, 2p) basis set. The pinched conformation for the trans imine was 3.61 kcal/mol
more stable (in vacuo) than a wide conformation in which the imine nitrogen was
well away from the carbonyl group. The optimised geometry conformation for the cis
imine (Fig. 3.14c) was also a little higher in energy than the trans pinched conformer
and no N–CO transannular interaction was observed in the former conformation
(Griffith and Bremner unpublished results).
There are a number of potential advantages of quasi bonds over covalent bonds
in the antibacterial design (and wider drug design) area. More compact or feasible
syntheses of these non-covalent bond based ring systems may be apparent. Also
they may open up possibilities for new chemistry and different synthetic routes.
In addition, the restraint on otherwise rotatable bonds could give better control of
exo-pharmacophoric group positioning or access to different positions and hence
different binding sites on the biological targets. Such transannular or simply annular
interactions also offer scope for the introduction of new skeletal atoms and new
functional groups together with modified electrostatic potential energy distributions.
In addition, with non-bonded but interacting structural components, different or
better pharmacokinetic characteristics in the molecule might be possible. These interactions would need to be maintained, however, in aqueous solution and on binding
to the respective targets. Possibly, though, it may be advantageous for them to be
overcome at the point of binding resulting in something like a quasi-prodrug situation
and the intentional incorporation of such interactions in prodrug antibacterial design
is worth considering further.
Annular non-bonded interactions have been shown to be important in the
methylcarbapenem type antibiotics where an intramolecular non-covalent bonded
S….
− OOC (classified as a 1,5-type with a quasi 5-membered ring formed) was
indicated involving S in a thioether substituent and the carboxylate group O on the
adjacent substituent (Nagao 2013; Nagao et al. 2001). Further annular non-bonded
interactions of S with other atoms such as N or halogens have also been investigated
by the Nagao group (Nagao 2013).
The annular interaction to form a quasi ring may also involve hydrogen bonding.
An example of this from the anti-cancer drug area is the quasi-cyclization involving
intramolecular hydrogen bonding of a pyrimidine substituted NH with a pyridine
ring N to form a quasi-6 membered ring in new Mer kinase inhibitors (Zhang et al.
2013). This quasi ring replaced a pyrazole ring in a known Mer inhibitor (UNC1062)
and further optimization produced a potent new series of inhibitors. Scope exists for
further use of this quasi ring replacement strategy in the antibacterial intentional
hybrid design area.
Another interesting aspect of non-covalent interactions is that they can also assist
in, or drive, further covalent bond forming transformations as noted in the review of
lactone macrolide—based antibacterials (Janas and Przybylski 2019).