76
3 Single Molecule Non-cleavable Multiply Active Antibacterials
molecular expressions of these parameters. The extension of dual action design principles is a reasonable starting point for the design of non-cleavable triple action
agents (Bremner 2017).
The general design parameters for triple action design are similar to those involved
with antibacterial dual-acting hybrids (Tevyashova et al. 2015; Poäovskaya and
Baasov 2010; Bremner et al. 2007) and prodrugs (Bremner et al. 2007), although
there are extra possibilities when three separate interaction modes with respect to
the biological targets are considered. Known dual acting hybrids as well as known
combinations are good starting points for triple action design. In addition to direct
antibacterial targets like those involved with cell wall formation, or bacterial DNA
function or protein synthesis, the indirect activities could encompass variations such
as dislocation of quorum sensing (Kalia 2013) and toxin blockade or the inhibition
or attenuation of bacterial efflux pump activity.
Much has been done in the neuropharmacology area with regard to triple action
anti-depressant design (Millan 2009) and this review is a helpful one generally for
its good terminology discussion, and coverage of triple acting agents, higher order
agents and the chemical challenge of the synthesis of such compounds. In the design
protocol, the classes of ligand that were of interest in the clinical treatment of depression were considered first and then the single molecule hybridic design was based on
exemplars in these classes. A similar approach could be adopted for single molecule
multi-target antibacterials. In this context one could consider:
(i) Antibacterials that interact with a key target A and are more potent than other
drugs targeting other sites.
(ii) Drug combinations that involve interactions at sites other than A.
(iii) Drugs with a clinically confirmed mechanism involving A and some other
non-A mechanism.
In the antibacterial context not all ligands need be directly antibacterial, so one
could look at a ligand which potently inhibits say bacterial DNA function plus two
other ligands one of which blocks efflux pumps and the other blocks dihydrofolate
reductase, and then try and incorporate the pharmacophoric elements in a single
compound as discussed generally in the next Sect. (3.3.2).
3.3.2 Potential Design Based on Pharmacophoric Elements
In general terms one can consider firstly the pharmacophoric elements or recognition
features as A, B and C for interaction with the bacterial targets. Features A, B, and
C need not be those of the complete original drugs in each case but may incorporate
similar characteristics to the original drugs. It is also important to try and minimize
molecular weight increases if possible with this design approach. This can be illustrated in the following general design progressions starting with combinations and
variations as the reference point and including three general pharmacophoric features
or sites A, B and C as part of generic structures as indicated (Fig. 3.13). Variations
3 Single Molecule Non-cleavable Multiply Active Antibacterials
molecular expressions of these parameters. The extension of dual action design principles is a reasonable starting point for the design of non-cleavable triple action
agents (Bremner 2017).
The general design parameters for triple action design are similar to those involved
with antibacterial dual-acting hybrids (Tevyashova et al. 2015; Poäovskaya and
Baasov 2010; Bremner et al. 2007) and prodrugs (Bremner et al. 2007), although
there are extra possibilities when three separate interaction modes with respect to
the biological targets are considered. Known dual acting hybrids as well as known
combinations are good starting points for triple action design. In addition to direct
antibacterial targets like those involved with cell wall formation, or bacterial DNA
function or protein synthesis, the indirect activities could encompass variations such
as dislocation of quorum sensing (Kalia 2013) and toxin blockade or the inhibition
or attenuation of bacterial efflux pump activity.
Much has been done in the neuropharmacology area with regard to triple action
anti-depressant design (Millan 2009) and this review is a helpful one generally for
its good terminology discussion, and coverage of triple acting agents, higher order
agents and the chemical challenge of the synthesis of such compounds. In the design
protocol, the classes of ligand that were of interest in the clinical treatment of depression were considered first and then the single molecule hybridic design was based on
exemplars in these classes. A similar approach could be adopted for single molecule
multi-target antibacterials. In this context one could consider:
(i) Antibacterials that interact with a key target A and are more potent than other
drugs targeting other sites.
(ii) Drug combinations that involve interactions at sites other than A.
(iii) Drugs with a clinically confirmed mechanism involving A and some other
non-A mechanism.
In the antibacterial context not all ligands need be directly antibacterial, so one
could look at a ligand which potently inhibits say bacterial DNA function plus two
other ligands one of which blocks efflux pumps and the other blocks dihydrofolate
reductase, and then try and incorporate the pharmacophoric elements in a single
compound as discussed generally in the next Sect. (3.3.2).
3.3.2 Potential Design Based on Pharmacophoric Elements
In general terms one can consider firstly the pharmacophoric elements or recognition
features as A, B and C for interaction with the bacterial targets. Features A, B, and
C need not be those of the complete original drugs in each case but may incorporate
similar characteristics to the original drugs. It is also important to try and minimize
molecular weight increases if possible with this design approach. This can be illustrated in the following general design progressions starting with combinations and
variations as the reference point and including three general pharmacophoric features
or sites A, B and C as part of generic structures as indicated (Fig. 3.13). Variations