90
3 Single Molecule Non-cleavable Multiply Active Antibacterials
of the triple action agent required and achievable at each site, are important further
aspects to consider (Bremner 2017).
Any new designed trihybrid agents should be likely to be chemically stable and
be relatively readily accessible and scalable synthetically. In addition, a range of
physicochemical parameters like molecular weight, water solubility, lipophilicity,
and numbers of H-bond donors and acceptors need to be considered, amongst others
(for example possible ADME properties) for potential oral administration, although
intravenous administration is an alternative if this is not feasible. Physicochemical
parameters for any new proposed hybrids could be calculated using appropriate
software like the Molecular Operating Environment software (MOE) as done in
the case of an analysis of 14 different physicochemical features of known antituberculosis drugs (Koul et al. 2011). In new drug design potentially toxic structural
moieties also need to be avoided together with functionality likely to be problematic
metabolically. Biologically, the potential antibacterial activity spectrum (particularly
for Gram-negative pathogens), potency (particularly against drug resistant strains),
the assessment of resistance development to the new agents, and possible off target
effects all need to be taken into account.
Further pre-synthesis assessment of proposed new agents can be undertaken using
the open access program LLAMA for drug-lead likeness and molecular analysis
before deciding on synthesis (Colomer et al. 2016). The drug lead likeness alogarithm
involves determining what is termed a ‘lead-likeness penalty’ for each structure rather
than applying strong filters. The molecular analysis capability in LLAMA can also
assses the originality of the molecular structure proposed.
After the initial design proposal it is always useful to look at refinements based on
in silico considerations and literature analysis. It is also suggested that it is beneficial
to look as well for ways to test or partly validate designs for triple activity in a
preliminary way if biological target structures are known and other ligand interactions
with the target are known with some precision. That is, try and go one step beyond
intuitive structural suggestions.
In molecular terms, intentional non-cleavable triple action designs can be grouped
in many different ways, but in this book the non-cleavable designs have been subdivided into six types (i. to vi.) (Sect. 3.3.4.1) with structural recognition elements
generalised for simplicity by the letters A, B, and C. These elements could involve
functional groups embedded in, or attached to, one or more rings or acyclic units.
3.3.4.1 General Non-cleavable Types with Three Different Recognition
Elements
In the design types below, dashed lines are used to indicate variations in the nature of
the linking groups between the recognition elements indicative of the many different
linkage architectures possible. In turn this affords much scope for different relative
dispositions of the three different recognition element regions as designated by A,
B, and C. The recognition elements represent the structural patterns likely to interact
with the specific bacterial target sites. As these are general design motifs, in each
3 Single Molecule Non-cleavable Multiply Active Antibacterials
of the triple action agent required and achievable at each site, are important further
aspects to consider (Bremner 2017).
Any new designed trihybrid agents should be likely to be chemically stable and
be relatively readily accessible and scalable synthetically. In addition, a range of
physicochemical parameters like molecular weight, water solubility, lipophilicity,
and numbers of H-bond donors and acceptors need to be considered, amongst others
(for example possible ADME properties) for potential oral administration, although
intravenous administration is an alternative if this is not feasible. Physicochemical
parameters for any new proposed hybrids could be calculated using appropriate
software like the Molecular Operating Environment software (MOE) as done in
the case of an analysis of 14 different physicochemical features of known antituberculosis drugs (Koul et al. 2011). In new drug design potentially toxic structural
moieties also need to be avoided together with functionality likely to be problematic
metabolically. Biologically, the potential antibacterial activity spectrum (particularly
for Gram-negative pathogens), potency (particularly against drug resistant strains),
the assessment of resistance development to the new agents, and possible off target
effects all need to be taken into account.
Further pre-synthesis assessment of proposed new agents can be undertaken using
the open access program LLAMA for drug-lead likeness and molecular analysis
before deciding on synthesis (Colomer et al. 2016). The drug lead likeness alogarithm
involves determining what is termed a ‘lead-likeness penalty’ for each structure rather
than applying strong filters. The molecular analysis capability in LLAMA can also
assses the originality of the molecular structure proposed.
After the initial design proposal it is always useful to look at refinements based on
in silico considerations and literature analysis. It is also suggested that it is beneficial
to look as well for ways to test or partly validate designs for triple activity in a
preliminary way if biological target structures are known and other ligand interactions
with the target are known with some precision. That is, try and go one step beyond
intuitive structural suggestions.
In molecular terms, intentional non-cleavable triple action designs can be grouped
in many different ways, but in this book the non-cleavable designs have been subdivided into six types (i. to vi.) (Sect. 3.3.4.1) with structural recognition elements
generalised for simplicity by the letters A, B, and C. These elements could involve
functional groups embedded in, or attached to, one or more rings or acyclic units.
3.3.4.1 General Non-cleavable Types with Three Different Recognition
Elements
In the design types below, dashed lines are used to indicate variations in the nature of
the linking groups between the recognition elements indicative of the many different
linkage architectures possible. In turn this affords much scope for different relative
dispositions of the three different recognition element regions as designated by A,
B, and C. The recognition elements represent the structural patterns likely to interact
with the specific bacterial target sites. As these are general design motifs, in each