3.1 Introduction to General Design Considerations
53
work in the area with respect to bifunctional antimicrobials has been reviewed more
recently by Klahn and Brönstrup (2017). These authors differentiate such bifunctional compounds into two general classes for dual targeting agents: antimicrobial
hybrids (both functional elements of the hybrid express antibacterial activity) and
antimicrobial conjugates (in which one functional element exerts its effect through
non-direct antibacterial activity means). The non-direct activity expression may be
through enabling active transport of the molecule as a whole into the bacterial cell
structure or through interfering with the bacterial efflux process, while the other
functional element expresses the direct antibacterial effect. Complications in this
classification arise, however, on moving to potentially three or more different functional elements in the same molecule. It is considered better then to distinguish
separate hybrid types as done in this book.
Designed hybrid compounds should be reasonably accessible synthetically with
possibilities for scale up. Initially, though, smaller quantities are sufficient to assess
properties (enzyme inhibition; cell culture) in vitro and to pursue initial mode of
action studies including separate enzyme inhibition studies if required. Having scale
up capability is important if progression to pre-clinical and then clinical studies
are justified or indicated. Aside from these considerations, often there is also a
complex interplay between chemical priorities and biological imperatives. A potentially fruitful area to explore in the synthetic design phase is that of using readily
available, structurally advanced starting materials such as particular natural products or derivatives with known capabilities for interacting with biological targets.
Synthetically, and to enable good SAR studies, one also needs to prioritise routes
that are compact yet versatile, with tolerance of various functional groups, and
with good stereoselectivity if required. Also one needs to allow scope for late stage
changes in groups tailored for appropriate in vivo biological properties to meet drug
absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic
needs and with the flexibility to address possible toxicity issues. In the deliberate
design of hybrid structures it is also important to embed scope for various structural
modifications to improve potency.
3.1.2 Factors in Antibacterial Hybrid Design
Aside from synthesisability issues as mentioned above in Sect. 3.1.1, one can divide
the factors for antibacterial hybrid design into those pertinent in vitro at the bacterial
cell level and then additional factors to these which need to be considered for in vivo
use at the pre-clinical and clinical level.
At the cell level in vitro, important factors include solubility of the hybrid to allow
for addition to the cell culture at a range of concentrations, and to have the required
degree of penetration or permeation depending on the positioning of the bacterial
targets: on or near the outer cell surface; within the cell wall at different locations;
on the cytosolic side of the cell wall; or intracellular. Also one needs to consider the
likelihood or not of drug efflux.
53
work in the area with respect to bifunctional antimicrobials has been reviewed more
recently by Klahn and Brönstrup (2017). These authors differentiate such bifunctional compounds into two general classes for dual targeting agents: antimicrobial
hybrids (both functional elements of the hybrid express antibacterial activity) and
antimicrobial conjugates (in which one functional element exerts its effect through
non-direct antibacterial activity means). The non-direct activity expression may be
through enabling active transport of the molecule as a whole into the bacterial cell
structure or through interfering with the bacterial efflux process, while the other
functional element expresses the direct antibacterial effect. Complications in this
classification arise, however, on moving to potentially three or more different functional elements in the same molecule. It is considered better then to distinguish
separate hybrid types as done in this book.
Designed hybrid compounds should be reasonably accessible synthetically with
possibilities for scale up. Initially, though, smaller quantities are sufficient to assess
properties (enzyme inhibition; cell culture) in vitro and to pursue initial mode of
action studies including separate enzyme inhibition studies if required. Having scale
up capability is important if progression to pre-clinical and then clinical studies
are justified or indicated. Aside from these considerations, often there is also a
complex interplay between chemical priorities and biological imperatives. A potentially fruitful area to explore in the synthetic design phase is that of using readily
available, structurally advanced starting materials such as particular natural products or derivatives with known capabilities for interacting with biological targets.
Synthetically, and to enable good SAR studies, one also needs to prioritise routes
that are compact yet versatile, with tolerance of various functional groups, and
with good stereoselectivity if required. Also one needs to allow scope for late stage
changes in groups tailored for appropriate in vivo biological properties to meet drug
absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic
needs and with the flexibility to address possible toxicity issues. In the deliberate
design of hybrid structures it is also important to embed scope for various structural
modifications to improve potency.
3.1.2 Factors in Antibacterial Hybrid Design
Aside from synthesisability issues as mentioned above in Sect. 3.1.1, one can divide
the factors for antibacterial hybrid design into those pertinent in vitro at the bacterial
cell level and then additional factors to these which need to be considered for in vivo
use at the pre-clinical and clinical level.
At the cell level in vitro, important factors include solubility of the hybrid to allow
for addition to the cell culture at a range of concentrations, and to have the required
degree of penetration or permeation depending on the positioning of the bacterial
targets: on or near the outer cell surface; within the cell wall at different locations;
on the cytosolic side of the cell wall; or intracellular. Also one needs to consider the
likelihood or not of drug efflux.