14
1 Antibacterials
required for human immunodeficiency virus (HIV) replication, as well as details
of a hybrid compound based on the anti-malarial agents quinine and artemisinin
which displayed potent in vitro activity against against two drug resistant strains of
Plasmodium falciparum.
A useful overview of multi-target drugs against Mycobacterium tuberculosum is
contained in the review by Viana et al. (2018) and similarly in the earlier treatment by
Scotti et al. (2016) on multi-target drugs for the treatment of AIDS and tuberculosis.
A key aim of this book is to emphasise ideas and possibilities for the design of
multi-target molecules for triple or greater antibacterial activities. As an alternative
to multi-action combinations of two or more compounds, one can also envisage
multiple activities for a single non-cleavable hybrid agent. These single molecules
may be hybrids or agents which remain intact after administration and prior to interacting with biological targets associated with bacteria, staying intact at each target
site. Alternatively, prodrugs could be designed which are selective for bacteria and
are cleaved in or near the bacteria to give two, or subsequently more, products with
different synchronous or near-synchonous actions through bacterial target interactions (Bremner 2017). Such molecules could also be components of combinations
which may include single action antibacterials as well.
The design of such multi-targeted compounds can be problematic and sometimes
there is a contradictory combination of parameters required for single molecule
design and one may need to consider quite new and intricate types of structures.
However, in this as in other design areas, much can be gained by working meticulously
on a small canvass while letting the imagination flourish—think of the powerful
beauty and effect achieved by Dutch artist Johannes Vermeer in the masterpiece ‘Girl
with a Pearl Earring’. The painting is only quite small but is painted to such radiant
effect and attention to detail. The important thing is to think widely and curiously
outside the square before filling in the essential details. To start with partial ideas or
‘stubs’ and then build on these. Many will fail to develop, but a few might, which
is the important thing. With bacteria we are dealing with very small but intricate
biological systems and detailed thinking is required to multiply block or attenuate
these systems.
Extensive potential exists for the further design and development of such hybrids
or prodrugs and detailed exploration of these ideas with both actual and potential
examples is a key unifying theme of this book.
In this book, the terms action and activity refer to the effects on the bacterium
exposed to the antibacterial or non-direct antibacterial (or adjuvant) as a result of
interaction with the bacterial molecular target or target site(s). This process is referred
to as targeting. The site might involve biomacromolecular systems or smaller endogenous molecules such as quorum sensing signalling agents. One should also note that
there could also be more than one binding site per target molecule. Lange et al. (2007)
have discussed targeting and presented useful data on different bacterial targets,
including binding site numbers. Deliberately designed single molecules acting on
multiple targets (multiple target compounds) or displaying two or more pharmacological activities in a ‘multifactorial disease’ (multifunctional compounds) have been
discussed by Bansal and Silakari (Bansal and Silakari 2014). Included in this review,
1 Antibacterials
required for human immunodeficiency virus (HIV) replication, as well as details
of a hybrid compound based on the anti-malarial agents quinine and artemisinin
which displayed potent in vitro activity against against two drug resistant strains of
Plasmodium falciparum.
A useful overview of multi-target drugs against Mycobacterium tuberculosum is
contained in the review by Viana et al. (2018) and similarly in the earlier treatment by
Scotti et al. (2016) on multi-target drugs for the treatment of AIDS and tuberculosis.
A key aim of this book is to emphasise ideas and possibilities for the design of
multi-target molecules for triple or greater antibacterial activities. As an alternative
to multi-action combinations of two or more compounds, one can also envisage
multiple activities for a single non-cleavable hybrid agent. These single molecules
may be hybrids or agents which remain intact after administration and prior to interacting with biological targets associated with bacteria, staying intact at each target
site. Alternatively, prodrugs could be designed which are selective for bacteria and
are cleaved in or near the bacteria to give two, or subsequently more, products with
different synchronous or near-synchonous actions through bacterial target interactions (Bremner 2017). Such molecules could also be components of combinations
which may include single action antibacterials as well.
The design of such multi-targeted compounds can be problematic and sometimes
there is a contradictory combination of parameters required for single molecule
design and one may need to consider quite new and intricate types of structures.
However, in this as in other design areas, much can be gained by working meticulously
on a small canvass while letting the imagination flourish—think of the powerful
beauty and effect achieved by Dutch artist Johannes Vermeer in the masterpiece ‘Girl
with a Pearl Earring’. The painting is only quite small but is painted to such radiant
effect and attention to detail. The important thing is to think widely and curiously
outside the square before filling in the essential details. To start with partial ideas or
‘stubs’ and then build on these. Many will fail to develop, but a few might, which
is the important thing. With bacteria we are dealing with very small but intricate
biological systems and detailed thinking is required to multiply block or attenuate
these systems.
Extensive potential exists for the further design and development of such hybrids
or prodrugs and detailed exploration of these ideas with both actual and potential
examples is a key unifying theme of this book.
In this book, the terms action and activity refer to the effects on the bacterium
exposed to the antibacterial or non-direct antibacterial (or adjuvant) as a result of
interaction with the bacterial molecular target or target site(s). This process is referred
to as targeting. The site might involve biomacromolecular systems or smaller endogenous molecules such as quorum sensing signalling agents. One should also note that
there could also be more than one binding site per target molecule. Lange et al. (2007)
have discussed targeting and presented useful data on different bacterial targets,
including binding site numbers. Deliberately designed single molecules acting on
multiple targets (multiple target compounds) or displaying two or more pharmacological activities in a ‘multifactorial disease’ (multifunctional compounds) have been
discussed by Bansal and Silakari (Bansal and Silakari 2014). Included in this review,