1.4 Approaches to Meeting Needs
13
could be useful in the design of new combination treatments for bacterial disease but
negative effects would also need to be carefully considered. This approach may also
provide opportunities for suggestions of new combinations for multiple activity.
As alternatives to antibacterial agents, vaccines and other biological approaches
are also being actively pursued to help address the needs but these are outside the
scope of this book for detailed treatment. Such approaches are complementary to
new small molecule development. Vaccines provide the trigger for the production
of antibacterial ‘antibody agents’ in situ through the immune system but biological
macromolecules are involved. Vaccine approaches have been successful in fighting
some bacterially-induced diseases, including for example Menigococcal meningitis and Pneumococcal disease amongst others. A number are also in the pipeline
including one from Pfizer which has a prophylactic vaccine PF-06425090 in Phase
III development for C. difficile infections and results are due later in 2020 (Shen and
Cooke 2019).
1.5 Ways to Achieve Multi-action Effects
While much effort in medicinal chemistry in the past has been directed toward the
development of therapeutic agents with one main site of binding to then mediate
the desired biological effect(s), the possibilities inherent in deliberate or intentional
design for more than one action is rightly an increasing focus of research activity,
including in the antibacterial space. The emphasis in this book is on compounds with
three or more synchronous or near synchronous actions or multi-targeting ability. This
deliberate design paradigm, which is also known as a multivalent approach (Long
et al. 2008), is, along with multiple drug combinations whose components interact
with different biological targets but are normally administered simultaneously or
near simultaneously, part of the area referred to in general as polypharmacology.
The case for polypharmacology is a convincing one (Hopkins 2012) and the area,
including applications in antibacterial drug discovery (Silver 2012; Brötz-Oesterhelt
and Brunner 2008), has been well reviewed by a number of authors (Morphy 2012a,
b; Bolognesi 2013; Peters 2013).
Polypharmacology continues to develop as a trend in antibacterial discovery and
is gaining considerable contemporary traction with good reason. Key aspects of this
area are covered in the excellent recent review by Gray and Wenzel (2020) on multitarget approaches to counter drug resistant bacteria. The strategies employed in the
deliberate design of multi-target therapeutics are clearly outlined with specific examples in this review, while Zhou and co-authors have also discussed rational design
aspects for multi-target directed ligands or ‘designed multiple ligands’ (Morphy
and Rankovic 2005) for a range of potential disease-treatment applications (Zhou
et al. 2019). Single molecule hybrids with more than one action are also referred
to as multifunctional compounds and these have been well developed for the treatment of multi-factorial diseases. Zhou et al. (2019) also briefly discuss, in the infectious disease area, dual inhibitors of the integrase and reverse transcriptase enzymes
13
could be useful in the design of new combination treatments for bacterial disease but
negative effects would also need to be carefully considered. This approach may also
provide opportunities for suggestions of new combinations for multiple activity.
As alternatives to antibacterial agents, vaccines and other biological approaches
are also being actively pursued to help address the needs but these are outside the
scope of this book for detailed treatment. Such approaches are complementary to
new small molecule development. Vaccines provide the trigger for the production
of antibacterial ‘antibody agents’ in situ through the immune system but biological
macromolecules are involved. Vaccine approaches have been successful in fighting
some bacterially-induced diseases, including for example Menigococcal meningitis and Pneumococcal disease amongst others. A number are also in the pipeline
including one from Pfizer which has a prophylactic vaccine PF-06425090 in Phase
III development for C. difficile infections and results are due later in 2020 (Shen and
Cooke 2019).
1.5 Ways to Achieve Multi-action Effects
While much effort in medicinal chemistry in the past has been directed toward the
development of therapeutic agents with one main site of binding to then mediate
the desired biological effect(s), the possibilities inherent in deliberate or intentional
design for more than one action is rightly an increasing focus of research activity,
including in the antibacterial space. The emphasis in this book is on compounds with
three or more synchronous or near synchronous actions or multi-targeting ability. This
deliberate design paradigm, which is also known as a multivalent approach (Long
et al. 2008), is, along with multiple drug combinations whose components interact
with different biological targets but are normally administered simultaneously or
near simultaneously, part of the area referred to in general as polypharmacology.
The case for polypharmacology is a convincing one (Hopkins 2012) and the area,
including applications in antibacterial drug discovery (Silver 2012; Brötz-Oesterhelt
and Brunner 2008), has been well reviewed by a number of authors (Morphy 2012a,
b; Bolognesi 2013; Peters 2013).
Polypharmacology continues to develop as a trend in antibacterial discovery and
is gaining considerable contemporary traction with good reason. Key aspects of this
area are covered in the excellent recent review by Gray and Wenzel (2020) on multitarget approaches to counter drug resistant bacteria. The strategies employed in the
deliberate design of multi-target therapeutics are clearly outlined with specific examples in this review, while Zhou and co-authors have also discussed rational design
aspects for multi-target directed ligands or ‘designed multiple ligands’ (Morphy
and Rankovic 2005) for a range of potential disease-treatment applications (Zhou
et al. 2019). Single molecule hybrids with more than one action are also referred
to as multifunctional compounds and these have been well developed for the treatment of multi-factorial diseases. Zhou et al. (2019) also briefly discuss, in the infectious disease area, dual inhibitors of the integrase and reverse transcriptase enzymes