124
4 Design Principles and Development of Prodrugs for Multiply …
no linkage. The molecular modification normally involves some functional group
change but it can be a fine distinction between a carrier group and a directly attached
functional group unit susceptible to enzymatic or non-enzymatic change.
Bioprecursor prodrugs can also be targeted through site-specific activation where
the modifying functional group is activated by a specific enzyme at the site. Illustrative of this approach is the prodrug Secnidazole. Secnidazole is a marketed 5nitroimidazole-based bactericidal drug for the treatment in adult women of bacterial
vaginosis. Secnidazole is thought to enter bacteria through passive diffusion and the
nitro group is then reduced by bacterial nitroreductases within the bacterium with the
active radical anion intermediate produced then inhibiting DNA synthesis (Subbaiah
and Meanwell 2019; Rautio et al. 2018). These useful reviews also cover prodrug
design approaches to improve formulations as well as pharmacokinetic and targeting
properties with a range of drugs.
4.2 Introduction to Prodrugs for Triple or Higher Action
Antibacterials
4.2.1 Design Considerations
As with the design of hybrids, with prodrug design, for both carrier prodrugs and
bioprecursor prodrugs, the overall goal should be to incorporate the minimum number
of atoms or groups to achieve a number of sub-goals including: as low a molecular weight as possible, atom arrangements in the bioactive component to minimise
or avoid unwanted stereoelectronic issues on interaction at the target sites, good
pharmacokinetic properties after oral absorption, bacterial targeting and selective
release, potent antibacterial activity for resistant and non-resistant pathogens, and
maintenance of activity after likely or predicted changes in the pathogen targets to
overcome the antibacterial. If possible every atom or group should be cut back to a
minimum while maintaining efficacy in the active drug(s) released. With prodrugs,
extra atoms are necessarily required in the promoiety to meet the penetration and
selectivity requirements, but one should also consider further reinforcing functions
for this moiety once released from the drug. These prodrug design paradigms and
challenges are also covered in the excellent review by Rautio and co-authors (Rautio
et al. 2018).
A further important consideration with any prodrug is to achieve good targeting
to minimise unwanted side-effects; good molecular ‘targeting’ once the active drug
is exposed is also vital. In general the initial targeting is realised through either
site-directed delivery or site-specific bioactivation (Rautio et al. 2018). Enzymes
are normally utilised to make or break bonds or undertake specific functional group
transformations to create the active drug on or near the site of the target interactions.
With antibacterials both site-directed and site-specific activation approaches have
been assessed although the latter is more common. Multiply active prodrug design
4 Design Principles and Development of Prodrugs for Multiply …
no linkage. The molecular modification normally involves some functional group
change but it can be a fine distinction between a carrier group and a directly attached
functional group unit susceptible to enzymatic or non-enzymatic change.
Bioprecursor prodrugs can also be targeted through site-specific activation where
the modifying functional group is activated by a specific enzyme at the site. Illustrative of this approach is the prodrug Secnidazole. Secnidazole is a marketed 5nitroimidazole-based bactericidal drug for the treatment in adult women of bacterial
vaginosis. Secnidazole is thought to enter bacteria through passive diffusion and the
nitro group is then reduced by bacterial nitroreductases within the bacterium with the
active radical anion intermediate produced then inhibiting DNA synthesis (Subbaiah
and Meanwell 2019; Rautio et al. 2018). These useful reviews also cover prodrug
design approaches to improve formulations as well as pharmacokinetic and targeting
properties with a range of drugs.
4.2 Introduction to Prodrugs for Triple or Higher Action
Antibacterials
4.2.1 Design Considerations
As with the design of hybrids, with prodrug design, for both carrier prodrugs and
bioprecursor prodrugs, the overall goal should be to incorporate the minimum number
of atoms or groups to achieve a number of sub-goals including: as low a molecular weight as possible, atom arrangements in the bioactive component to minimise
or avoid unwanted stereoelectronic issues on interaction at the target sites, good
pharmacokinetic properties after oral absorption, bacterial targeting and selective
release, potent antibacterial activity for resistant and non-resistant pathogens, and
maintenance of activity after likely or predicted changes in the pathogen targets to
overcome the antibacterial. If possible every atom or group should be cut back to a
minimum while maintaining efficacy in the active drug(s) released. With prodrugs,
extra atoms are necessarily required in the promoiety to meet the penetration and
selectivity requirements, but one should also consider further reinforcing functions
for this moiety once released from the drug. These prodrug design paradigms and
challenges are also covered in the excellent review by Rautio and co-authors (Rautio
et al. 2018).
A further important consideration with any prodrug is to achieve good targeting
to minimise unwanted side-effects; good molecular ‘targeting’ once the active drug
is exposed is also vital. In general the initial targeting is realised through either
site-directed delivery or site-specific bioactivation (Rautio et al. 2018). Enzymes
are normally utilised to make or break bonds or undertake specific functional group
transformations to create the active drug on or near the site of the target interactions.
With antibacterials both site-directed and site-specific activation approaches have
been assessed although the latter is more common. Multiply active prodrug design