140
4 Design Principles and Development of Prodrugs for Multiply …
Similarly cleavage of a β-lactam could be used to ultimately expel a triple acting
moiety (Scheme 4.5). A generalized structure is shown for this hybrid for illustrative
purposes.
Russian doll-type prodrugs
An additional speculative prodrug variation which is recommended for further investigation is one that is not really covered by the above prodrug types although can
be viewed as an extension of the Trojan horse-type design discussed in Chap. 3
(Sect. 3.3.3). These proposed compounds are based on what might be called ‘Russian
Doll-type prodrugs’ or molecular assemblies for the selective and sequential delivery
of three components at different bacterial target sites. This would be a significant
molecular challenge but one which could beneficially expand the boundaries of drug
synthesis and design. It would essentially entail a nesting design, which could be
unpealed successively to release the drug as such or a precursor for metabolic activation in situ. Some chemical work has been described covering molecular Russian
doll motifs based on organic compounds, but these compounds are generally complex
molecular assemblies (Cai et al. 2018; Zhang et al. 2019; Gong et al. 2016) which
might detract from their exploration in the drug discovery space. However, this design
strategy should not be discarded for this purpose particularly with regard to potential
multi-action antibacterials. One can envisage adapting the idea to systems requiring
for example two bacterial enzymes to sequentially unpeel layer 1 with the release of
drug 1, then layer 2 with the release of drug 2. The active components, which might
Scheme 4.5 Potential release of a single trihybrid from a cephalosporin prodrug
4 Design Principles and Development of Prodrugs for Multiply …
Similarly cleavage of a β-lactam could be used to ultimately expel a triple acting
moiety (Scheme 4.5). A generalized structure is shown for this hybrid for illustrative
purposes.
Russian doll-type prodrugs
An additional speculative prodrug variation which is recommended for further investigation is one that is not really covered by the above prodrug types although can
be viewed as an extension of the Trojan horse-type design discussed in Chap. 3
(Sect. 3.3.3). These proposed compounds are based on what might be called ‘Russian
Doll-type prodrugs’ or molecular assemblies for the selective and sequential delivery
of three components at different bacterial target sites. This would be a significant
molecular challenge but one which could beneficially expand the boundaries of drug
synthesis and design. It would essentially entail a nesting design, which could be
unpealed successively to release the drug as such or a precursor for metabolic activation in situ. Some chemical work has been described covering molecular Russian
doll motifs based on organic compounds, but these compounds are generally complex
molecular assemblies (Cai et al. 2018; Zhang et al. 2019; Gong et al. 2016) which
might detract from their exploration in the drug discovery space. However, this design
strategy should not be discarded for this purpose particularly with regard to potential
multi-action antibacterials. One can envisage adapting the idea to systems requiring
for example two bacterial enzymes to sequentially unpeel layer 1 with the release of
drug 1, then layer 2 with the release of drug 2. The active components, which might
Scheme 4.5 Potential release of a single trihybrid from a cephalosporin prodrug