138
4 Design Principles and Development of Prodrugs for Multiply …
sulfur dioxide and Wang and Wang (2018) have reviewed recent developments with
SO 2 releasing prodrugs with antibacterial activity. Sulfur dioxide and bisulfite have
antibacterial properties and like NO, sulfur dioxide is also endogenously produced.
A better alternative to a β-lactamase trigger might be to use a bacterial nitroreductase to initiate the cleavage, for example a p-nitrobenzyl goup, as used successfully
for nitric oxide release (Hibbard and Reynolds 2019b). Although this restricts use
to anaerobic pathogenic bacteria it would bring the molecular weights down significantly. The reduction of nitro groups to amines by nitroreductases can be variable
but the factors involved have been helpfully and broadly analysed by Miller et al.
(2018).
Instead of using a cephalosporin as the basis for the triggering event, another
possibility is to use a simpler monobactam for this purpose. A suggested prodrug
construct based on a monobactam is illustrated in Scheme 4.4. After ring opening of
the β-lactam, a cascade of non-enzymatic reactions may then proceed as shown to ultimately release the antibacterial ciprofloxacin (A), a sulfonamide (B), and the potentially bioactive vinyl imine-diamino diene (C). The product (B) could be designed to
be a sulfonamide antibacterial with the appropriate substituents including one on the
sulfonamide nitrogen, while (C) has the potential to act in the vinyl imine tautomeric
form as a Michael acceptor for protein-based nucleophilic groups.
One of the keys to the cleavage reactions seen with a number of prodrugs is the
generation of a core unit based on an enamine unit of the type: –NH–CH=CH–CH 2 –
LG where the leaving group contains one or more pharmacophoric units as in a triple
acting hybrid. The conjugated imine fragment also released might be designed to
target a different bacterial site and express other activity or activities. This a powerful
release mechanism which has the potential for further applications in the type iii
category. The basic core enamine can also be added to resulting in the generation
of moieties like –NH–CH=C(…pharmacophore C)–CH 2 –LG (pharmacophore B) by
bacterially specific enzymatic means from an enzymatically vulnerable group on N in
the prodrug. The pharmacophore B-containing group could be released by subsequent
chemical hydrolysis in the cell to afford say an α,β-unsaturated aldehyde unit which
might also display multi-reactivity with other nucleophilic sites via Michael-type
additions. Alternatively, after release of pharmacophore B, the resultant imine unit
may favour tautomerisation to another enamine unit if some stabilisation is provided
by an appropriate substituent, followed by release of another leaving group from this
second enamine.
4.2.6 Cleavable Type IV
A- -B- -C- -X → A- -B- -C
+ X
With this design type, selective cleavage of one linking group could result in
the fully active triple action agent being released near the biological target sites. To
add a further action, fragment X
might also be designed to have a synergistic fourth
4 Design Principles and Development of Prodrugs for Multiply …
sulfur dioxide and Wang and Wang (2018) have reviewed recent developments with
SO 2 releasing prodrugs with antibacterial activity. Sulfur dioxide and bisulfite have
antibacterial properties and like NO, sulfur dioxide is also endogenously produced.
A better alternative to a β-lactamase trigger might be to use a bacterial nitroreductase to initiate the cleavage, for example a p-nitrobenzyl goup, as used successfully
for nitric oxide release (Hibbard and Reynolds 2019b). Although this restricts use
to anaerobic pathogenic bacteria it would bring the molecular weights down significantly. The reduction of nitro groups to amines by nitroreductases can be variable
but the factors involved have been helpfully and broadly analysed by Miller et al.
(2018).
Instead of using a cephalosporin as the basis for the triggering event, another
possibility is to use a simpler monobactam for this purpose. A suggested prodrug
construct based on a monobactam is illustrated in Scheme 4.4. After ring opening of
the β-lactam, a cascade of non-enzymatic reactions may then proceed as shown to ultimately release the antibacterial ciprofloxacin (A), a sulfonamide (B), and the potentially bioactive vinyl imine-diamino diene (C). The product (B) could be designed to
be a sulfonamide antibacterial with the appropriate substituents including one on the
sulfonamide nitrogen, while (C) has the potential to act in the vinyl imine tautomeric
form as a Michael acceptor for protein-based nucleophilic groups.
One of the keys to the cleavage reactions seen with a number of prodrugs is the
generation of a core unit based on an enamine unit of the type: –NH–CH=CH–CH 2 –
LG where the leaving group contains one or more pharmacophoric units as in a triple
acting hybrid. The conjugated imine fragment also released might be designed to
target a different bacterial site and express other activity or activities. This a powerful
release mechanism which has the potential for further applications in the type iii
category. The basic core enamine can also be added to resulting in the generation
of moieties like –NH–CH=C(…pharmacophore C)–CH 2 –LG (pharmacophore B) by
bacterially specific enzymatic means from an enzymatically vulnerable group on N in
the prodrug. The pharmacophore B-containing group could be released by subsequent
chemical hydrolysis in the cell to afford say an α,β-unsaturated aldehyde unit which
might also display multi-reactivity with other nucleophilic sites via Michael-type
additions. Alternatively, after release of pharmacophore B, the resultant imine unit
may favour tautomerisation to another enamine unit if some stabilisation is provided
by an appropriate substituent, followed by release of another leaving group from this
second enamine.
4.2.6 Cleavable Type IV
A- -B- -C- -X → A- -B- -C
+ X
With this design type, selective cleavage of one linking group could result in
the fully active triple action agent being released near the biological target sites. To
add a further action, fragment X
might also be designed to have a synergistic fourth