4.2 Introduction to Prodrugs for Triple or Higher Action …
135
In an extension of the work of Hibbard and Reynolds (2019b), utilisation of
intracellular nitroreductase enzymes in anaerobic bacteria is indicated as well to
release nitric oxide together with an amine-containing antibacterial like ciprofloxacin
to intensify the antibacterial effects through further actions. A drawback may be that
ciprofloxacin could form the N-nitroso derivative with other detrimental effects or
with reduced antibacterial activity. For example N-nitrosonorfloxacin is less active
as an antibacterial compared with norfloxacin (Adjei et al. 2006). This approach
may be useful in treating tuberculosis with a judicious choice of the fluoroquinolone
(Schluger 2013).
Interesting prodrug hybrids of quorum sensing inhibitors with nitric oxide donors
have also been investigated such as fimbrolide-nitric oxide donor hybrids of the
nitroxy and diazeniumdiolate types with different linkers or direct attachment.
These hybrids also offer further opportunities for potentiating interactions (Kutty
et al. 2013). They seem to act through dual pathways mediated through biofilm
morphology alteration and increasing susceptibility to NO. Other hybrids of acylated
homoserine lactone and nitric oxide donors have also been reported with good
antibacterial properties based on the complementary inhibition of quorum sensing
and virulence factors (Kutty et al. 2015).
Apart from the release of nitric oxide, another possibility is the release of carbon
monoxide (CO). Considerable work has been undertaken to develop prodrugs which
could release carbon monoxide after suitable activation and good reviews on the topic
are those by Ling et al. (2018) and Ji and Wang (2018). Carbon monoxide and carbon
monoxide releasing molecules (CORMs) have shown activity against both Grampositive and Gram-negative bacteria. Carbon monoxide acts as a bactericide primarily
through inhibiting the respiratory chain via stopping adenosine triphosphate supply
(Ling et al. 2018). A number of the CORMs are metal ion complexes and their bactericidal activity may also stem from this. Ways to achieve selectivity in the actions of
CO-releasing prodrugs are also important considerations. In the anti-cancer context,
an interesting way to achieve this involved enrichment-triggered prodrug activation
through mitochondria targeted delivery of doxorubicin or CO prodrugs which are
biorthogonally activated by a cycloaddition reaction with a substituted cyclooctyne
derivative (Zheng et al. 2018). Mitochondrial targeting was achieved through the
inclusion of terminal triphenylphosphonium ion functionality on substituent groups
on the prodrugs and on the cyclooctyne unit; such functionality is known to greatly
increase enrichment in the mitochondria of the molecules to which it is attached. This
approach is elegant conceptually but it may be difficult to selectively adapt this design
to antibacterial demands (no mitochondria) and have selective concentration only in
bacterial cells, however it deserves further consideration in the antibacterial prodrug
context. Further interesting possibilities present themselves in the case of visible
light-induced CO release from transition metal-free flavonoid-based systems (photoCORMs) (Anderson et al. 2015). One might, for example, attach a cephalosporin unit
via ether formation using the 3-hydroxy group in the flavone which could then be
released after interaction of the prodrug with β-lactamase, and in the presence of
light result in possibly more bacterially localised co-release of CO. Extension of the
light-induced reaction to activation by radiation in the near infrared region would
135
In an extension of the work of Hibbard and Reynolds (2019b), utilisation of
intracellular nitroreductase enzymes in anaerobic bacteria is indicated as well to
release nitric oxide together with an amine-containing antibacterial like ciprofloxacin
to intensify the antibacterial effects through further actions. A drawback may be that
ciprofloxacin could form the N-nitroso derivative with other detrimental effects or
with reduced antibacterial activity. For example N-nitrosonorfloxacin is less active
as an antibacterial compared with norfloxacin (Adjei et al. 2006). This approach
may be useful in treating tuberculosis with a judicious choice of the fluoroquinolone
(Schluger 2013).
Interesting prodrug hybrids of quorum sensing inhibitors with nitric oxide donors
have also been investigated such as fimbrolide-nitric oxide donor hybrids of the
nitroxy and diazeniumdiolate types with different linkers or direct attachment.
These hybrids also offer further opportunities for potentiating interactions (Kutty
et al. 2013). They seem to act through dual pathways mediated through biofilm
morphology alteration and increasing susceptibility to NO. Other hybrids of acylated
homoserine lactone and nitric oxide donors have also been reported with good
antibacterial properties based on the complementary inhibition of quorum sensing
and virulence factors (Kutty et al. 2015).
Apart from the release of nitric oxide, another possibility is the release of carbon
monoxide (CO). Considerable work has been undertaken to develop prodrugs which
could release carbon monoxide after suitable activation and good reviews on the topic
are those by Ling et al. (2018) and Ji and Wang (2018). Carbon monoxide and carbon
monoxide releasing molecules (CORMs) have shown activity against both Grampositive and Gram-negative bacteria. Carbon monoxide acts as a bactericide primarily
through inhibiting the respiratory chain via stopping adenosine triphosphate supply
(Ling et al. 2018). A number of the CORMs are metal ion complexes and their bactericidal activity may also stem from this. Ways to achieve selectivity in the actions of
CO-releasing prodrugs are also important considerations. In the anti-cancer context,
an interesting way to achieve this involved enrichment-triggered prodrug activation
through mitochondria targeted delivery of doxorubicin or CO prodrugs which are
biorthogonally activated by a cycloaddition reaction with a substituted cyclooctyne
derivative (Zheng et al. 2018). Mitochondrial targeting was achieved through the
inclusion of terminal triphenylphosphonium ion functionality on substituent groups
on the prodrugs and on the cyclooctyne unit; such functionality is known to greatly
increase enrichment in the mitochondria of the molecules to which it is attached. This
approach is elegant conceptually but it may be difficult to selectively adapt this design
to antibacterial demands (no mitochondria) and have selective concentration only in
bacterial cells, however it deserves further consideration in the antibacterial prodrug
context. Further interesting possibilities present themselves in the case of visible
light-induced CO release from transition metal-free flavonoid-based systems (photoCORMs) (Anderson et al. 2015). One might, for example, attach a cephalosporin unit
via ether formation using the 3-hydroxy group in the flavone which could then be
released after interaction of the prodrug with β-lactamase, and in the presence of
light result in possibly more bacterially localised co-release of CO. Extension of the
light-induced reaction to activation by radiation in the near infrared region would