4.2 Introduction to Prodrugs for Triple or Higher Action …
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4.2.4 Cleavable Type II
This cleavable type in its basic form can be represented by:
A- -B- -C → A- -B
+ C
With this general type of prodrug design, cleavage of one of the linking groups
could reveal a dual action hybrid (A--B
) together with another molecule C
capable
of interacting with a third separate target involved with the bacterium. In this case
the selective advantage hinges on the active components being released in or near
the bacterium. While the initial molecule may have no inherent antibacterial activity,
the aim would be to expose active components in high concentration on reaching
the bacterium utilizing bacterially specific enzymes for the initial activation and then
non-enzymatic steps if required.
One possible molecular realisation of this cleavable type ii prodrug is illustrated
by (I) (Scheme 4.1) (Bremner 2017) which incorporates the dual release prodrug
design. In this case a monocyclic β-lactam triggering unit, to which C is attached,
could be linked to a fluoroquinolone core B also associated with a further target recognition moiety A (Scheme 4.1). If the β-lactam in (I) was cleavable by a β-lactamase
enzyme or on interaction with a PBP, then, by analogy with some N-sulfonyloxy-βlactam inhibitor studies of Mourey et al. (1999) and Swarén et al. (1999), subsequent
elimination step (1) might then follow to give the fluoroquinolone derivative (II)
(a substituted ciprofloxacin with the further recognition unit A attached) in which
the key 3-carboxylic acid would be present. The iminium group produced in the
remaining acyl enzyme unit (or the ketone hydrolysis product, Mourey et al. 1999)
from elimination step (1) might then serve in turn to activate a second elimination
step (2) to give C
(III) if the attached fragment C had an appropriately positioned
electron acceptor group. C
could be designed to interact with another bacterial target
site and express another synergistic activity.
While (II) and (III) (Scheme 4.1) could potentially be separately prepared and then
used in a two-component combination, the prodrug design strategy suggested would
provide a means to help overcome any pharmacokinetic issues when used in vivo to
treat resistant bacterial infections. From a synthetic perspective, the N-acyloxy substituted β-lactam unit in (I) should be accessible based on the established carbodiimide
and Mitsunobu reaction methodology for other mono β-lactams (Swarén et al. 1999).
The review on monocyclic β-lactams as antibacterials and β-lactamase inhibitors may
also provide a guide to rational design of new triple acting prodrugs taking note of
regions which can be altered structurally without affecting activity (Decuyper et al.
2018).
In the type (ii) construct even greater targeting can be achieved if the product
C
is a gaseous compound with actual or possible multi-actions as for example
with nitric oxide or carbon monoxide. Kelso, Rineh and colleagues have published
some compelling work on the release of nitric oxide from a cephalosporindiazeniumdiolate prodrug (Scheme 4.2) utilising β-lactamase activation or PBP
131
4.2.4 Cleavable Type II
This cleavable type in its basic form can be represented by:
A- -B- -C → A- -B
+ C
With this general type of prodrug design, cleavage of one of the linking groups
could reveal a dual action hybrid (A--B
) together with another molecule C
capable
of interacting with a third separate target involved with the bacterium. In this case
the selective advantage hinges on the active components being released in or near
the bacterium. While the initial molecule may have no inherent antibacterial activity,
the aim would be to expose active components in high concentration on reaching
the bacterium utilizing bacterially specific enzymes for the initial activation and then
non-enzymatic steps if required.
One possible molecular realisation of this cleavable type ii prodrug is illustrated
by (I) (Scheme 4.1) (Bremner 2017) which incorporates the dual release prodrug
design. In this case a monocyclic β-lactam triggering unit, to which C is attached,
could be linked to a fluoroquinolone core B also associated with a further target recognition moiety A (Scheme 4.1). If the β-lactam in (I) was cleavable by a β-lactamase
enzyme or on interaction with a PBP, then, by analogy with some N-sulfonyloxy-βlactam inhibitor studies of Mourey et al. (1999) and Swarén et al. (1999), subsequent
elimination step (1) might then follow to give the fluoroquinolone derivative (II)
(a substituted ciprofloxacin with the further recognition unit A attached) in which
the key 3-carboxylic acid would be present. The iminium group produced in the
remaining acyl enzyme unit (or the ketone hydrolysis product, Mourey et al. 1999)
from elimination step (1) might then serve in turn to activate a second elimination
step (2) to give C
(III) if the attached fragment C had an appropriately positioned
electron acceptor group. C
could be designed to interact with another bacterial target
site and express another synergistic activity.
While (II) and (III) (Scheme 4.1) could potentially be separately prepared and then
used in a two-component combination, the prodrug design strategy suggested would
provide a means to help overcome any pharmacokinetic issues when used in vivo to
treat resistant bacterial infections. From a synthetic perspective, the N-acyloxy substituted β-lactam unit in (I) should be accessible based on the established carbodiimide
and Mitsunobu reaction methodology for other mono β-lactams (Swarén et al. 1999).
The review on monocyclic β-lactams as antibacterials and β-lactamase inhibitors may
also provide a guide to rational design of new triple acting prodrugs taking note of
regions which can be altered structurally without affecting activity (Decuyper et al.
2018).
In the type (ii) construct even greater targeting can be achieved if the product
C
is a gaseous compound with actual or possible multi-actions as for example
with nitric oxide or carbon monoxide. Kelso, Rineh and colleagues have published
some compelling work on the release of nitric oxide from a cephalosporindiazeniumdiolate prodrug (Scheme 4.2) utilising β-lactamase activation or PBP