Chapter 4
Design Principles and Development
of Prodrugs for Multiply Active
Antibacterials
“Every problem is an opportunity in disguise.”
—John Adams, American Statesman and Second U.S. President.
Abstract Added layers of complexity in design are inherent with multi-action agents
released from prodrugs, and though challenging, such prodrugs do offer potential
advantages over the non-cleavable multi-action hybrids. In particular the pro-moiety
of the prodrug can be designed to increase solubility and permeability while the
prodrug itself can enable effective delivery and site specific release of the bioactive
component or components. This is particularly the case if the prodrug can be concentrated in bacteria or on their surface or in close proximity to them. The shorthand
terminology ‘multiply active prodrugs’ covers compounds which need to be cleaved
or activated to afford a multiply active product, or products, leading to antibacterial
action. This chapter discusses known prodrugs affording multiply active products on
cleavage and expands the conceptual framework to new possibilities for the design of
such prodrugs. A number of release mechanisms are considered (enzymatic, chemical
and physical) and implications for bacterial selectivity are explored in this Chapter.
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021
J. Bremner, Multiple Action-Based Design Approaches to Antibacterials,
https://doi.org/10.1007/978-981-16-0999-2_4
121
Design Principles and Development
of Prodrugs for Multiply Active
Antibacterials
“Every problem is an opportunity in disguise.”
—John Adams, American Statesman and Second U.S. President.
Abstract Added layers of complexity in design are inherent with multi-action agents
released from prodrugs, and though challenging, such prodrugs do offer potential
advantages over the non-cleavable multi-action hybrids. In particular the pro-moiety
of the prodrug can be designed to increase solubility and permeability while the
prodrug itself can enable effective delivery and site specific release of the bioactive
component or components. This is particularly the case if the prodrug can be concentrated in bacteria or on their surface or in close proximity to them. The shorthand
terminology ‘multiply active prodrugs’ covers compounds which need to be cleaved
or activated to afford a multiply active product, or products, leading to antibacterial
action. This chapter discusses known prodrugs affording multiply active products on
cleavage and expands the conceptual framework to new possibilities for the design of
such prodrugs. A number of release mechanisms are considered (enzymatic, chemical
and physical) and implications for bacterial selectivity are explored in this Chapter.
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021
J. Bremner, Multiple Action-Based Design Approaches to Antibacterials,
https://doi.org/10.1007/978-981-16-0999-2_4
121