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Über dieses Buch

This book covers intentional design aspects for combinations of drugs, single-molecule hybrids with potential or actual multiple actions, pro-drugs which could yield multiple activity outcomes, and future possibilities. The approach of the book is interdisciplinary, and it provides greater understanding of the complex interplay of factors involved in the medicinal chemistry design and laboratory development of multiply active antibacterials. The scope of the book appeals to readers who are researching in the field of antibacterials using the approach of medicinal chemistry design and drug development.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Antibacterials

Abstract
This chapter sets the basic perspectives for the other chapters in the book. In this context, aspects discussed include the ever-rising global health problem from drug resistant pathogenic bacteria, a basic review of bacterial resistance mechanisms, and the need for innovative solutions to overcome resistance to antibacterials. General ways to achieve multiple-action effects through drug combinations, one or more being directly antibacterial, and through single molecule hybrids and prodrugs, are introduced. Relevant definitions are also outlined in Sect. 1.5 and the chapter concludes with an introduction to approaches towards achieving bacterial over host selectivity.
John Bremner

Chapter 2. Antibacterial Combinations

Abstract
There has been much activity in the area of multiple drug combinations in treating various diseases including bacterially mediated ones. Work in the field is continuing and in this chapter design principles for combinations of separate drugs aimed at more than two types of antibacterial activity or associated activity which contributes to increased potency or overcoming antimicrobial resistance strategies are covered. This chapter concisely reviews previous work over the past decade or so and details current work on combinations of drugs with multiple activities through specific interactions with one or more biological target molecules.
John Bremner

Chapter 3. Single Molecule Non-cleavable Multiply Active Antibacterials

Abstract
Multiply active non-cleavable antibacterials constitute a complex molecular design area. The emphasis in this chapter is on design parameters for small molecule triple or higher action single agents based on background information from drug combinations and dual action hybrids. Established multiple action agents or multi-targeting of bacterial sites by single ligands are discussed and then new structural possibilities are suggested illustrating the key design principles involved. A feature of this chapter is the use of a known antibacterial, the natural product berberine, as the starting point to illustrate potentially generalizable structural modifications for deliberate multiple action design. Cross referencing to sections of other chapters is included where appropriate. In this chapter there is a concentration on the medicinal chemistry aspects in new antibacterial design.
John Bremner

Chapter 4. Design Principles and Development of Prodrugs for Multiply Active Antibacterials

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.
John Bremner

Chapter 5. Future Possibilities

Abstract
There are many possibilities for the future design of new multi-targeted antibacterials based on developing knowledge of synergistic combinations and new modes of action being discovered. This final chapter includes a comparative assessment of the combination, hybrid and prodrug approaches, together with a discussion of the potential for using new drug combinations, especially incorporating new modes of action, in new hybrid or prodrug designs. A concluding section covers some more general thoughts on the need to think well outside the square in the design and development of antibacterials to help in the fight against the ever increasing threat of resistance.
John Bremner

Backmatter

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