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Diversity Oriented Synthesis of Peptide Derivatives as Antibiotics

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Chemical space - where molecules have never gone

Diversity-orientated synthesis is being used to generate small molecules with a high degree of structural diversity in the quest to find new antibiotics.


Every molecule occupies space but its structural diversity defines exactly what area of chemical space it invades. In the search for new drugs, it is the extent of the differences in structure, and therefore function, that determine the probability of finding new modulators of biological systems. the 'Diversity oriented synthesis of peptide derivatives as antibiotics' (Antibiotics DOS) project used just this method to generate libraries of structurally and therefore functionally unique molecules to be screened for bioactive hits. antibiotics DOS scientists devised a strategy to generate potential antibiotics using simple organic molecules – azides, amines, alkynes and carboxylic acids – to introduce the maximum of stereochemical diversity. Coupling three of these building blocks with an amide bond then produced tripeptide derivatives for the structural variety. Two unique cyclisation processes introduced the ring structure to form the basic diketopiperazine (DKP) unit into the macrocyclic framework. computer analysis confirmed that the new molecules occupied space not normally in traditional pharmaceutical products. The enhanced functionality was verified by the fact that one compound showed antibacterial activity against Staphylococcus aureus, source of the main 'superbug', Methicillin-resistant Staphylococcus aureus (MRSA). project work proved that the processes developed by Antibiotics DOS for the macrocyclic ring structure gives superior yields to previous protocols. Furthermore, there is considerable scope for production of robust macrocyclic peptidomimetics and DKPs with greater levels of diversity. the new Antibiotics DOS methods stand to become the basis for further molecular assemblies for a wide range of chemical synthesis. For now, the results already look promising for overcoming bacterial resistance to existing drugs and development of new protocols for diversity-orientated synthesis and chemical genetics.

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