Disease is increasingly viewed as a network state, potentially resulting from and influenced by multiple contributing factors.  Complementing this view is the growing understanding that many effective drugs interact with multiple targets through polypharmacology, and that new therapies might be designed by taking this into consideration rather than by the reductionist one target-one disease model.  By merging these ideas with the rationale of polypharmacology and combination therapy, we seek to modulate multiple target sites with hybrid compounds, which are multi-target ligands formed by covalent union of two or more drug molecules.  In general, hybrid compounds can be used for probing academic questions, and they may lay the groundwork for intentional multi-target drug design of privileged or otherwise combined scaffolds.We report the synthesis and biological evaluation of dimeric antibiotic hybrids based on the fluoroquinolone family.  Through structure-based design and consideration of mechanism, modular series of hybrids were prepared around two design hypotheses, then tested for antibiotic activity.  Several compounds were found to be more active than the parent monomers.  These results are reported and the models for enhanced activity are compared.

Hybrid probe molecules in infectious disease

247th National Meeting (2014)

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