Polymyxins are an important class
of antibiotics for the treatment
of bacterial infections due to multidrug resistant Gram-negative pathogens.
However, their clinical utility is limited by nephrotoxicity. Here,
we report a series of promising next generation polymyxin nonapeptides
identified on the basis of our understanding of the relationship of
structure with activity, cytotoxicity, and kidney compartment accumulation.
We demonstrate that nonapeptides with an amine-containing N-terminal
moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared
to polymyxin B. We further demonstrate that compounds with a β-branched
aminobutyrate N-terminus with an aryl substituent offer a promising
combination of low cytotoxicity and kidney exposure, leading to low
toxicity in the mouse. From this series, SPR206 has been selected
as a development candidate.
Isoquinoline ring the changes: A novel strategy for the title reaction involves ortho‐haloarylalkynes which undergo sequential intermolecular addition of N heterocycles onto alkynes and subsequent intramolecular ring closure by arylation. The process involves the use of hydroxymethyl benzotriazole as an efficient and inexpensive ligand for the CN and CC coupling reactions.
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