Abstract
Natural products are a rich source for drug development. However, some biologically relevant natural products possess rather large, complex or labile chemical structures compared to synthetic drugs, which limits chemical modification in a process pursuing a structure-activity relationship. Here we describe the rational simplification of the muraymycins and caprazamycins class of nucleoside natural products to address the issue associated with their molecular complexity. First, the systematic structure-activity relationship (SAR) study of the muraymycins using an Ugi four-component reaction was investigated. Our SAR study of the muraymycins suggests a probable mechanism for inhibition of the MraY. The predicted binding model would provide further direction towards the design of potent MraY inhibitors. Next, function-oriented synthesis (FOS) of caprazamycins was investigated. Based on the conformation-activity relationship study of a series of analogs 36-38, we designed the oxazolidine-containing uridine derivatives 41-44 by restricting the conformation of 36-38. As a result, the tert-butyl ester derivatives 43 were found to be the most active against a range of bacterial strains containing VRE with a similar potency to the parent natural products. These studies provide a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
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