Rickettsia prowazekii is a bacterium responsible for the human infection of typhus, a disease with mortality rates between 10 and 60 percent if left untreated. Methionine aminopeptidases (MetAP’s) are a class of enzymes whose function is to cleave N-terminal methionine residues from nascent proteins. The necessity of MetAP on cellular function is well established and its inhibition results in rapid cell death. MetAP’s have therefore become an attractive therapeutic target for the treatment of bacterial infection. We have designed and synthesized a wide variety of RpMetAP inhibitors based upon several chemical scaffolds including triazoles, hydroxyquinolines, aryl furans and anthranilic acids. The compounds exhibit a wide range of activity against RpMetAP with IC50 values from 10 µM to less than 600 nM.

Design, synthesis, and biological evaluation of Rickettsia prowazekii methionine aminopeptidase (MetAP) Inhibitors

249th National Meeting (2015)

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