Tuberculosis is a global health problem with the existence and spreading of multidrug resistant and extensive drug resistant strains. The development of new drugs for tuberculosis that inhibit different activities than the current drugs is thus urgent. The prokaryotic ubiquitin like protein proteasome system is an attractive target for the development of new drugs. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, a depupylase, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG53 (2). The hits were validated and determined to be fast reversible non-ATP competitive inhibitors. The SAR was established by testing 27 synthesized analogs of 1 and 2. Several of the synthesized compounds also inhibited the depupylation of a native substrate, FabD~Pup. Importantly, the pupylation and depupylation activities of PafA, the sole Pup ligase in M. tuberculosis, was also inhibited by some of these compounds. With the identification of the first described lead compounds for Dop and PafA inhibition, this study shows that high throughput screening can be a successful strategy for this purpose.
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