1 research outputs found
Structure Guided Lead Generation for <i>M. tuberculosis</i> Thymidylate Kinase (Mtb TMK): Discovery of 3‑Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors
<i>M. tuberculosis</i> thymidylate
kinase (Mtb TMK) has
been shown in vitro to be an essential
enzyme in DNA synthesis. In order to identify novel leads for Mtb
TMK, we performed a high throughput biochemical screen and an NMR
based fragment screen through which we discovered two novel classes
of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively.
We describe three cyanopyridone subseries that arose during our hit
to lead campaign, along with cocrystal structures of representatives
with Mtb TMK. Structure aided optimization of the cyanopyridones led
to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead
generation, augmented by crystal structures and the SAR from the cyanopyridones,
enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment
hit from 500 μM to 200 nM while simultaneously improving the
ligand efficiency. Cyanopyridone derivatives containing sulfoxides
and sulfones showed cellular activity against <i>M. tuberculosis</i>. To the best of our knowledge, these compounds are the first reports
of non-thymidine-like inhibitors of Mtb TMK