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Published on: June 23, 2019
Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase
Tasir S Haque1, Seifu Tadesse, Jovita Marcinkeviciene
1Department of Medicinal Chemistry, Bristol-Myers Squibb Company, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA. Tasir.haque@bms.com
Abstract:
The identification of several potent pyrazole-based inhibitors of bacterial dihydroorotate dehydrogenase (DHODase) via a directed parallel synthetic approach is described below. The initial pyrazole-containing lead compounds were optimized for potency against Helicobacter pylori DHODase. Using three successive focused libraries, inhibitors were rapidly identified with the following characteristics: K(i) < 10 nM against H. pylori DHODase, sub-microg/mL H. pylori minimum inhibitory concentration activity, low molecular weight, and >10 000-fold selectivity over human DHODase.
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