Parallel Synthesis of Potent, Pyrazole-Based Inhibitors of Helicobacter pylori Dihydroorotate Dehydrogenase

• Published in: Journal of medicinal chemistry Vol. 45; no. 21; pp. 4669 - 4678
• Main Authors: HAQUE, Tasir S., TADESSE, Seifu, MARCINKEVICIENE, Jovita, ROGERS, M. John, SIZEMORE, Christine, KOPCHO, Lisa M., AMSLER, Karen, ECRET, Lisa D., ZHAN, Dong Liang, HOBBS, Frank, SLEE, Andrew, TRAINOR, George L., STERN, Andrew M., COPELAND, Robert A., COMBS, Andrew P.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 10-10-2002
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Combinatorial Chemistry Techniques; Digestive system; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - enzymology; Humans; Medical sciences; Oxidoreductases - antagonists & inhibitors; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Automation; Five membered ring; Spirillales; Enzyme; Nitrogen heterocycle; Spirillaceae; Combinatorial chemistry; Enzyme inhibitor; Selectivity; In vitro; Pyrrolidine derivatives; Screening; Helicobacter pylori; Structure activity relation; Chemical compound library; Pyrazole derivatives; Bacteria; Carboxamide; Oxidoreductases; Antibacterial agent; Chemical synthesis; Anilide; Dihydroorotate dehydrogenase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020112w

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.