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Design, Synthesis And Biological Evaluation Of Pyrido[2,3-D]Pyrimidines As Inhibitors Of N5-Cair Synthetase, Qian Lin

Wayne State University Dissertations

The spread of drug-resistant bacterial infections has increased the need for novel antimicrobial agents. One potential but unexplored target is the de novo purine biosynthetic pathway. PurK, found only in bacteria, yeast, and fungi, catalyzes the sixth step in purine biosynthesis and has no human homolog. Herein we disclose the discovery of the first PurK inhibitor with submicromolar potency.

PurK is a member of the ATP-grasp superfamily of enzymes and recently, nanomolar inhibitors of biotin carboxylase, a related enzyme, were published. We hypothesized that those inhibitors, which target the ATP-binding site, could also inhibit PurK. To explore this hypothesis, four …