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Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity
Talukdar, Arindam Breen, Megan Bacher, Adelbert Illarionov, Boris Fischer, Markus Georg, Gunda I. Ye, Qi-Zhuang Cushman, Mark
Talukdar, Arindam
Breen, Megan
Bacher, Adelbert
Illarionov, Boris
Fischer, Markus
Georg, Gunda I.
Ye, Qi-Zhuang
Cushman, Mark
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Abstract
(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione (9) was identified as a novel inhibitor of Schizosaccharomyces pombe lumazine synthase by high-throughput screening of a 100,000 compound library. The Ki of 9 vs. Mycobacterium tuberculosis lumazine synthase was 95 μM. Compound 9 is a structural analog of the lumazine synthase substrate, 5-amino-6-(D-ribitylamino)-2,4-(1H,3H)pyrimidinedione (1). This indicates that the ribitylamino side chain of the substrate is not essential for binding to the enzyme. Optimization of the enzyme inhibitory activity through systematic structure modification of the lead compound 9 led to (E)-5-nitro-6-(4-nitrostyryl)pyrimidine-2,4(1H,3H)-dione (26), which has a Ki of 3.7 μM vs. M. tuberculosis lumazine synthase.
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2009
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American Chemical Society
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Talukdar, A., Breen, M., Bacher, A., Illarionov, B., Fischer, M., Georg, G., … Cushman, M. (2009). Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity. The Journal of Organic Chemistry, 74(15), 5123–5134. http://doi.org/10.1021/jo900238q