Discovery and development of a small molecule library with lumazine synthase inhibitory activity

Arindam Talukdar, Meghan Breen, Adelbert Bacher, Boris Illarionov, Markus Fischer, Gunda Georg, Qi Zhuang Ye, Mark Cushman

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

(Chemical Equation Presented) (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 100000 compound library. The Ki of 9 vs Mycobacterium tuberculosis lumazine synthase was 95 μM. Compound 9 is a structural analogue 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.

Original languageEnglish (US)
Pages (from-to)5123-5134
Number of pages12
JournalJournal of Organic Chemistry
Volume74
Issue number15
DOIs
StatePublished - Aug 7 2009
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Talukdar, A., Breen, M., Bacher, A., Illarionov, B., Fischer, M., Georg, G., Ye, Q. Z., & Cushman, M. (2009). Discovery and development of a small molecule library with lumazine synthase inhibitory activity. Journal of Organic Chemistry, 74(15), 5123-5134. https://doi.org/10.1021/jo900238q