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, Qizhuang Ye, Mark Cushman

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

Fingerprint

Molecules
Lead compounds
Uracil
Enzyme activity
Substrates
Screening
Throughput
6,7-dimethyl-8-ribityllumazine synthase
Enzymes
(E)-5-nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione
pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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. Journal of Organic Chemistry, 74(15), 5123-5134. https://doi.org/10.1021/jo900238q

Discovery and development of a small molecule library with lumazine synthase inhibitory activity. / Talukdar, Arindam; Breen, Meghan; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Georg, Gunda; Ye, Qizhuang; Cushman, Mark.

In: Journal of Organic Chemistry, Vol. 74, No. 15, 07.08.2009, p. 5123-5134.

Research output: Contribution to journalArticle

Talukdar, A, Breen, M, Bacher, A, Illarionov, B, Fischer, M, Georg, G, Ye, Q & Cushman, M 2009, 'Discovery and development of a small molecule library with lumazine synthase inhibitory activity', Journal of Organic Chemistry, vol. 74, no. 15, pp. 5123-5134. https://doi.org/10.1021/jo900238q
Talukdar, Arindam ; Breen, Meghan ; Bacher, Adelbert ; Illarionov, Boris ; Fischer, Markus ; Georg, Gunda ; Ye, Qizhuang ; Cushman, Mark. / Discovery and development of a small molecule library with lumazine synthase inhibitory activity. In: Journal of Organic Chemistry. 2009 ; Vol. 74, No. 15. pp. 5123-5134.
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