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J Org Chem. 2009 Aug 7;74(15):5123-34.

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

Talukdar A, Breen M, Bacher A, Illarionov B, Fischer M, Georg G, Ye QZ, Cushman M.

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Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and The Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.

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 100000 compound library. The K(i) of 9 vs Mycobacterium tuberculosis lumazine synthase was 95 microM. 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 K(i) of 3.7 microM vs M. tuberculosis lumazine synthase.

PMID:: 19552377; [PubMed - indexed for MEDLINE]
PMCID:: PMC2760403

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Cited by 1 PubMed Central article

Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase. [Bioorg Med Chem. 2010]
Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase.
Talukdar A, Morgunova E, Duan J, Meining W, Foloppe N, Nilsson L, Bacher A, Illarionov B, Fischer M, Ladenstein R, et al. Bioorg Med Chem. 2010 May 15; 18(10):3518-34. Epub 2010 Apr 8.

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