2. Academic Validation
  3. Discovery and development of a small molecule library with lumazine synthase inhibitory activity

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

  • J Org Chem. 2009 Aug 7;74(15):5123-34. doi: 10.1021/jo900238q.
Arindam Talukdar 1,  Meghan Breen,  Adelbert Bacher,  Boris Illarionov,  Markus Fischer,  Gunda Georg,  Qi-Zhuang Ye,  Mark Cushman
Affiliations

Affiliation

  • 1 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.
PMID: 19552377 DOI: 10.1021/jo900238q
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.

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