(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.
(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione (9) was identified as a novel inhibitor of n class="Species">Schizosaccharomyces pombelumazine synthase by high-throughput screening of a 100000 compound library. The K(i) of 9 vs Mycobacterium tuberculosislumazine 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.
Authors: Markus Fischer; Ilka Haase; Richard Feicht; Nicholas Schramek; Peter Köhler; Peter Schieberle; Adelbert Bacher Journal: Biol Chem Date: 2005-05 Impact factor: 3.915
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