Discovery and development of a small molecule library with lumazine synthase inhibitory activity.
(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.
Talukdar
Arindam
A
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.
Breen
Meghan
M
Bacher
Adelbert
A
Illarionov
Boris
B
Fischer
Markus
M
Georg
Gunda
G
Ye
Qi-Zhuang
QZ
Cushman
Mark
M
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000201:enzymology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C545160:(E)-5-nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011744:Pyrimidinones; D054852:Small Molecule Libraries; C044822:6,7-dimethyl-8-ribityllumazine synthase