Structure–Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase<SUP>†</SUP>

J. Med. Chem., 51 (3), 439–448, 2008. 10.1021/jm7010673
Web Release Date: January 12, 2008

Structure–Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase^†

Angelica M. Bello,^‡ Ewa Poduch,^‡ Yan Liu,^§ Lianhu Wei,^‡ Ian Crandall,^△^⊥ Xiaoyang Wang,^‡ Christopher Dyanand,^‡^# Kevin C. Kain,^△^⊥ Emil F. Pai,^§^∇ and Lakshmi P. Kotra^*^‡^⊥^#^○

Center for Molecular Design and Preformulations and Division of Cell and Molecular Biology, Toronto General Research Institute/University Health Network, MaRS/TMDT, 101 College Street, Toronto, Ontario M5G 1L7, Canada, Departments of Pharmaceutical Sciences and Chemistry, University of Toronto, Toronto, Ontario, Canada, Division of Cancer Genomics and Proteomics, Ontario Cancer Institute/University Health Network, MaRS/TMDT, 101 College Street, Toronto, Ontario M5G 1L7, Canada, Departments of Biochemistry, Medical Biophysics, and Molecular Genetics, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada, Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, UHN-Toronto General Hospital and the University of Toronto and McLaughlin-Rotman Center/UHN, McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada, and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina 27412

Received August 28, 2007

Abstract:

Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5′-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5′-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure–activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6-N-methylamino, and 6-N,N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5′-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6-N-Methylamino and 6-N,N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.

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