title: Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase.
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.
authors.affiliation: Center for Molecular Design and Preformulations and Division of Cell and Molecular Biology, Toronto General Research Institute/University Health Network, MaRS/TMDT, Toronto, ON, Canada.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Bello
authors.forename: Ewa
authors.initials: E
authors.lastname: Poduch
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Ian
authors.initials: I
authors.lastname: Crandall
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Dyanand
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors*; D010961:Plasmodium / Q000187:drug effects* / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D010966:Plasmodium vivax / Q000187:drug effects; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D014542:Uridine Monophosphate; D009964:Orotidine-5'-Phosphate Decarboxylase; D014529:Uridine