Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase

Journal of Medicinal Chemistry
Angelica M BelloLakshmi P Kotra

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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Citations

Mar 23, 2011·Journal of Medicinal Chemistry·Melissa LewisLakshmi P Kotra
Sep 21, 2012·Journal of Medicinal Chemistry·Meena K PurohitLakshmi P Kotra
Feb 16, 2013·Journal of Medicinal Chemistry·Ian E CrandallLakshmi P Kotra
Jun 5, 2010·Organic Letters·Mohannad AbdoSpencer Knapp
Sep 3, 2010·BMC Systems Biology·Carola HuthmacherHermann-Georg Holzhütter
Jun 2, 2012·Future Medicinal Chemistry·Marcela Krečmerová, Miroslav Otmar
Jan 29, 2014·Future Medicinal Chemistry·Sourabh Mundra, Lakshmi P Kotra
Jun 11, 2015·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Masahiro FujihashiLakshmi P Kotra
Feb 25, 2014·Journal of Biomolecular Structure & Dynamics·Shirin JamshidiHashem Rafii-Tabar
Oct 25, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ifedayo Victor Ogungbe, William N Setzer
Feb 26, 2015·Chemical Communications : Chem Comm·E-K Kim, R Krishnamurthy
Dec 17, 2008·Organic & Biomolecular Chemistry·Jessica H WongJacquelyn Gervay-Hague
May 28, 2009·Chemistry : a European Journal·Daniel HeinrichMarkus Georg Rudolph
Mar 6, 2009·Journal of Medicinal Chemistry·Angelica M BelloLakshmi P Kotra
Oct 25, 2013·Journal of the American Chemical Society·Masahiro FujihashiKunio Miki

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