کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1358969 981374 2011 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase
چکیده انگلیسی

We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5′-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. β-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a Ki of 0.5 μM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC50 0.6 μM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 7, 1 April 2011, Pages 2378–2391
نویسندگان
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