β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase

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• 作者：Beatriz Baragañ ; a^a ; Orla McCarthy^a ; Paula Sá ; nchez^b ; Cristina Bosch-Navarrete^b ; Marcel Kaiser^c ; Reto Brun^c ; Jean L. Whittingham^d ; Shirley M. Roberts^d ; Xiao-Xiong Zhou^e ; Keith S. Wilson^d ; Nils Gunnar Johansson^e ; Dolores Gonzá ; lez-Pacanowska^b ; Ian H. Gilbert^a ; ^{i.h.gilbert@dundee.ac.uk}
• 关键词：Plasmodium falciparum ; dUTPase
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：1 April 2011
• 年：2011
• 卷：19
• 期：7
• 页码：2378-2391
• 全文大小：1436 K

文摘

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 K_i 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.