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

TY - JOUR

T1 - beta-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase

AU - Baragana, Beatriz

AU - McCarthy, Orla

AU - Sanchez, Paula

AU - Bosch-Navarrete, Cristina

AU - Kaiser, Marcel

AU - Brun, Reto

AU - Whittingham, Jean L.

AU - Roberts, Shirley M.

AU - Zhou, Xiao-Xiong

AU - Wilson, Keith S.

AU - Johansson, Nils Gunnar

AU - Gonzalez-Pacanowska, Dolores

AU - Gilbert, Ian H.

PY - 2011/4/1

Y1 - 2011/4/1

N2 - We report a series of beta-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. beta-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 mu M 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 mu M). 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. (C) 2011 Elsevier Ltd. All rights reserved.

AB - We report a series of beta-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. beta-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 mu M 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 mu M). 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. (C) 2011 Elsevier Ltd. All rights reserved.

KW - Plasmodium falciparum

KW - dUTPase

KW - MOLECULAR-GRAPHICS

KW - DESIGN

KW - NUCLEOTIDOHYDROLASE

KW - MALARIA

KW - CLONING

KW - TARGET

U2 - 10.1016/j.bmc.2011.02.012

DO - 10.1016/j.bmc.2011.02.012

M3 - Article

C2 - 21411327

SN - 0968-0896

VL - 19

SP - 2378

EP - 2391

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 7

ER -