Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase

TY - JOUR

T1 - Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase

AU - Cui, Huaqing

AU - Ruda, Gian Filippo

AU - Carrero-Lerida, Juana

AU - Ruiz-Perez, Luis M.

AU - Gilbert, Ian H.

AU - Gonzalez-Pacanowska, Dolores

PY - 2010/11

Y1 - 2010/11

N2 - Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (K-m = 51 mu M, k(cat)/K-m = 7.4 x 10(4) M-1 s(-1)), but can also use uridine, albeit less efficiently (K-m = 85 mu M, k(cat)/K-m = 306 M-1 s(-1)). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, K-i = 6 mu M). (C) 2010 Elsevier Masson SAS. All rights reserved.

AB - Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (K-m = 51 mu M, k(cat)/K-m = 7.4 x 10(4) M-1 s(-1)), but can also use uridine, albeit less efficiently (K-m = 85 mu M, k(cat)/K-m = 306 M-1 s(-1)). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, K-i = 6 mu M). (C) 2010 Elsevier Masson SAS. All rights reserved.

KW - Malaria

KW - Purine nucleoside phosphorylase

KW - Uridine phosphorylase

KW - Transition state inhibitor

KW - Drug discovery

KW - TRANSITION-STATE ANALOG

KW - URIDINE PHOSPHORYLASE

KW - FORCE-FIELD

KW - MALARIA

KW - MAB

U2 - 10.1016/j.ejmech.2010.08.026

DO - 10.1016/j.ejmech.2010.08.026

M3 - Article

C2 - 20817362

SN - 0223-5234

VL - 45

SP - 5140

EP - 5149

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 11

ER -