Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase.
2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action.
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
Gian Filippo
GF
Ruda
Corinne
C
Nguyen
Przemysław
P
Ziemkowski
Krzysztof
K
Felczak
Ganasan
G
Kasinathan
Alexander
A
Musso-Buendia
Christian
C
Sund
Xiao Xiong
XX
Zhou
Marcel
M
Kaiser
Luis M
LM
Ruiz-Pérez
Reto
R
Brun
Tadeusz
T
Kulikowski
Nils Gunnar
NG
Johansson
Dolores
D
González-Pacanowska
Ian H
IH
Gilbert
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009705:Nucleosides; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase