Modified 5′‐Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase

Abstract

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.

QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities

“…Additionally, the absence of the trityl group results in drastic decrease in activity against Pf dUTPase, as observed in compounds 4 and 127 ( Figures 2A,B , respectively), and a clear decrease in selectivity, when we compare compounds 20 and 87 ( Figures 2C,D , respectively). These observations corroborate previous studies ( Whittingham et al, 2005 ; McCarthy et al, 2009 ; Baragaña et al, 2011 ; Hampton et al, 2011 ; Recio et al, 2011 ; Ruda et al, 2011 ; Ojha and Roy, 2013 ), indicating that two of the three phenyl rings from the trityl group have significant interactions with the hydrophobic pocket formed by residues Phe46 and Ile117 from Pf dUTPase ( Hampton et al, 2011 ). In contrast, in the human enzyme, such residues are replaced by hydrophilic residues Val42 and Gly87.…”

“…2D and 3D QSAR models were built using a series of Pf dUTPase inhibitors reported in the literature (Supplementary Table S1 ) ( Nguyen et al, 2005 , 2006 ; Whittingham et al, 2005 ; McCarthy et al, 2009 ; Baragaña et al, 2011 ; Hampton et al, 2011 ; Ruda et al, 2011 ). The data set was prepared and curated according to the protocol described by Fourches et al (2010 , 2015 , 2016 ).…”

Deinococcus radiodurans DR2231 is a two‐metal‐ion mechanism hydrolase with exclusive activity on dUTP

“…Tight regulation avoids incorporation of uracil into DNA, which could ultimately cause cell damage and consequently cell death . For this reason, dUTPases have been proposed as possible pharmaceutical targets in cancer cells or pathogenic microorganisms . Furthermore, it was recently found that virus/phage dUTPases could also regulate some cellular processes, acting as signalling molecules .…”

Automated Synthesis and Purification of Guanidine‐Backbone Oligonucleotides

“…The authors routinely begin this synthesis with 20 g of thymidine to prepare 6 g (~ 7 mmol) of P6 monomer. This synthetic sequence is based upon published literature with modifications by the authors (Challa & Bruice, 2004;Eleuteri et al, 1996;Lavandera et al, 2001;Ruda et al, 2011). Similar synthetic protocols have been reported for the other bases; however, they have not been verified by the authors (Linkletter et al, 2001;Szabo & Bruice, 2004).…”