Design, Synthesis, and Evaluation of 5′‐Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase

Abstract

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.

Catalytic mechanism of α-phosphate attack in dUTPase is revealed by X-ray crystallographic snapshots of distinct intermediates, 31P-NMR spectroscopy and reaction path modelling

“…Uracil-substituted DNA transforms base-excision repair into a hyperactive cycle inducing DNA double-strand breaks and thymine-less cell death. In this respect, dUTPases, important for preserving genomic integrity (12), have been proposed as targets against cancer (13–18) and multiple infectious pathogens, as well (5,7,19–25). The potential use of dUTPase antagonism in inducing thymine-less cell death requires a detailed understanding of the enzymatic mechanism.…”

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets

“…Therefore, the enzyme has been and still is the focus of intense research efforts in targeting this enzyme using different methodologies including design, synthesis, and evaluation of analogues (Nguyen et al, 2005 and 2006; Whittingham et al, 2005; McCarthy et al, 2009; Baragaña et al, 2011; Ruda et al, 2011; Hampton et al, 2011), and high throughput searches (Crowther et al, 2011). These studies established that the uracil ring is of utmost importance in binding of ligands to the active site, whereas more variations are allowed at the 3′- and 5′-positions (Recio et al, 2011).…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…1QB7, 1QB8, 1QCC, 1QCD [18] Adenosine kinase (AK) 2XTB, 3OTX [19], 4N09 [20] Adenoylsuccinate synthetase (AdSS) 1P9B [21] Aminopeptidase (Apase) 4EFD; 4FUK [22] Apical membrane antigen I (AMA1) 3SRI, 3SRJ, 3ZWZ [23] Arginase ( [51], 3T60, 3T64, 3T6Y, 3T70 [52] 4DK2, 4DK4, 4DKB, 4DL8, 4DLC [53] 1OGK, 1OGL [54] Diadenosine tetraphosphatase (DATP) 1QJC [55] 2EWG, 2I19 [101]; 2P1C [102]; 3DYF, 3DYG, 3DYH, 3EFQ, 3EGT [103]; 2OGD [104] 1YHL, 1YHM [105]; 3IBA, 3ICK, 3ICM, 3ICN, 3ICZ, 3ID0 [106]; 4DWB, 4DWG, 4DXJ, 4DZW, 4E1E [107] Ferredoxin-NADP+ reductase (FNR) 2OK7, 2OK8 [108] FK506 binding protein (FKBP35) 4J4N [109] Fructose-1,6-bisphosphate aldolase (ALDO)…”