Abstract

Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays.

Highlights

  • Malaria is a major global problem, affecting millions of people each year

  • We have previously reported the synthesis and biological evaluation of tritylated acyclic uracil analogues,[9,10,11] which were shown to be potent and selective inhibitors of the Plasmodium falciparum Deoxyuridine 50-triphosphate nucleotidohydrolase (dUTPase) (PfdUTPase)

  • More recently in an attempt to decrease lipophilicity and increase water solubility, we have shown when replacing the trityl group with a diphenyl moiety, in both acyclic and cyclic molecules, that it is possible under certain circumstances to retain PfdUTPase enzyme inhibition[13] (Table 1 and Table 2)

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Summary

Introduction

Malaria is a major global problem, affecting millions of people each year. If not treated promptly; malaria can kill rapidly, especially children. We have previously reported the synthesis and biological evaluation of tritylated acyclic uracil analogues,[9,10,11] which were shown to be potent and selective inhibitors of the Plasmodium falciparum dUTPase (PfdUTPase). These analogues, which were synthesised with varying chain lengths (Table 1), showed comparable activities to their preceding cyclic counterparts,[12] are of equal interest in terms of inhibitory activities. Insertion of the amide bond into the cyclic compounds gave an overall comparison of the effect of this increased rigidity in the restrained nucleoside upon enzyme inhibition (Fig. 3)

Chemistry
Results and discussion
Acyclic analogues
Cyclic analogues
Conclusions
Enzyme purification and inhibition assays
General procedure B
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