Acyclic Nucleoside Analogues as Inhibitors ofPlasmodiumfalciparumdUTPase

Abstract

We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assayed against both P.falciparum dUTPase and intact parasites. A good correlation was observed between enzyme inhibition and cellular assays. Acyclic uracil derivatives were identified that showed greater or similar potency and in general increased selectivity compared to previously reported inhibitors. The most active compound reported here against the P. falciparum enzyme had a K(i) of 0.2 microM. Molecular modeling studies provided a good rationale for the observed activities. Preliminary ADME studies indicated that some of the lead compounds are drug-like molecules. These compounds are useful tools for further investigating P. falciparum dUTPase for the development of much-needed novel antimalarial drugs.

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

“…Having completed the diphenyl linker chain, attachment of the uracil was carried out with Mitsunobu methodology. The use of polymer-supported triphenylphosphine, a procedure previously used in our laboratories, [9] ensured a cleaner reaction without the triphenylphosphine oxide by-product, which is sometimes difficult to remove. To ensure monoalkylation at the N1 position of uracil, N3-protected uracil was used.…”

“…However, following Mitsunobu coupling and benzoyl deprotection, a low yield of alcohol intermediate 10 was obtained. It was found that coupling of ethyl 4-bromobutanoate to N3 benzoyl-protected uracil 7 [9] could be achieved cleanly in good yield after heating in N,N-dimethylformamide for 1 h. Reduction of the ester using a sodium borohydride/methanol system reported by Da Costa et al [11] led to simultaneous reduction and benzoyl deprotection to give 10.…”

“…Selectivity of PfdUTPase over the human enzyme was retained in compound 15 a versus the trityl derivative 24 (> 500 versus 230). Introduction of the addi- [9] but are included here for comparison. tional methylene group led to a significant decrease in selectivity, with only twofold preference for PfdUTPase observed over the human enzyme.…”

“…The diphenyl moiety is oriented so that the two phenyl groups lie in the "buried" sites (R1 and R2). R1 superposes almost exactly on the compound F/compound 24 ring, [e] Compound 24 has been published, [9] but is included here for comparison. while the orientation of the R2 ring is slightly rotated, probably reflecting the greater mobility of the diphenyl over the trityl unit.…”

“…[4,9] These consist of both cyclic and acyclic nucleoside analogues in which the potency and selectivity arises from those that carry the trityl functionality. Complete removal of the trityl group results in a significant decrease in both biological activity and selectivity of these compounds for the Plasmodium over the human enzyme ( Figure 1).…”