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. 2013 Mar 28;56(6):2630-41.
doi: 10.1021/jm400058j. Epub 2013 Mar 7.

Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs

Bryan T Mott  1 , Abhai Tripathi, Maxime A Siegler, Cathy D Moore, David J Sullivan, Gary H Posner
Affiliations

Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs

Bryan T Mott et al. J Med Chem. .

Abstract

Malaria continues to be a difficult disease to eradicate largely because of the widespread populations it affects and the resistance that malaria parasites have developed against once very potent therapies. The natural product artemisinin has been a boon for antimalarial chemotherapy, as artemisinin combination therapy (ACT) has become the first line of chemotherapy. Because the threat of resistance is always on the horizon, it is imperative to continually identify new treatments, comprising both advanced analogues of all antimalarial drugs, especially artemisinin, and the exploration of novel combinations, ideally with distinct mechanisms of action. Here we report for the first time the synthesis of a series of two-carbon-linked artemisinin-derived dimers, their unique structural features, and demonstration of their antimalarial efficacy via single oral dose administration in two 60-day survival studies of Plasmodium berghei infected mice. Several of the new endoperoxide chemical entities consistently demonstrated excellent antimalarial efficacy, and combinations with two non-peroxide antimalarial drugs have been studied.

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Figures

Figure 1
Figure 1
Antimalarial agents to which resistance has developed
Figure 2
Figure 2
artemisinin, currently used first generation derivatives, and dihydroartmesinin
Figure 3
Figure 3
currently used therapeutic drugs in ACT
Figure 4
Figure 4
Representative artemisinin dimers of varying linker length
Figure 5
Figure 5
Carbon numbering for proton NMR analysis
Figure 6
Figure 6
a) proposed interactions in the less polar dimer methyloxime (Z)-26; b) proposed interactions in the more polar dimer methyloxime (E)-26
Scheme 1
Scheme 1
Nucleophilic substitution at C10 and competing elimination pathway
Scheme 2
Scheme 2
Preparation of DHA-OAc (19) and C10 β-alkyne (21) a) DIBALH, CH2Cl2, −78 °C, b) DMAP, py, 2,4 dimethoxybenzoyl chloride (18), 98% over 2 steps; c) DMAP, py, Ac2O, 98% over 2 steps; d) 1.1 eq ZnCl2, 3.5 eq ethynylmagnesium chloride, Et2O, 74%.
Scheme 3
Scheme 3
synthesis of two-carbon linked artemisinin dimer ketone (24) a) pTsOH, Hg(OAc)2, acetone: H2O, rt, 90%; b) TMSOTf, Et3N, THF, −78 °C to rt, 81%; c) DHA-OAc (19), SnCl4, CH2Cl2, −78 °C, 69%.
Scheme 4
Scheme 4
preparation of two-carbon linked dimer oxime analogs from 24 a) RONH2-HCl, py, rt; b) R-X, NaH, THF, 0 °C.
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References

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