Optimisation of the synthesis of second generation 1,2,4,5 tetraoxane antimalarials

Neill, Paul M. O'; Sabbani, Sunil; Nixon, Gemma L.; Schnaderbeck, Matthew J.; Roberts, Natalie L.; Shore, Emma R.; Riley, Christopher; Murphy, Ben; McGillan, Paul; Ward, Stephen A.; Davies, Jill; Amewu, Richard K.

doi:10.1016/j.tet.2016.08.043

Cited by 16 publications

(30 citation statements)

References 23 publications

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“…The tetraoxanes 7a – c were synthesized from 6a – c by dihydroperoxide formation promoted by formic acid followed by Re 2 O 7 -catalyzed condensation with the 2-adamantanone . The yield of this step was relatively low but consistent with yields obtained in other literature . Formation was evidenced by appearance of characteristic peaks on the 13 C NMR spectrum corresponding to the two tetraoxane carbons at 100–110 ppm.…”

supporting

confidence: 81%

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Woodley

Nixon

Basilico

et al. 2021

ACS Med. Chem. Lett.

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Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

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supporting

confidence: 81%

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Woodley

Nixon

Basilico

et al. 2021

ACS Med. Chem. Lett.

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“…Among these, trioxolanes and tetraoxanes have shown activity against different parasites, such as the protozoans Plasmodium spp. [10][11][12][13][14][15][16][17][18][19], Perkinsus spp. [20], and the parasitic flatworms Schistosoma spp [21].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

et al. 2020

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A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.

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“…133 Two syntheses of E209 have been published to date, the earliest of which was the synthetic route used for the preparation of the initial series of second-generation tetraoxanes. 133,134 An optimized synthesis (Scheme 11) was published after optimizing for yield of the tetraoxane forming step as well as cost of synthesis. 134 E209 also displayed potent antimalarial activity in the P. berghei infected mouse model, with an ED 50 determined to be 4 mg/kg in a 4-day suppressive test after three doses.…”

Section: E209mentioning

confidence: 99%

“…133,134 An optimized synthesis (Scheme 11) was published after optimizing for yield of the tetraoxane forming step as well as cost of synthesis. 134 E209 also displayed potent antimalarial activity in the P. berghei infected mouse model, with an ED 50 determined to be 4 mg/kg in a 4-day suppressive test after three doses. More importantly, E209 displayed a 66% cure rate in the P. berghei infected mice 30-day survival assay, following a single oral dose of 30 mg/kg suggesting that, like artefenomel, E209 might be suitable for a single-dose cure-although artefenomel attained a 100% cure rate in the same assay.…”

Section: E209mentioning

confidence: 99%

Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies

Woodley

Amado

Cristiano

et al. 2021

Medicinal Research Reviews

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Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-

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Optimisation of the synthesis of second generation 1,2,4,5 tetraoxane antimalarials

Cited by 16 publications

References 23 publications

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies

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