Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

Neill, Paul M. O'; Stocks, Paul A.; Sabbani, Sunil; Roberts, Natalie L.; Amewu, Richard K.; Shore, Emma R.; Aljayyoussi, Ghaith; Angulo-Barturen, Íñigo; Belén, María; Jiménez-Díaz,; Ferrer-Bazaga, Santiago; Martínez, María Santos; Campo, Brice; Sharma, Raman; Charman, Susan A.; Ryan, Eileen; Gong, Chen; Shackleford, David M.; Davies, Jill; Nixon, Gemma L.; Biagini, Giancarlo A.; Ward, Stephen A.

doi:10.1016/j.bmc.2018.05.006

Cited by 14 publications

(10 citation statements)

References 25 publications

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“…2, αmono-substituted, αdisubstituted, and αtrisubstituted aliphatic amines were smoothly converted. Briefly, aliphatic amines bearing alkyl and alkoxyl groups (41 to 52), Boc-and benzyl (Bn-) protected amines (53 to 64), ester (65), alcohol (66 to 67), sulfide (68), sulfone (69), and trifluoromethyl (70) groups all underwent the desired transformation to afford the products smoothly. And no erosion was observed when stereocenters were presented (54, 56 to 58, 64 to 66, and 70).…”

Section: Resultsmentioning

confidence: 99%

Dehydrogenative synthesis of N -functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly

Xu,

Liu,

Deng

et al. 2024

Sci. Adv.

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Polyfunctionalized arenes are privileged structural motifs in both academic and industrial chemistry. Conventional methods for accessing this class of chemicals usually involve stepwise modification of phenyl rings, often necessitating expensive noble metal catalysts and suffering from low reactivity and selectivity when introducing multiple functionalities. We herein report dehydrogenative synthesis of N -functionalized 2-aminophenols from cyclohexanones and amines. The developed reaction system enables incorporating amino and hydroxyl groups into aromatic rings in a one-shot fashion, which simplifies polyfunctionalized 2-aminophenol synthesis by circumventing issues associated with traditional arene modifications. The wide substrate scope and excellent functional group tolerance are exemplified by late-stage modification of complex natural products and pharmaceuticals that are unattainable by existing methods. This dehydrogenative protocol benefits from using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as oxidant that offers interesting chemo- and regio-selective oxidation processes. More notably, the essential role of in situ generated water is disclosed, which protects aliphatic amine moieties from overoxidation via hydrogen bond–enabled interaction.

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Section: Resultsmentioning

confidence: 99%

Dehydrogenative synthesis of N -functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly

Xu,

Liu,

Deng

et al. 2024

Sci. Adv.

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“…The finding that N205 178b had the same effectiveness as four times the amount of artesunate 4b suggested a solo dosage of N205 had comparable effectiveness with the multiples of artesunate 4b when given orally (Figure 39). 260 …”

Section: Some Antimalarial Endoperoxide Moieties Other Than 124‐triox...mentioning

confidence: 99%

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

Shukla

Rathi

Hassam³

et al. 2023

Medicinal Research Reviews

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The demand for novel, fast‐acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre‐existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4‐trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide‐based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug‐resistant strain in this area. Many 1,2,4‐trioxanes, 1,2,4‐trioxolanes, and 1,2,4,5‐tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight‐forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4‐trioxane‐based functional scaffolds. The present system of 1,2,4‐trioxane, 1,2,4‐trioxolane, and 1,2,4,5‐tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963–December 2022).

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“…In docking conformations performed by the same group, they have found that the shortest distance was between heme Fe(II) assay. 136 Looking forward, the incorporation of synthetic endoperoxide antimalarials into ACT regimens might be the solution to the looming threat of ART resistance.…”

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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Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

Cited by 14 publications

References 25 publications

Dehydrogenative synthesis of N -functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly

Dehydrogenative synthesis of N -functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

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

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