<scp>d</scp>-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity

Sonawane, Dhiraj P.; Corbett, Yolanda; Dhavale, Dilip D.; Taramelli, Donatella; Trombini, Claudio; Quintavalla, Arianna; Lombardo, Marco

doi:10.1021/acs.orglett.5b01996

Cited by 13 publications

(3 citation statements)

References 51 publications

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“…We recently proposed new structurally simple 3-methoxy-1,2-dioxanes 2 (Figure ), obtained through an efficient and cheap synthetic approach. − The simple and flexible protocol developed for their synthesis allowed us to collect a small library of 1,2-dioxanes 2 , variably substituted on C3, C4, and C6. When tested for in vitro antileishmanial activity on promastigotes of L.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

et al. 2020

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Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro , and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania .

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Section: Introductionmentioning

confidence: 99%

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

et al. 2020

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“…Then, the library of endoperoxides so obtained was subjected to a campaign of bioactivity in vitro tests against two parasites, Plasmodium falciparum and Leishmania donovani . Artemisinin and other peroxy compounds are known, indeed, to be active toward both parasites. − Several endoperoxides of our library revealed promising activities as anti-malarial ,− and anti-leishmanial agents. , …”

Section: Introductionmentioning

confidence: 86%

Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, via Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen

Lardani

Martí

Quintavalla

et al. 2021

Org. Process Res. Dev.

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From screening experimental parameters to scaling up, a safe approach is reported for the multidecagram scale preparation of methyl ester of 6,6-dibutyl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylic acid (7), a flexible common intermediate for the synthesis of a variety of anti-malarial and/or anti-leishmanial compounds. The critical feature of the reaction is the use of a pure oxygen flow under batch conditions using methyl acetoacetate and 2-butyl-1-hexene as reagents, and a mixture of Mn(II) and Mn(III) acetates as catalysts, in acetic acid. Once the best solvent, catalyst loading, temperature, and reaction time in the small-scale procedure (10 mL vial) were defined, the process was adapted up to a 3 L flask, eventually resulting in the production of about 70 g of 7. The developed reaction protocol gives a satisfactory result considering: (i) the inexpensive starting materials used, (ii) the 100% atom economy of the [2 + 2 + 2]-annulation reaction, (iii) the stoichiometric ratio of the two reagents (only oxygen is used in excess) coupled with low catalyst loading, and (iv) the mild conditions adopted. The calorimetric studies allow us to classify this reaction as an inherently safe process. On a larger scale, the possible formation of a flammable vapor mixture in the reactor headspace was minimized using two parallel continuous flows of oxygen and argon, thus ensuring a constant headspace vapor phase renewal.

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“…Numerous peroxide‐containing natural products have been isolated, and many of them possess highly potent antitumor, antibacterial, and antimalarial activities . For example, artemisinin (qinghaosu) has been proven to be a highly effective drug for eradicating malaria, one of the most widespread and life‐threatening parasitic diseases . Focused on the special peroxide structure, many pharmaceuticals and molecules with peroxide moieties have been designed and synthesized .…”

Section: Introductionmentioning

confidence: 99%

Merging Photoredox with Brønsted Acid Catalysis: The Cross‐Dehydrogenative C−O Coupling for sp³ C−H Bond Peroxidation

Xia

Wang

Yan

et al. 2017

Chemistry A European J

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A photoredox and Brønsted acid synergistically catalyzed cross-dehydrogenative C-O coupling reaction is developed in which isochroman peroxyacetals are formed through sp C-H bond peroxidation. The reported method is characterized by its extremely mild reaction conditions, excellent yields, and broad substrate scope. An oxocarbenium ion p-chlorobenzenesulfonate was speculated to be the reactive intermediate. The role of hemiacetals and oxygenated dimers on the effective stabilization of the oxocarbenium ion was investigated; the presence of acid appeared to establish equilibrium between hemiacetals and oxygenated dimers with the oxocarbenium ion pairs. The broad applicability of the method highlights the potential of the protocol for molecule synthesis.

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d-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity

Cited by 13 publications

References 51 publications

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, via Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen

Merging Photoredox with Brønsted Acid Catalysis: The Cross‐Dehydrogenative C−O Coupling for sp³ C−H Bond Peroxidation

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d-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity

Cited by 13 publications

References 51 publications

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

Evaluation of the Pharmacophoric Role of the O–O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans

Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, via Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen

Merging Photoredox with Brønsted Acid Catalysis: The Cross‐Dehydrogenative C−O Coupling for sp3 C−H Bond Peroxidation

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Merging Photoredox with Brønsted Acid Catalysis: The Cross‐Dehydrogenative C−O Coupling for sp³ C−H Bond Peroxidation