Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant <i>Plasmodium yoelii nigeriensis</i> in a Swiss Mice Model

Hassam, Mohammad; Singh, Ajit Shankar; Yadav, Dinesh Kumar; Singh, Chandan; Puri, Sunil K.; Verma, Ved Prakash

doi:10.1021/acsomega.1c05041

Cited by 3 publications

(3 citation statements)

References 56 publications

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“…This study demonstrated that the 1,2,4‐trioxane pharmacophore has an aryl moiety at the C‐5 position when employed to aid in drug discovery (Figure 23). 158,159 Diimide reduction of the double bond of 6‐arylvinyl‐1,2,4‐trioxane 123g had shown remarkable results by giving 100% protection to the infected mice at 12 mg/kg × 4 days by oral route 160 …”

Section: Synthetic Derivatives Of 124‐trioxane and Their Activitiesmentioning

confidence: 99%

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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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Section: Synthetic Derivatives Of 124‐trioxane and Their Activitiesmentioning

confidence: 99%

“…1,2,4-trioxane 123g had shown remarkable results by giving 100% protection to the infected mice at 12 mg/ kg × 4 days by oral route 160. F I G U R E 21Rudrapal et al161 tested the AM potential of new 1,2,4-trioxanes against CQ-sensitive (3D7) and CQ-resistant (RKL9) P.…”

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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“…In the multidrug‐resistant P. yoelii nigeriensis ‐infected mice model, 1,2,4‐trioxane‐adamantane hybrids 13a , b provided 100% protection to the mice at a dose of 24 mg/kg × 4 days via the oral route and all of the treated mice survived over 28 days, while β‐arteether provided only 20% protection at the same dose. [ 34 ] The SAR revealed that halogen atom on the phenyl ring was critical for the high activity, while the phenyl ring was not essential for the activity as evidenced by that hybrids 14 and 15 could completely suppress parasitemia at doses of 24 mg/kg × 4 days and 12 mg/kg × 4 days, respectively. Accordingly, all these four hybrids, especially 15 , were promising preclinical candidates to fight against multidrug‐resistant malaria.…”

Section: 24‐trioxolane/trioxane Hybridsmentioning

confidence: 99%

The antimalarial activity of 1,2,4‐trioxolane/trioxane hybrids and dimers: A review

Fang

Song

Wang

2022

Archiv der Pharmazie

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Malaria, a mosquito‐borne parasitic infection caused by protozoan parasites belonging to the genus Plasmodium, is a dangerous disease that contributes to millions of hospital visits and hundreds and thousands of deaths across the world, especially in Sub‐Saharan Africa. Antimalarial agents are vital for treating malaria and controlling transmission, and 1,2,4‐trioxolane/trioxane‐containing agents, especially artemisinin and its derivatives, own antimalarial efficacy and low toxicity with unique mechanisms of action. Moreover, artemisinin‐based combination therapies were recommended by the World Health Organization as the first‐line treatment for uncomplicated malaria infection and have remained as the mainstay of the treatment of malaria, demonstrating that 1,2,4‐trioxolane/trioxane derivatives are useful prototypes for the control and eradication of malaria. However, malaria parasites have already developed resistance to almost all of the currently available antimalarial agents, creating an urgent need for the search of novel pharmaceutical interventions for malaria. The purpose of this review article is to provide an emphasis on the current scenario (January 2012 to January 2022) of 1,2,4‐trioxolane/trioxane hybrids and dimers with potential antimalarial activity and the structure–activity relationships are also discussed to facilitate further rational design of more effective candidates.

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Recent advances in the synthesis and antimalarial activity of 1,2,4-trioxanes

Rathi,

Shukla,

Hassam

et al. 2024

Bioorganic Chemistry

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Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model

Cited by 3 publications

References 56 publications

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

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

The antimalarial activity of 1,2,4‐trioxolane/trioxane hybrids and dimers: A review

Recent advances in the synthesis and antimalarial activity of 1,2,4-trioxanes

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