Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Peter, Sijongesonke; Jama, Siphesihle; Alven, Sibusiso; Aderibigbe, Blessing Atim

doi:10.3390/molecules26247521

Cited by 22 publications

(15 citation statements)

References 67 publications

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“…The hydroxylation artemisinin derivatives generated from microbial transformation may provide advantages over artemisinin itself by increasing water solubility and binding affinity to its targets. Conjugation of artemisinin with (iso)quinoline and other compounds into hybrid compounds has been demonstrated to be an effective way to tackle multidrug-resistant malaria (Capci et al 2019;Peter et al 2021). Therefore, making novel hybrid molecules based on the hydroxylation artemisinin derivative with a reactive hydroxy group and other antimalarial compounds such as (iso)quinonline (Capci et al 2019), gallic acid (Aldulaimi et al 2017), thymoquinone (Johnson-Ajinwo et al 2018) and cycleanine derivatives (Uche et al 2021(Uche et al , 2018 with different mechanisms of action could be a promising approach to attack artemisinin resistance.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger

Luo

Mobley

Woodfine

et al. 2022

Appl Microbiol Biotechnol

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Artemisinin is a component part of current frontline medicines for the treatment of malaria. The aim of this study is to make analogues of artemisinin using microbial transformation and evaluate their in vitro antimalarial activity. A panel of microorganisms were screened for biotransformation of artemisinin (1). The biotransformation products were extracted, purified and isolated using silica gel column chromatography and semi-preparative HPLC. Spectroscopic methods including LC-HRMS, GC–MS, FT-IR, 1D and 2D NMR were used to elucidate the structure of the artemisinin metabolites.1H NMR spectroscopy was further used to study the time-course biotransformation. The antiplasmodial activity (IC50) of the biotransformation products of 1 against intraerythrocytic cultures of Plasmodium falciparum were determined using bioluminescence assays. A filamentous fungus Aspergillus niger CICC 2487 was found to possess the best efficiency to convert artemisinin (1) to a novel derivative, 4-methoxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (2) via ring rearrangement and further degradation, along with three known derivatives, compound (3), deoxyartemisinin (4) and 3-hydroxy-deoxyartemisinin (5). Kinetic study of the biotransformation of artemisinin indicated the formation of artemisinin G as a key intermediate which could be hydrolyzed and methylated to form the new compound 2. Our study shows that the anti-plasmodial potency of compounds 2, 3, 4 and 5 were ablated compared to 1, which attributed to the loss of the unique peroxide bridge in artemisinin (1). This is the first report of microbial degradation and ring rearrangement of artemisinin with subsequent hydrolysis and methoxylation by A.niger. Key points • Aspergillus niger CICC 2487 was found to be efficient for biotransformation of artemisinin • A novel and unusual artemisinin derivative was isolated and elucidated • The peroxide bridge in artemisinin is crucial for its high antimalarial potency • The pathway of biotransformation involves the formation of artemisinin G as a key intermediate

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Section: Discussionmentioning

confidence: 99%

Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger

Luo

Mobley

Woodfine

et al. 2022

Appl Microbiol Biotechnol

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“…Dihydroartemisinin (DHA, Figure 1), a sesquiterpene lactone with a 1,2,4‐endoperoxide bridge, could exert anticancer effects via diverse molecular mechanisms, inclusive of inhibition of proliferation, induction of apoptosis, inhibition of tumor metastasis and angiogenesis, promotion of immune function, induction of autophagy and endoplasmic reticulum stress (Dai et al, 2021; Yu et al, 2021). Consequently, DHA and its derivatives demonstrated potential in vitro and in vivo efficiency against various cancers including breast cancers (Kiani et al, 2020; Peter et al, 2021). In particular, DHA hybrids with other anticancer pharmacophores at C‐10 position of DHA skeleton have the potential to conquer drug resistance, enhance anticancer efficacy, and improve physicochemical properties, representing useful prototypes for clinical deployment in the control of breast cancer (Gao et al, 2020; Zhang, Yi, et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Novel ester tethered dihydroartemisinin‐3‐(oxime/thiosemicarbazide)isatin hybrids as potential anti‐breast cancer agents: Synthesis, in vitro cytotoxicity and structure–activity relationship

Liu

Wang

et al. 2023

Drug Development Research

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A series of ester tethered dihydroartemisinin‐3‐(oxime/thiosemicarbazide)isatin hybrids 7a–p were designed, synthesized, and assessed for their antiproliferative activity against MCF‐7, MDA‐MB‐231, MCF‐7/ADR, and MDA‐MB‐231/ADR breast cancer cell lines. Among them, hybrids 7a,f (IC50: 1.33–3.84 µM) showed potent activity against triple‐negative (MDA‐MB‐231 and MDA‐MB‐231/ADR) breast cancer cell lines, and hybrid 7f (IC50: 3.90 and 10.18 µM) also demonstrated promising activity against estrogen receptor‐positive breast cancer cells (MCF‐7 and MCF‐7/ADR), and the activity was superior to these of artemisinin, dihydroartemisinin, and ADR, revealing their potential to fight against both drug‐sensitive and drug‐resistant breast cancers. The enriched structure–activity relationships may facilitate further design of more active candidates.

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“…In 2015 she was awarded the Nobel Prize in physiology or medicine in honor of her work for discovering artemisinin and dihydroartemisinin. These drugs are incredibly effective in the antimalarial (AM) formulation and are now considered classic medications for malaria around the globe 34–36 …”

Section: Introductionmentioning

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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Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Cited by 22 publications

References 67 publications

Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger

Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger

Novel ester tethered dihydroartemisinin‐3‐(oxime/thiosemicarbazide)isatin hybrids as potential anti‐breast cancer agents: Synthesis, in vitro cytotoxicity and structure–activity relationship

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

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