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Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins...
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Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 14917

Special Issue Editors

Prof. Dr. Svetlana B. Tsogoeva

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Guest Editor
Department of Chemistry and Pharmacy, Friedrich-Alexander-University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
Interests: asymmetric organocatalysis; domino reactions toward bioactive heterocycles; one-pot processes; natural product hybrids for medicinal chemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Michael Gütschow

E-Mail Website
Guest Editor
Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Interests: medicinal chemistry; drug design; PROTACs; inhibitors of proteases; biochemistry of enzyme–inhibitor interactions
Prof. Dr. Alexander O. Terent'ev

E-Mail Website
Guest Editor
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences (RAS), Leninsky prospect, 47 119991 Moscow, Russia
Interests: organic chemistry; medical and agricultural chemistry; chemical technology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. Artemisinin, along with its derivatives, has become one of the most studied natural products by scientists, especially by medicinal chemists. Artemisinin is an enantiomerically pure sesquiterpene, containing a 1,2,4-trioxane ring, which was isolated from the Chinese medicinal plant Artemisia annua L. (sweet wormwood) in 1972 by Youyou Tu. “For her discoveries concerning a novel therapy against Malaria”, Youyou Tu was awarded the 2015 Nobel Prize in Physiology or Medicine.

Artemisinin and its semisynthetic derivatives artesunate and dihydroartemisinin not only antimalarial activity exert but also display inhibitory activity toward other diseases, including viral infections and cancer in vitro and in vivo.

Despite the effectiveness of artemisinin in the treatment of several diseases, it is limited in the cure of malaria by its poor bioavailability and solubility, short half-life, and upcoming drug resistance. Due to the aforementioned pharmacological limitations, new artemisinin-derived compounds (dimers and hybrids) and other organic peroxides with enhanced therapeutic effects have been developed in recent years. In addition, much attention has been paid to the substantially cheaper biologically active synthetic peroxides, and of a wide variety of their hybrid molecules as lead compounds of interest.

These new molecular structures demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance and low bioavailability), making the dimerization/hybridization concept highly compelling for the development of efficient antimalarial, anticancer, and antiviral drugs. Continued research on the design of effective natural and synthetic peroxides for applications in chemotherapy has improved the understanding of the mechanism of action of these drugs, expanded their activity/function spectrum, and opened new potential applications for improved treatments.

The present Special Issue intends to highlight recent advances in the design and development of new biologically active natural and synthetic peroxides toward highly efficient antimalarial, antiviral, and antitumoral therapies.

Prof. Dr. Svetlana Tsogoeva
Prof. Dr. Michael Gütschow
Prof. Dr. Alexander O. Terent'ev
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • artemisinins
  • synthetic peroxides
  • viruses
  • malaria
  • cancer
  • antiviral
  • antimalarial
  • anticancer agents

Published Papers (4 papers)

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Research

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18 pages, 4458 KiB  
Article
Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes
by Jerome P. L. Ng, Mohit K. Tiwari, Ali Adnan Nasim, Rui Long Zhang, Yuanqing Qu, Richa Sharma, Betty Yuen Kwan Law, Dharmendra K. Yadav, Sandeep Chaudhary, Paolo Coghi and Vincent Kam Wai Wong
Pharmaceuticals 2022, 15(3), 360; https://doi.org/10.3390/ph15030360 - 16 Mar 2022
Cited by 6 | Viewed by 2704
Abstract
1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, [...] Read more.
1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of −7.089 and −8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics)
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20 pages, 3413 KiB  
Article
Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs
by Lukas von Bredow, Thomas Martin Schäfer, Julian Hogenkamp, Maik Tretbar, Daniel Stopper, Fabian B. Kraft, Julian Schliehe-Diecks, Andrea Schöler, Arndt Borkhardt, Sanil Bhatia, Jana Held and Finn K. Hansen
Pharmaceuticals 2022, 15(3), 333; https://doi.org/10.3390/ph15030333 - 09 Mar 2022
Cited by 4 | Viewed by 2809
Abstract
Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment of malaria, but the efficacy is threatened by the development of parasite resistance. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. In this work, we present the [...] Read more.
Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment of malaria, but the efficacy is threatened by the development of parasite resistance. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. In this work, we present the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin–HDACi hybrid molecules. The screening of the hybrid molecules for their activity against selected human HDAC isoforms, asexual blood stage P. falciparum parasites, and a panel of leukemia cell lines delivered important structure–activity relationships. All synthesized compounds demonstrated potent activity against the 3D7 and Dd2 line of P. falciparum with IC50 values in the single-digit nanomolar range. Furthermore, the hybrid (α)-7c displayed improved activity against artemisinin-resistant parasites compared to dihydroartemisinin. The screening of the compounds against five cell lines from different leukemia entities revealed that all hydroxamate-based hybrids (7a–e) and the ortho-aminoanilide 8 exceeded the antiproliferative activity of dihydroartemisinin in four out of five cell lines. Taken together, this series of hybrid molecules represents an excellent starting point toward the development of antimalarial and antileukemia drug leads. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics)
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18 pages, 2841 KiB  
Article
Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle
by Helenita C. Quadros, Aysun Çapcı, Lars Herrmann, Sarah D’Alessandro, Diana Fontinha, Raquel Azevedo, Wilmer Villarreal, Nicoletta Basilico, Miguel Prudêncio, Svetlana B. Tsogoeva and Diogo R. M. Moreira
Pharmaceuticals 2021, 14(11), 1129; https://doi.org/10.3390/ph14111129 - 06 Nov 2021
Cited by 11 | Viewed by 2677
Abstract
A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei [...] Read more.
A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics)
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18 pages, 26934 KiB  
Review
The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs
by Helenita C. Quadros, Mariana C. B. Silva and Diogo R. M. Moreira
Pharmaceuticals 2022, 15(1), 60; https://doi.org/10.3390/ph15010060 - 04 Jan 2022
Cited by 15 | Viewed by 5141
Abstract
Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of [...] Read more.
Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of a radical species. This can alkylate proteins vital for parasite survival and alkylate heme into hematin–drug adducts. Heme alkylation is abundant and accompanied by interconversion from the ferrous to the ferric state, which may induce an imbalance in the iron redox homeostasis. In addition to this, hematin–artemisinin adducts antagonize the spontaneous biomineralization of hematin into hemozoin crystals, differing strikingly from artemisinins, which do not directly suppress hematin biomineralization. These hematin–drug adducts, despite being devoid of the peroxide bond required for radical-induced alkylation, are powerful antiplasmodial agents. This review addresses our current understanding of Fe-PPIX as a bioreductive activator and molecular target. A compelling pharmacological model is that by alkylating heme, endoperoxide drugs can cause an imbalance in the iron homeostasis and that the hematin–drug adducts formed have strong cytocidal effects by possibly reproducing some of the toxifying effects of free Fe-PPIX. The antiplasmodial phenotype and the mode of action of hematin–drug adducts open new possibilities for reconciliating the mechanism of endoperoxide drugs and for malaria intervention. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics)
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