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The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1 H-NMR and 13 C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI 50 values of 4.87±0.23 μM and 9.97±1.44 μM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC 50 value of 0.135±0.041 μM, and its activity was approximately 1/3 of the positive control Palbociclib., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.

A library of new spiroisoxazoline analogues of arteannuin B was synthesized through 1, 3-dipolar cycloaddition in stereoselective fashion and consequently screened for anti-inflammatory activity in RAW 264.7 macrophage cells. Three potent analogues (8i, 8 m, and 8n) were found to attenuate the LPS induced release of cytokines IL-6 and TNF-α more potently than the parent molecule. Also, the inhibition of LPS induced nitric oxide production in these cells show moderate to high efficacy. None of the three potent molecules have altered the viability of RAW 264.7 cells following 48 h incubation suggesting that the inhibition of cytokines and nitric oxide production exhibited in the cells was not due to toxicity. In addition, these compounds exhibit an IC 50 range of 0.17 µM-1.57 µM and 0.09 µM-0.35 µM for the inhibition of IL-6 release and nitric oxide production respectively. The results disclose potent inhibition of pro-inflammatory mediators which are encouraging and warrant further investigations to develop new therapeutic agents for inflammatory diseases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Gliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents., (© 2021. The Author(s).)

Dihydroartemisinin (DHA), a natural product isolated from the traditional Chinese herb Artemisia annua and one of the clinical frontline drugs against malarial infections, has recently been discovered as a Toll-like Receptor 4 (TLR4) antagonist. However, the TLR4 antagonistic activity of DHA is modest and it exhibits cellular toxicity. In this work, the structure-activity relationship (SAR) of DHA as TLR4 antagonist was explored. Since destroying the sesquiterpene endoperoxide scaffold substantially compromised the TLR4 antagonistic activity and molecular dynamics analysis showed that the C-10 hydroxyl group formed a hydrogen bond with E72 of myeloid differentiation factor 2 (MD2) to prevent it moving deeper into MD2, SAR of DHA was focused on the C-10 hemiacetal position. With extending the length of the linear alkane chain at C10 position, the TLR4 antagonistic activity of DHA analogs increased first and then decreased with the best TLR4 antagonism occurring at the length of the carbon chain of 3-4 carbons. In contrast, the cellular toxicity of DHA analogs was raised with the increasing length of the linear alkane chain. The TLR4 antagonistic activity of DHA derivatives with substituted halogen as the terminal functional group decreased with the decrease of electronegativity of the substituted halogen, which implies the electron-rich functional group at the end of the alkane chain appears preferred. Therefore, DHA derivative 2k with alkynyl as the end functional group, exhibited 14 times more potent TLR4 antagonistic activity than DHA. Moreover, 2k showed less cellular toxicity than DHA. Cellular signaling characterizations indicated that 2k inhibited LPS-induced TLR4 dimerization and endocytosis and suppressed LPS-induced NF-κB but not MAPKs activation, culminating in blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO and IL-1β. Further, 2k was active in vivo; it significantly increased and prolonged morphine analgesia. Collectively, this study provides a structural guidance to reposition DHA derivatives as TLR4 antagonists., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A new access to artemisinin is reported based on a selective photochemical hydrothiolation of amorphadiene, a waste product of the industrial semisynthetic route. This study highlights the discovery of two distinctive activation pathways under solvent-free conditions or using a photocatalyst promoting H-abstraction. Subsequently, a chemoselective oxidation of the resulting photochemically generated thioether, followed by a Pummerer rearrangement, affords dihydroartemisinic aldehyde, a key intermediate in the synthesis of artemisinin.

Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC 50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P. falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)

Artemisinin is the plant natural product used to treat malaria. The endoperoxide bridge of artemisinin confers its antiparasitic properties. Dihydroartemisinic acid is the biosynthetic precursor of artemisinin that was previously shown to nonenzymatically undergo endoperoxide formation to yield artemisinin. This report discloses the synthesis of [15,15,15- 2 H 3 ]-dihydroartemisinic acid and its use to determine the mechanism of endoperoxide formation. Several new observations were made: (i) Ultraviolet-C (UV-C) radiation initially accelerates artemisinin formation and subsequently promotes homolytic cleavage of the O-O bond and rearrangement of artemisinin to a different product, and (ii) dideuterated and trideuterated dihydroartemisinic acid isotopologues at C3 and C15 converted to artemisinin at a slower rate compared to nondeuterated dihydroartemisinic acid, revealing a kinetic isotope effect in the initial ene reaction toward endoperoxide formation (k H /k D ∼ 2-3). (iii) The rate of conversion from dihydroartemisinic acid to artemisinin increased with the amount of dihydroartemisinic acid, suggesting an intermolecular interaction to promote endoperoxide formation, and (iv) 18 O 2 -labeling showed incorporation of three and four oxygen atoms from molecular oxygen into the endoperoxide bridge of artemisinin. These results reveal new insights toward understanding the mechanism of endoperoxide formation in artemisinin biosynthesis.

A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC 50 >300 μM) and high antimelanoma activity (IC 50 =0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

An efficient synthesis of rac -6-desmethyl-5β-hydroxy-d-secoartemisinin 2 , a tricyclic analog of R -(+)-artemisinin 1 , was accomplished and the racemate was resolved into the (+)- 2b and (-)- 2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R -(-)- 2a . Several new compounds 9 - 16 , 19a , 19b , 22 and 29 were synthesized from rac - 2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2 , a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum . Several of the analogs had moderate activity in comparison to the natural product 1 . Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22 , while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.

Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and antimalarial activities. Moreover, one terpenoid lactone, artemisinin, is used as a drug against malaria. Because of these abilities, there is constant interest in new terpenoid lactones that are both isolated and synthesized, and their biological activities have been verified. In some cases, the activity of the terpenoid lactone is specifically connected to the lactone moiety. Recent works have revealed that new terpenoid lactones can demonstrate such functions and are thus considered to be potential active agents against many diseases.

A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC 50  = 3.0 μM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

For the first time, eight novel artemisinin-piperazine-furane ether hybrids (5a-h) were efficiently synthesized and investigated for their in vitro cytotoxic activity against some human cancer and benign cells. The absolute configuration of hybrid 5c was determined by X-ray crystallographic analysis. Hybrids 5a-h exhibited more pronounced growth-inhibiting action on hepatocarcinoma cell lines than their parent dihydroartemisinin (DHA) and the reference cytosine arabinoside (ARA). The hybrid 5a showed the best cytotoxic activity against human hepatocarcinoma cells SMMC-7721 (IC 50  = 0.26 ± 0.03 μM) after 24 h. Furthermore, hybrid 5a also showed good cytotoxic activity against human breast cancer cells MCF-7 and low cytotoxicity against human breast benign cells MCF-10A in vitro. We found the cytotoxicity of hybrid 5a did not change when tumour cells absorb iron sulfate (FeSO 4 ); thus, we conclude the anti-tumour mechanism induced by iron ions (Fe 2+ ) is unclear., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Malaria is a life-threatening infectious disease caused by protozoal parasites belonging to the genus Plasmodium. It caused an estimated 405,000 deaths and 228 million malaria cases globally in 2018 as per the World Malaria Report released by World Health Organization (WHO) in 2019. Artemisinin (ART), a "Nobel medicine" and its derivatives have proven potential application in antimalarial drug discovery programs. In this review, antimalarial activity of the most active artemisinin derivatives modified at C-10/C-11/C-16/C-6 positions and synthetic peroxides (endoperoxides, 1,2,4-trioxolanes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes) are systematically summarized. The developmental trend of ART derivatives, and cyclic peroxides along with their antimalarial activity and how the activity is affected by structural variations on different sites of the compounds are discussed. This compilation would be very useful towards scaffold hopping aimed at avoiding the unnecessary complexity in cyclic peroxides, and ultimately act as a handy resource for the development of potential chemotherapeutics against Plasmodium species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC 50s below 0.86 μM against Hep3B and A2780 cell lines, which are superior to that of ARS4. Four compounds (11, 15, 16 and 18) were selected to further evaluate their antitumor activities in in vitro and in vivo ovarian and liver cancer models, the results indicated that compound 18 exhibited the best therapeutic effect, not only effectively inhibited the growth of 7404 xenograft and Huh7 xenograft, but also presented a good dose-dependent inhibition toward the growth of A2780 xenograft. Overall, based on these positive results, these novel chemical structures may provide a new inspiration for the discovery of novel antitumor agents originated from artemisinin scaffolds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Masson SAS.)

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC 50  = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC 50  = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca 2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer., (Copyright © 2020. Published by Elsevier Inc.)

With the inspiration to develop new cancer nanotherapeutics by repurposing old drugs, in the current study, a novel two dimensional nanomedicine namely Mn doped, dihydroartemisinin (DHA) loaded layered double hydroxide (MnMgFe-LDH/DHA) with peroxide self-supplying properties for enhanced photothermal-chemodynamic therapy was proposed. Such nanostructures could be synthesized by a simple coprecipitation method, and the as-prepared MnMgFe-LDH/DHA exhibits excellent photothermal properties with a photothermal conversion efficiency up to 10.7%. Besides, the in situ reaction between the released DHA and Fe2+/Mn2+ produced by the degradation of LDH can lead to a burst of intracellular reactive oxygen species (ROS) by Fenton-like reactions. Furthermore, the in vivo experiments demonstrate that MnMgFe-LDH/DHA exhibits a remarkable chemodynamic/photothermal therapy (CDT/PTT) synergistic effect on tumor treatment with negligible damage to normal tissues. Finally, this research provides a smart strategy to construct a DHA repurposing nanomedicine for tumor specific treatment.

Leishmaniasis is a neglected tropical disease affecting thousands worldwide, especially in developing countries where it co-exists with malaria. Only a handful of drugs are clinically available to treat the disease, but significant limitations threaten their very use. New, safe and effective drugs, including those against malaria-leishmaniasis co-infections, are thus imperative. We assessed the in vitro anti-infective potential of previously synthesized, potent antimalarial artemisinin derivatives. Analogue esters featuring 1,1'-biphenyl and thiophenyl moieties were as much as 30-fold more potent than clinical artemisinins against L. donovani parasites, qualifying them as antipromastigote hits for further investigation in the search for malaria-leishmaniasis co-infection therapies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Eight new dihydroartemisinin-O-glycosides were synthesized with their relative configurations were determined based on NMR spectrum. In vitro immunosuppressive assay showed that 10α-dihydroartemisinin-β-O-d-mannoside (19a) demonstrate 88% inhibition towards T cells proliferation and 98% reduction in IFN-γ levels in cell media. These results suggest that dihydroartemisinin-O-glycoside as a potential lead for further in vivo evaluation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite-resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 "Nobel Prize in Physiology or Medicine" was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as "Nobel medicine." The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971-2019) in the medicinal chemistry of ART-derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery., (© 2020 Wiley Periodicals, Inc.)

Artemisinin (ART) is an antimalarial compound that possesses a variety of novel biological activities. Due to the low abundance of ART in natural sources, agricultural supply has been erratic, and prices are highly volatile. While heterologous biosynthesis and semi-synthesis are advantageous in certain aspects, these approaches remained disadvantageous in terms of productivity and cost-effectiveness. Therefore, further improvement in ART production calls for approaches that should supplement the agricultural production gap, while reducing production costs and stabilising supply. The present review offers a discussion on the elicitation of plants and/or in vitro cultures as an economically feasible yield enhancement strategy to address the global problem of access to affordable ART. Deemed critical for the manipulation of biosynthetic potential, the mechanism of ART biosynthesis is reviewed. It includes a discussion on the current biotechnological solutions to ART production, focusing on semi-synthesis and elicitation. A brief commentary on the possible aspects that influence elicitation efficiency and how oxidative stress modulates ART synthesis is also presented. Based on the critical analysis of current literature, a hypothesis is put forward to explain the possible involvement of enzymes in assisting the final non-enzymatic transformation step leading to ART formation. This review highlights the critical factors limiting the success of elicitor-induced modulation of ART metabolism, that will help inform strategies for future improvement of ART production. Additionally, new avenues for future research based on the proposed hypothesis will lead to exciting perspectives in this research area and continue to enhance our understanding of this intricate metabolic process.

The emergence of drug-resistance and the low specificity of anticancer agents are the major challenges in the treatment of cancer and can result in many side effects, creating an urgent demand to develop novel anticancer agents. Artemisinin-derived compounds, bearing a peroxide-containing sesquiterpene lactone moiety, could form free radicals with high reactivity and possess diverse pharmaceutical properties including in vitro and in vivo anticancer activity besides their typical antimalarial activity. Hybrid molecules have the potential to improve the specificity and overcome the drug resistance, therefore hybridization of artemisinin skeleton with other anticancer pharmacophores may provide novel anticancer candidates with high specificity and great potency against drug-resistant cancers. The review outlines the recent advances of artemisinin-derived hybrids as potential anticancer agents, and the structure-activity relationships are also discussed to provide an insight for rational designs of novel hybrids with high activity., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects. Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure-activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer. This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Dihydroartemisinic acid is the biosynthetic precursor to artemisinin, the endoperoxide-containing natural product used to treat malaria. The conversion of dihydroartemisinic acid to artemisinin is a cascade reaction that involves C-C bond cleavage, hydroperoxide incorporation, and polycyclization to form the endoperoxide. Whether or not this reaction is enzymatically controlled has been controversial. A method was developed to quantify the nonenzymatic conversion of dihydroartemisinic acid to artemisinin using LC-MS. A seven-step synthesis of 3,3-dideuterodihydroartemisinic acid ( 23 ) was accomplished beginning with dihydroartemisinic acid ( 1 ). The nonenzymatic rates of formation of 3,3-dideuteroartemisinin ( 24 ) from 3,3-dideuterodihydroartemisinic acid ( 23 ) were 1400 ng/day with light and 32 ng/day without light. Moreover, an unexpected formation of nondeuterated artemisinin ( 3 ) from 3,3-dideuterodihydroartemisinic acid ( 23 ) was detected in both the presence and absence of light. This formation of nondeuterated artemisinin ( 3 ) from its dideuterated precursor ( 23 ) suggests an alternative mechanistic pathway that operates independent of light to form artemisinin, involving the loss of the two C-3 deuterium atoms.

In this study, four series of dihydroartemisinin derivatives were designed, synthesized, and evaluated for anti-toxoplasma gondii activity, and calculated the selectivity index (SI). It was the higher the SI, the better the effect of this compound against Toxoplasma gondii. Our goal was to filter out compounds that were bigger SI than the lead compound. The compound with the highest SI was selected for the anti-toxoplasmosis test in mice in vivo. Among the synthesized compounds, the (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-decahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3 -i]isochromen-10-yl-(te-rt-butoxycarbonyl)-l-alaninate (A2) exhibited the most potent anti-T. gondii activity and low cytotoxicity (SI: 6.44), yielding better results than the lead compound DHA (SI: 1.00) and the clinically used positive-control drug spiramycin (SI: 0.72) in vitro. Furthermore, compound A2 had better growth inhibitory effects on T. gondii in vivo than spiramycin did and significantly reduced the number of tachyzoites in the peritoneal cavity of mice (P < 0.01). The evaluation of the data generated in the T. gondii mouse infection model indicates that compound A2 treatment was a good inhibitor of T. gondii in vivo and that it was effective in relieving the liver damage induced by T. gondii. In addition, the results of a docking study revealed that A2 could become a better T. gondii calcium-dependent protein kinase1 (TgCDPK1) inhibitor. For this reason, compound A2 has potential as an anti-parasitic drug. Further studies are required to elucidate the mechanism of the action of compound A2, as well as to develop drug delivery systems for patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy., Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis., Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro., Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents., Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of novel derivatives of artemisinin-4-(arylamino)quinazoline have been designed and synthesized, and most of them showing potent in vitro cytotoxic activity against HCT116 and WM-266-4 cell lines. Compound 32 was the most active derivative against HCT116 cell line with an IC 50 of 110 nM, and significantly improved the antitumor activity of the parent compounds dihydroartemisinin (DHA) (IC 50  = 2.85 μM) and Gefitinib (IC 50  = 19.82 μM). In vivo HCT116 xenografts assay showed that compound 32 exhibited potent antitumor activity with obvious tumor growth delay and tumor shrunken after 18 days treatment on xenografted mice, and especially without loss of body weight. Our results indicate that compounds 32 may represent a safe, novel structural lead for developing new chemotherapy of colorectal cancer., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

10-deoxoartemisinin is a semisynthetic derivative of artemisinin that lacks a lactone carbonyl group at the 10-position, and has stronger antimalarial properties than artemisinin. However, 10-deoxoartemisinin has limited utility as a therapeutic agent because of its low solubility and bioavailability. Hydroxylated 10-deoxoartemisinins are a series of properties-improved derivatives. Via microbial transformation, which can hydroxylate 10-deoxoartemisinin at multiple sites, the biotransformation products of 10-deoxoartemisinin have been investigated in this paper. Using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS E ) combined with UNIFI software, products of microbial transformation of 10-deoxoartemisinin were rapidly and directly analyzed. The hydroxylation abilities of nine microorganisms were compared using this method. All of the microorganisms evaluated were able to hydroxylate 10-deoxoartemisinin, and a total of 35 hydroxylated products were identified. These can be grouped into dihydroxylated 10-deoxoartemisinins, monohydroxylated 10-deoxoartemisinins, hydroxylated dehydrogenated 10-deoxoartemisinins, and hydroxylated hydrogenated 10-deoxoartemisinins. Cunninghamella echinulata and Cunninghamella blakesleeana are able to hydroxylate 10-deoxoartemisinin, and their biotransformation products are investigated here for the first time. Cunninghamella elegans CICC 40250 was shown to most efficiently hydroxylate 10-deoxoartemisinin, and could serve as a model organism for microbial transformation. This method could be used to generate additional hydroxylated 10-deoxoartemisinins for further research.

We report herein the synthesis and anticancer activity of a set of novel S-linked artemisinins bearing an aliphatic/aromatic/heterocyclic nucleus as a substituent on the sulfur. The compounds were prepared from artemisinin via its lactol-form by an acid-catalyzed condensation of the desired thiol with the lactol. Both the C-10-α- and β-configured thiol ethers were synthesized with a view to making them available for the anticancer activity evaluation using a variety of cell lines. The results show that many of the synthetic derivatives studied possessed good potential as anticancer agents. In order to draw more information on the origin of the anticancer activity, one of the compounds (9a), that showed a broad-spectrum activity in terms of reducing the viability of most of the cell lines studied, in particular proven to be most effective against Prostate (PC-3) cells, was studied in detail to find the underlying mechanism of its action by MTT assay, immunoblotting, flow cytometry and microscopy. Pretreatment of the PC-3 cells with N-acetyl cysteine affected the efficacy of 9a, suggesting the role of reactive oxygen species in reducing their viability. Cell cycle analysis showed increase in G1 phase that was indicative of G1 cell cycle arrest. Wound healing assay revealed anti-migratory effect of 9a Quantitative PCR and western blot analysis showed changes in the gene expression of PCNA, E2F1, Pin1, cyclinD1, phospho-c-jun, c-Myc, eIF4E and other genes involved in proliferation and maintaining the transformed phenotype of prostate cancer cells. Here we report the anti-proliferative property of 9a with a vital and potent target(s) in prostate cancer cells with one of such targets being Pin1 belonging to the parvulin family of PPIases. The results suggest that 9a could be a promising agent in combating prostate cancer., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART-isoquinoline and ART-quinoline hybrids showing highly improved potencies against CQ-resistant and multidrug-resistant P. falciparum strains (EC 50  (Dd2) down to 1.0 nm; EC 50  (K1) down to 0.78 nm) compared to CQ (EC 50  (Dd2)=165.3 nm; EC 50  (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C-H activation and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In recent years, a great deal of attention has been given towards re-purposing and re-innovating the potential drugs. In this regard, dihydroartemisinin (DHA) has been reported to demonstrate anti-proliferative effects on various cancerous cells viz. breast, liver and lung. However, it is associated with some limitations, such as low bioavailability which is hampered by its poor aqueous solubility and its rapid metabolism in systemic circulation. Therefore, in order to overcome these limitations, we synthesized a novel hyaluronic acid-dihydroartemisinin conjugate in which the hydroxyl group of DHA was covalently linked to carboxylic group of hyaluronic acid (HA). The conjugate was successfully characterized using 1 H NMR, Fourier transform infrared spectroscopy (FT-IR) and gel permeation chromatography (GPC). The synthesized conjugate self-assembled into nanoparticles in aqueous solution. The developed nanoparticles were characterized for their average size, zeta potential, Transmission Electron Microscopy (TEM), X-ray Powder Diffraction (XRD) and loading efficiency. The nanoparticles were cytotoxic to lung cancer (A549) cell line which was determined using CCK-8 cell viability assay. This was further supported by Annexin-V-FITC-Propidium iodide apoptosis assay, reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) loss. Conclusively, present findings demonstrate hyaluronic acid conjugates can be used to improve the therapeutic outcomes of anticancer drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Artemisinin (ART) is an endoperoxide sesquiterpene lactone, commonly used in the treatment of malaria. Although it was isolated from Artemisia annua L. , a plant widely applied in Chinese Traditional Medicine, its mechanism of action remains uncertain and its clinical use is still limited due to its low solubility, its poor bioavailability and short in vivo half-life. Over time, several studies have been aimed towards the discovery of potent ART derivatives that could overcome clinical drawbacks. In this review, we focus on the multifaced aspects of ART and on the efforts spent to improve its pharmacological profile that so far culminated in the discovery of more effective drugs. Lastly, we outline the new perspectives in the ART-derivatives scenario.

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC 50 6.78 μM and 5.25 μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC 50 0.76 μM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cancer patients frequently suffer from cancer-related fatigue (CRF), which is a complex syndrome associated with weakness and depressed mood. Neuroinflammation is one of the major inducers of CRF. The aim of this study is to find a potential agent not only on the treatment of cancer, but also for reducing CRF level of cancer patients. In this study, total-thirty new Dihydroartemisinin-Coumarin hybrids (DCH) were designed and synthesized. The in vitro cytotoxicity against cancer cell lines (HT-29, MDA-MB-231, HCT-116, and A549) was evaluated. Simultaneously, we also tested the anti-neuroinflammatory activity of DCH. DCH could inhibit the activated microglia N9 release of NO, TNF-α, and IL-6. The docking analysis was shown that MD-2, the coreceptor of TLR4, might be one of the targets of DCH.

Severe malaria and viral infections cause life-threatening diseases in millions of people worldwide every year. In search for effective bioactive hybrid molecules, which may possess improved properties compared to their parent compounds, a series of betulinic acid/betulin based dimer and hybrid compounds carrying ferrocene and/or artesunic acid moieties, was designed and, synthesized de novo. Furthermore, they were analyzed in vitro against malaria parasites (growth inhibition of 3D7-strain P. falciparum-infected erythrocytes) and human cytomegalovirus (HCMV). From this series of hybrids/dimers, the betulinic acid/betulin and artesunic acid hybrids 11 and 12 showed the most potent activities against P. falciparum and HCMV. On the strength of results, additive and/or synergistic effects between the natural or semisynthetic products, such as betulinic acid-/betulin- and artesunic acid-derived compounds, are suggested on the basis of putatively complex modes of antimicrobial action. This advantage may be taken into account in future drug development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC 50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Purpose: Artemisinin (ART) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. In this study, the bioavailability, water solubility, and anti-plasmodial property of ART were improved by PCL-PEG-PCL tri-block copolymers., Methods: The structure of the copolymers was characterized by 1 H NMR, FT-IR, DSC, and GPC techniques. ART was encapsulated within micelles by a single-step nano-precipitation method, leading to the formation of ART-loaded PCL-PEG-PCL micelles. The obtained micelles were characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). The in vivo anti-plasmodial activity of ART-loaded micelles was measured against Plasmodium berghei infected Swiss albino mice., Results: The results showed that the zeta potential of ART-loaded micelles was about -8.37 mV and the average size was 91.87 nm. ART was encapsulated into PCL-PEG-PCL micelles with a loading capacity of 19.33 ± 0.015% and encapsulation efficacy of 87.21 ± 3.32%. In vivo anti-plasmodial results against P. berghei showed that multiple injections of ART-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of ART., Conclusion: These results suggested that PCL-PEG-PCL micelles would be a potential carrier for ART for the treatment of malaria.

Artemisinin, the initial and main drug for malaria prevention and treatment internationally, was first extracted from the plant Artemisia annua L. by Chinese scientists in 1972. Research on artemisinin in chemistry subject areas shows a rapid growth since the 1980s. To evaluate the evolutionary trends and draw the knowledge map of artemisinin research, 1316 relevant publications are analysed based on bibliometrics. The global research status, emerging trends and future directions are also visualised and discussed. Furthermore, a historical overview of chemical synthesis on artemisinin is illustrated via timeline in terms of industrialisation. Overall, this study provides a novel method to visualise further information about artemisinin research and a comprehensive perspective to understand the longitudinal trend over the last 30 years., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Dihydroartemisinin (DHA) and its analogs are reported to possess selective anticancer activity. Here, we reported a novel DHA derivative DHA-37 that exhibited more potent anticancer activity on the cells tested. Distinct from DHA-induced apoptosis, DHA-37 triggered excessive autophagic cell death, and became the main contributor to DHA-37-induced A549 cell death. Incubation of the cells with DHA-37 but not DHA produced increased dots distribution of GFP-LC3 and expression ratio of LC3-II/LC3-I, and enhanced the formation of autophagic vacuoles as revealed by TEM. Treatment with the autophagy inhibitor 3-MA, LY294002, or chloroquine could reverse DHA-37-induced cell death. In addition, DHA-37-induced cell death was associated significantly with the increased expression of HMGB1, and knockdown of HMGB1 could reverse DHA-37-induced cell death. More importantly, the elevated HMGB1 expression induced autophagy through the activation of the MAPK signal but not PI3K-AKT-mTOR pathway. In addition, DHA-37 also showed a wonderful performance in A549 xenograft mice model. These findings suggest that HMGB1 as a target candidate for apoptosis-resistant cancer treatment and artemisinin-based drugs could be used in inducing autophagic cell death.

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC 50  = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N -Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC 50 values of 0.58⁻0.87 nM against different strains of Plasmodium falciparum ( Pf ) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC 50 0.9⁻1.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC 50 values of 0.78⁻0.87 µM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC 50 of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the N -glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O -glycosides previously obtained from DHA.

Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC 50 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC 50 2.4 nm), artesunic acid (EC 50 8.9 nm) and chloroquine (EC 50 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC 50 value of 0.026 μm, representing an even higher activity than the two reference drugs ganciclovir (EC 50 2.60 μm) and artesunic acid (EC 50 5.41 μm). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G 0 /G 1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Active pharmaceutical ingredients are either extracted from biological sources-where they are synthesized in complex, dynamic environments-or prepared in stepwise chemical syntheses by reacting pure reagents and catalysts under controlled conditions. A combination of these two approaches, where plant extracts containing reagents and catalysts are utilized in intensified chemical syntheses, creates expedient and sustainable processes. We illustrate this principle by reacting crude plant extract, oxygen, acid, and light to produce artemisinin, a key active pharmaceutical ingredient of the most powerful antimalarial drugs. The traditionally discarded extract of Artemisia annua plants contains dihydroartemisinic acid-the final biosynthetic precursor-as well as chlorophyll, which acts as a photosensitizer. Efficient irradiation with visible light in a continuous-flow setup produces artemisinin in high yield, and the artificial biosynthetic process outperforms syntheses with pure reagents., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC 50 value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Artemisinin is one of the most potent anti-malaria drugs and many often-lengthy routes have been developed for its synthesis. Amorphadiene synthase, a key enzyme in the biosynthetic pathway of artemisinin, is able to convert an oxygenated farnesyl diphosphate analogue directly to dihydroartemisinic aldehyde, which can be converted to artemisinin in only four chemical steps, resulting in an efficient synthetic route to the anti-malaria drug., (Copyright © 2017. Published by Elsevier Ltd.)

According to the World Health Organization, malaria remains one of the biggest public health problems in the world. The development of resistance is a current concern, mainly because the number of safe drugs for this disease is limited. Artemisinin-based combination therapy is recommended by the World Health Organization to prevent or delay the onset of resistance. Thus, the need to obtain new drugs makes artemisinin the most widely used scaffold to obtain synthetic compounds. This review describes the drugs based on artemisinin and its derivatives, including hybrid derivatives and dimers, trimers and tetramers that contain an endoperoxide bridge. This class of compounds is of extreme importance for the discovery of new drugs to treat malaria.

Background: Malaria, one of the World's biggest billers' is on the schedule for biomedical research and public health policies. The introduction of the artemisinin, a Chinese traditional drug from Artemisia annua is a revolution in the treatment of malaria. Artemisinin-based combination treatment (ACT) is considered to be the best strategy for uncomplicated Falciparum malaria. The presence of 1,2,4-trioxane system in artemisinin is responsible for its antimalarial activity., Methods: In this study, twenty-nine analogues of artemisinin were taken into account for QSAR studies along with artemisinin. The most active analogue of artemisinin 21 was energy minimized. All the structures were prepared from the active conformer 21 and energy was minimized to the stable state using MMFF94 force field using ChemBioDraw-12. Genetic Algorithm is used to decide the descriptors best required for the model generation. The test set and training set division were done by using hierarchal clustering module available with NCSS statistical software., Results and Conclusion: The antimalarial activity of the artemisinin and its substituted analogues has been analyzed through the multiple linear regression (MLR) using various physiochemical and structural descriptors obtained from PADEL software. The models were prepared using the Sigma Plot version 11. The calculated 2D autocorrelation descriptors and the MLR model suggest that artemisinin and its analogues hold the scope in the optimization of antimalarial activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neosporosis caused by the apicomplexan parasite Neospora caninum is an economically important disease that induces abortion in dairy and beef cattle. There are no vaccines or drugs available on the market for control or treatment of the disease in bovines. The peroxide artemisinin and its derivatives used clinically for treatment of malaria are active against N. caninum and other apicomplexan parasites. We have now evaluated the activities of the readily accessible and chemically robust 11-azaartemisinin 5 and selected N-sulfonyl derivatives prepared as described in the accompanying paper against N. caninum tachyzoites grown in infected human foreskin fibroblasts. Azaartemisinin elicited an IC 50 value of 150 nm, and the 2',5'-dichloro-3'-thienylsulfonyl-11-azaartemisinin 17 was found to be the most active, with an IC 50 value of 40 nm. Comparison with normal human fetal lung fibroblasts HFLF WI-38 revealed relatively benign cytotoxicity. The compounds were also screened in vitro against TK-10 (renal), UACC-62 (melanoma) and MCF-7 (breast) cancer cell lines; overall, in line with activities against HFLF cells, most compounds in the series were found to be inactive., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)