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Dispiro-1,2,4,5-tetraoxanes: A new class of antimalarial peroxides
Abstract
Dispiro-1,2,4,5-tetraoxanes 2-4 were synthesized as potential peroxide antimalarial drugs. They had curative activity against Plasmodium berghei in vivo at single doses of 320 and 640 mg/kg which confirms earlier unpublished data. Moreover, artemisinin (1) and 4 had equivalent ED50's against P. berghei in vivo in the multiple-dose Thompson test; neither showed any evidence of acute toxicity at total doses of more than 12 g/kg. Dispiro-1,2,4,5-tetraoxane 4 had IC50's comparable to those of 1 against Plasmodium falciparum clones in vitro. These results confirm the potential of dispiro-1,2,4,5-tetraoxanes as a new class of inexpensive peroxide antimalarial drugs.
... Currently, the most promising classes of synthetic peroxides are 1,2-dioxolanes, 1,2,4-trioxolanes (ozonides), 1,2-dioxanes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes. Representatives of these families have demonstrated antimalarial [10,11,15], anthelmintic [16][17][18][19][20][21][22][23][24][25][26][27][28], antitumor [29,30], anti-tuberculosis [31][32][33], growth regulatory [34][35][36] and fungicidal activity [37][38][39][40]. In 2012, arterolane (ozonide OZ277) was the first synthetic peroxide to be approved for treatment of malaria in medical practice ( Figure 1) [41][42][43][44][45]. Ozonide artefenomel (OZ 439) is a second generation clinical candidate against malaria [46]. ...
... Pharmaceuticals 2022,15, 472 ...
Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly acids. This review consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) the synthesis of organic peroxides promoted by non-metal-based Lewis acids; and (3) the application of heteropoly acids in the synthesis of organic peroxides. The information covered in this review will be useful for specialists in the field of organic synthesis, reactions and processes of oxygen-containing compounds, catalysis, pharmaceuticals, and materials engineering.
... Another synthetically attainable endoperoxide warhead is 1,2,4,5-tetraoxane, which was first reported by Vennerstrom et al., 129 where a series of symmetrical bis-cyclohexyl tetraoxanes were found to possess antimalarial activity comparable to ART derivatives. This included WR148999 (95, Figure 14) which was found to possess an IC 50 of 28 nM against K1 P. falciparum as well as 27.7-day average survival after a single 100 mg/kg subcutaneous dose-however, survival after a single oral 100 mg/kg dose was found to be just 7.7 days, indicating poor oral bioavailability. ...
... This included WR148999 (95, Figure 14) which was found to possess an IC 50 of 28 nM against K1 P. falciparum as well as 27.7-day average survival after a single 100 mg/kg subcutaneous dose-however, survival after a single oral 100 mg/kg dose was found to be just 7.7 days, indicating poor oral bioavailability. 129,130 Further analogs of WR148999 have been reported, however, none displayed greatly improved in vivo activity following oral dosing. 131,132 Since, Vennerstrom's group has focussed mainly on the 1,2,4-trioxolane class of antimalarials, with development of the 1,2,4,5-tetraoxanes being continued by O'Neill. ...
Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolane and artefenomel) and the 1,2,4,5-tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.
... Tetraoxanes were discovered following findings which revealed that simpler cyclic peroxide 1 (Figure 1) can also be highly active and the complex artemisinin framework is not necessary to secure antimalarial potency. [3][4][5] There is an increasing interest in such a promising class and studying the structure adopted by tetraoxanes could be helpful in understanding the way these drugs act. Crystal structures of trimeric ring systems of tetraoxane with 6-6-6, 7-6-7, 8-6-6 and 12-6-7 were reported by Groth, Terent'ev et. ...
... Tetraoxanes were found to be stable to both basic (pH 12, room temp to 80 8C) and acidic (pH 1.6, 37 8C) conditions. [22] They have also shown that tetraoxane moiety is stable to reducing conditions (LiAlH 4 , NaBH(OAc) 3 , and NaBH 4 ). Further, O'Neill et al. had investigated chemical stability of tetraoxane in aqueous solution and in the presence of acid. ...
Structurally diverse and chemically stable tetraoxanes were formed by peroxidation of N-sulfonylpiperidones. X-ray analysis revealed that the crystal structures possess central spiro-2,5-disubstituted tetraoxane rings trans fused to 6-membered piperidine and cyclohexylidene substituents in classical chair conformations. The more flexible cycloheptane ring exhibited pseudorotation between chair and twist chair conformation. The two sulfonyl oxygen atoms act as hydrogen-bonding acceptors and participate in hydrogen bonding. Docking calculations showed that the tetraoxanes are aligned parallel to the plane of the porphyrin ring of heme so that the iron can attack the O−O bond to initiate redox-mediated reaction to render nanomolar antimalarial potency to these compounds against P. falciparum 3D7.
... TDD E209 is said to be a single-dose cure agent in resistant malaria which is currently under preclinical phase of development. 24,27,[34][35][36][37][38][39][40][41] Hybrid endoperoxides ...
... However, heme iron [Fe(II)] plays a crucial role in bioactivation of endoperoxides resulting in reactive oxygen metabolite-induced cytotoxicity. 34,64,70 ...
Mithun Rudrapal, Dipak Chetia Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India Abstract: Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents. Keywords: endoperoxide, structural diversity, 1,2,4-trioxane, pharmacophore, pharmacodynamic, antimalarial
... The SAR analysis showed that a methyl group at R 1 and R 4 positions was tolerated, whereas the introduction of a methyl group at R 2 , R 3 , R 5 , R 6 positions led to a loss of activity. 23 Compound 12 was evaluated for its antimalarial activity; it showed potent activity against NF54 (IC 50 = 6.5 nM) and K1 (IC 50 = 6.2 nM) strains as compared to artemisinin. The in vivo efficacy of compound 12 showed a decrease in the activity against the ANKA strain of P. berghei. ...
Malaria is a life‐threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5‐tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5‐tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid‐based 1,2,4,5‐tetraoxanes, triazine‐based 1,2,4,5‐tetraoxanes, aminoquinoline‐based 1,2,4,5‐tetraoxanes, dispiro‐based 1,2,4,5‐tetraoxanes, piperidine‐based 1,2,4,5‐tetraoxanes and diaryl‐based 1,2,4,5‐tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992–2022). We summarize the most significant in vitro, in vivo results and structure–activity relationship studies of 1,2,4,5‐tetraoxane‐based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5‐tetraoxane‐based hybrids to treat malaria.
... Tetraoxanes have considerably higher stability and superior antimalarial activity [23]. Some of the synthetic derivatives of tetraoxanes such as unsymmetrical dispiro-tetraoxanes were found to be equally or more potent than artemisinin [24]. They are purely synthetic and can be synthesized from readily accessible and low-cost starting materials. ...
The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N-sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogues with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (¹H NMR,¹³C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogues 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf3D7) strains of human malaria parasite. Furthermore, these selective analogues were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine.
... However, the target compounds were not active against papain or the P. falciparum cysteine protease falcipain-2, but some of them could effectively inhibit the in vitro development of P. falciparum in human red blood cells [43]. Especially, two squaramate derivatives 45a and 45b (Fig. 25) 1,2,4,5-Tetraoxanes as cyclic peroxides have strong antimalarial activity both in vitro and in vivo [44,45]. Accordingly, Oliveira et al. designed and synthesized a set of vinyl sulfone-tetraoxane hybrids (46, Fig. 26) to overcome the Artemisinin-resistant P. falciparum malaria through endoperoxide-based hybrid approach. ...
Kojic acid (KA) is a hydroxypyranone natural metabolite mainly known as tyrosinase inhibitor. Currently, this compound is used as a whitening agent in cosmetics and as an anti‐browning agent in food industry. Given the easy‐manipulation in different positions of the KA molecule, many investigations have been carried out to find new tyrosinase inhibitors derived from KA. Beside anti‐tyrosinase activity, many KA‐based compounds have been designed for targeting other enzymes including human neutrophil elastase, catechol‐O‐methyltransferase, matrix metalloproteinases, monoamine oxidase, human lactate dehydrogenase, endonucleases, D‐amino acid oxidase, as well as receptors such as histamine H3 and apelin (APJ) receptors. This review could help biochemists and medicinal chemists in designing diverse KA‐derived enzyme inhibitors. Kojic acid (KA) and its derivatives are well‐known tyrosinase inhibitors. KA‐based compounds have been considered for the design of inhibitors against other metalloenzymes. Diverse enzymes and receptors can be targeted by KA‐derived compounds.
... The first breakthrough came in 1992, when Jonathan reported on a novel class of symmetrical dispiro-1,2,4,5-tetraoxanes as a new class of antimalarial peroxides. 2 He continued to work on these compounds over the next decade to better understand their unique structure−activity relationships (SARs) and uncover the fascinating mechanistic basis for their selectivity and reactivity. A key advance during this time was the synthesis of unsymmetrical 1,2,4-trioxolanes using a newly developed coozonolysis procedure that greatly expanded the chemical diversity of the synthetic ozonides and enabled tuning of the reactivity to maximize antimalarial activity while minimizing nonspecific reactivity. ...
... In 2000, Vennerstrom and co-workers explored various alkyl-substituted dispiro-1,2,4,5-tetraoxanes [289]. Among all, five compounds 142a-e exhibited significant antimalarial activity with IC 50 values of 10e30 nM against CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum as compared to 1 (corresponding IC 50s ¼ 55 and 32 nM) and WR 14899929 (143; corresponding IC 50s ¼ 8.4 and 7.3 nM) (Fig. 60) [290]. Few compounds in this class have shown moderate in vivo activity against P. berghei-infected mice when administered via po route on days 3, 4, and 5 postinfection (40e60% cure at a dose of 128 mg/kg/day). ...
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, 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.
... Tetroxanes (161) and a naturally occurring plant-derived diterpene peroxide (66) are other organic peroxides with antimalarial activity. ...
Artemisinin and its derivatives are endoperoxide-containing compounds which represent a promising new class of antimalarial drugs. In the presence of intraparasitic iron, these drugs are converted into free radicals and other electrophilic intermediates which then alkylate specific malaria target proteins. Combinations of available derivatives and other antimalarial agents show promise both as first-line agents and in the treatment of severe disease.
... [3][4][5][6][7][8] In particular, 1,2,4,5-tetraoxanes were found to be promising antimalarial agents with potency comparable or superior over the semisynthetic artemisinin. [3][4][5][6][7][8][9][10][11][12][13][14] Moreover, tetraoxanes were shown to have antitumour and antihelmintic activities. [15][16][17][18][19][20] Apart from importance for medicine, these peroxy-species have also found utility as initiators in radical polymerization [21][22][23] and are of interest in regard to their application as an explosives [24][25][26] . ...
Reaction of biologically active bridged 1,2,4,5-tetraoxanes and diperoxide of trifluoroacetone with ferrous ions in the presence of xanthenes, methylene blue and methylene green is accompanied by bright chemiluminescence (CL) caused by the emission from the electronically-excited dyes. The promising perspectives for employment of CL method for analytical detection of tetraoxanes were demonstrated. The most convenient CL system was found to be their reaction with ferrous gluconate in the presence of rhodamine 3B, which allowed to detect up to 10⁻⁹ M of the diperoxides. The discovered CL-probe is selective towards tetraoxanes over reactive oxygen species such as singlet oxygen, hydroxyl radical, hydrogen peroxide, hypochlorite and superoxide ion. It is suggested that electronically-excited states may be involved in biological activities of cyclic organic peroxides.
... In the past three decades, the chemistry of organic peroxides was extensively developed because these compounds were found to have high antimalarial (Ghorai et al. 2008;Hao et al. 2013;Jefford 2012;Opsenica and Solaja 2009;Slack et al. 2012;Vennerstrom et al. 1992;Yadav et al. 2014) and anthelminthic (Boissier et al. 2012;Ingram et al. 2012;Keiser et al. 2012Keiser et al. , 2010Xiao et al. 2002) activities. Natural 1,2,4-trioxane artemisinin and its semisynthetic derivatives dihydroartemisinin, artemether, and artesunate have been used for malaria treatment for several decades ( Fig. 1) (WHO 2010;. ...
Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.
Graphical Abstract
... About 3.2 billion people remain at risk of malaria and in 2015 214 million cases of malaria and 438 thousands deaths from it have been registered [10]. Compounds with high antimalarial [11][12][13][14][15][16][17][18][19][20][21][22][23], antihelminthic [24][25][26][27][28], and antitumor activities [29][30][31][32][33][34] were found among natural, semisynthetic, and synthetic peroxides. The main biologically active frame of these compounds includes five-membered 1,2-dioxolane [35][36][37], 1,2,4-trioxolane [38,39], and six-membered 1,2-dioxane [40][41][42], 1,2-dioxene [43], 1,2,4-trioxane [22,44,45] cycles. ...
This review is the first to collate and summarize main data on named and unnamed rearrangement reactions of peroxides. It should be noted, that in the chemistry of peroxides two types of processes are considered under the term rearrangements. These are conventional rearrangements occurring with the retention of the molecular weight and transformations of one of the peroxide moieties after O–O-bond cleavage. Detailed information about the Baeyer−Villiger, Criegee, Hock, Kornblum−DeLaMare, Dakin, Elbs, Schenck, Smith, Wieland, and Story reactions is given. Unnamed rearrangements of organic peroxides and related processes are also analyzed. The rearrangements and related processes of important natural and synthetic peroxides are discussed separately.
... Artemisinins have a 1,2,4-trioxane core incorporating an endoperoxide linkage that is essential for activity (15). In the early 1990s, fully synthetic symmetrical dispiro-1,2,4,5-tetraoxane compounds with promising antimalarial activity were generated (16). Further medicinal chemistry efforts revealed that the antimalarial activity is maximized when the steric environment of the peroxide bond is carefully controlled. ...
Fully synthetic endoperoxide antimalarials, namely OZ277 (RBx11160, arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the
in vitro
responses of
Plasmodium falciparum
to the new ozonide antimalarials, using a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed exposure assay format to interrogate the time-dependence of the response. Because the ozonides have different physicochemical properties to the artemisinins, assay optimization was required to ensure that the drugs are completely removed following the pulsed exposure. Like the artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective that dihydroartemisinin; however when early ring stage parasites are exposed to drugs for time periods relevant to their
in vivo
exposure, the ozonide antimalarials are markedly more effective.
... 8-Amino-quinoline-type antimalarials cause hemolysis in patients with impaired glutathione metabolism [14,15], the antitrypanosomal nitrofurans and nitroimidazols are typical redox cyclers [16 -18], as are the experimental ortho-naphthoquinones [19]. The Chinese plant drug quinghaosu [20 -22] and novel derivatives thereof [23][24][25][26][27] shown to be efficacious against Plasmodia species are peroxides, as is the old anthelmintic ascaridole [28]. In part at least, these drugs are believed to mimic the oxidant host defence reaction, and their relative safety is explained by the less efficient antioxidant systems of the parasites. ...
Cyclocondensation reaction of linear α,ω-diols (C3, C5, C6, and C8) with 1,1-dihydroperoxycycloalkanes and formaldehyde with the participation of lanthanide catalysts affords spiromacrocyclic diperoxides.
Medicinal chemists around the world have been inspired by nature and have successfully extracted chemicals from plants. Research on enzymatic modifications of naturally occurring compounds has played a critical role in the search for biologically active molecules to treat diseases.
This book set explores compounds of interest to researchers and clinicians. It presents a comprehensive analysis about the medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, molecular modelling studies) of different compounds. Each chapter brings contributions from known scientists explaining experimental results which can be translated into clinical practice.
Volume 2 gives (1) a detailed overview of the sesquiterpenes polypharmacology, (2) an interesting journey around the world of cannabinoids that reveals the development of new synthetic Δ9-THC derivatives, (3) the design of specific formulations to overcome the volatility of small sized terpenes-based essential oils, (4) an update on the latest generations of endoperoxides endowed with antimalarial activity and finally (5) a summary of MedChem strategies to fix the most common issues in formulating terpene derivatives (like low potency and poor solubility).
The objective of this book set is to fulfill gaps in currently acquired knowledge with information from the recent years. It serves as a guide for academic and professional researchers and clinicians.
Malaria is a prevalent fatal disease in tropical and subtropical regions around the world. Combinations of Artemisinin, folate antagonists, quinolines, and antibiotics are major choices in clinics. Currently, wide range of parasite's resistance necessitates the search for chemical compounds with new structures and novel antimalarial targets.
The literature review was performed covering the relevant literatures published from 1966 to 2021. On the basis of structural classification (spiro-peroxides, spiroindolones, spirocyclohexadienones et al.), different types of molecules were summarized with resources, anti-malarial activities, structure-activity relationship, target introductions, resistance, development progress, and synthetic strategies, for the purpose of providing comprehensive information for developing antimalarial drugs to overcome drug resistance and highlighting the importance of the spiral structure in medicinal chemistry.
Vinyl sulfone with electrophilic character is not only a versatile building block for various organic transformations but also is a key structural unit in a large number of biologically active molecules. In the recent decades vinyl sulfone has attracted much attention due to its potential as a privileged structural motif in medicinal chemistry for the drug discovery and development. It can be found in the chemical structure of many leads and drug candidates such as Rigosertib, Recilisib, K11777, WRR-483 and BAY 11–7085. The vinyl sulfone motif has been especially used in the design of chemotherapeutics and neuroprotective as well as radioprotective agents. In this review, we have described design, chemical structures, biological properties and related mechanism of actions, and structure activity relationship (SAR) study of vinyl sulfone-based compounds.
Indium‐catalyzed sequential remote C−H functionalization (C‐6 position) and C3‐indolylation of peroxyoxindole using indole is described for the synthesis of terindolinone derivatives. Whereas, N‐substituted 3‐phenyl peroxyoxindole derivatives undergoes consecutive skeletal rearrangement to generate transient carbocation, which has been trapped with indole nucleophile to generate 2‐(1H‐indol‐3‐yl)‐4‐alkyl‐benzo[b][1,4]oxazin‐3(4H)‐one derivatives. In contrast with Indium (III) Chloride, FeCl3 ⋅ 6H2O facilitates oxidative cleavage of the peroxyoxindole (Hock cleavage) and further reaction with indole to afford biologically important trisindoline derivatives. A plausible mechanism has been proposed for these reactions with experimental evidences.
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Since the discovery of the endoperoxide sesquiterpene lactone artemisinin, numerous second-generation semisynthetic artemisinins and synthetic peroxides have been prepared and tested for their antimalarial properties. Using a case-study approach, we describe the discovery of the investigational semisynthetic artemisinins artelinic acid (8) and artemisone (9), and the structurally diverse synthetic peroxides arteflene (10), fenozan B07 (11), arterolane (12), PA1103/SAR116242 (13), and RKA182 (14).
Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of “Chimeric Bitherapy (CB)” which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.
In 1972, Chinese researchers discovered a potent antimalarial compound that they named qinghaosu. A natural product from the sweet wormwood plant, it is now more widely known as artemisinin, and was the first example of a structurally diverse class of endoperoxide-containing antimalarial drugs. With resistance to chloroquine increasingly widespread, the semi-synthetic artemisinin derivatives, dihydroartemisinin, artemether, and artesunate were soon employed clinically; they are fast acting, highly efficacious, and well-tolerated, with parasite resistance relatively slow to emerge. However, determining their mechanism of action has presented a huge challenge and it is still not fully understood. The endoperoxide bond contained within their structure is essential, but they display multifarious activities that are attributed to in vivo formation of one or more highly reactive and cytotoxic species. Consequently, their direct biomolecular targets have proved difficult to distinguish from their downstream effects. Nevertheless, significant progress has been made in the development of synthetic endoperoxide-containing antimalarials such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, examples of which are promising drug development candidates with extended half-lives and improved physicochemical and pharmacokinetic profiles when compared to the artemisinins. As a result, they offer new hope for the treatment of artemisinin-resistant infections. Most notably, two 1,2,4-trioxolanes, arterolane, and artefenomel, have progressed to clinical trials, with arterolane recently approved for clinical use.
Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study we report the synthesis of six gem ‐dihydroperoxides ( 2a‐f ), with yields ranging from 10% to 90%, utilizing a new methodology. The dihydroperoxides were converted into ten tetraoxanes ( 3a‐j ), among which six ( 3b , 3c , 3d , 3g , 3h and 3j ) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetraoxanes, 3b (IC 50 = 0.64 µM) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.
In this study, synthesis, biological activity, and structure-activity relationships of diverse compounds are described. In general, relationships between dipole moment and biological activities are discussed in detail. Despite progress in interdisciplinary science, the use of dipole moment values of organic compounds to understand their potent medicinal activities in various diseases remains unexplored. In contrast, it can be seen that many compounds demonstrate a direct correlation between biological activity and dipole moment. The analyses described herein are green and sustainable. This study is timely and highly significant since it indicates the medicinal activity of a series of compounds. Therefore, scientists may design more potent compounds prior to their synthesis which is tedious, time consuming, and not eco-friendly, in general.
Terminal and internal alkenes react contrarily with tert‐butyl hydroperoxide (TBHP) giving various products. A Cu(I) catalyzed decarbonylative C–C bond formation followed by a carbonylation–peroxidation of vinyl arenes has been achieved using tert‐butyl hydroperoxide (TBHP) as the oxidant in acetonitrile. Whereas, α‐methyl styrenes yielded aryl methyl ketones and the α‐substituted unsymmetrical internal alkenes afforded selective α‐peroxidation under the identical reaction conditions. Concurrent peroxidation–carbonylation–cycloalkylation/cycloetherifiction of internal cyclic alkene such as indene is achieved by switching the solvent system from acetonitrile to cycloalkanes/cyclic ether. All these reactions proceed via radical paths generating interesting peroxo‐compounds.
A new series of tetraoxanes were developed and screened for in vitro antimalarial activity against chloroquine sensitive strains of Plasmodium falciparum (3D7 and RKL-2) and chloroquine resistant strain of P. falciparum (RKL-9). Among the synthesized derivatives, few compounds showed mild to moderate activity against the parasites as compared to a standard drug. The test results revealed two compounds, 5a (3,3,6-trimethyl-1,2,4,5-tetraoxane) and 5k (3,3-dimethyl-6,6-diphenyl-1,2,4,5-tetraoxane) possessing significant activity against chloroquine sensitive 3D7 strain (IC50 = 1.953 ± 0.020 μg/mL) and RKL-2 strain (IC50 = 3.906 ± 0.010 μg/mL). At the same time, only compound 5j (3-methyl-3,6,6-triphenyl-1,2,4,5-tetraoxane) showed superior activity against chloroquine resistant RKL-9 strain (IC50 = 3.906 ± 0.006 μg/mL) in in contrast to all other derivatives of the set studied. In order to elucidate the vital drug interaction with falcipain-2 (FP-2), docking studies of potent ligands were performed.
Stereoelectronic interactions control reactivity of peroxycarbenium cations, the key intermediates in (per)oxidation chemistry. Computational analysis suggests that alcohol involvement as a third component in the carbonyl/peroxide reactions remained invisible due to the absence of sufficiently deep kinetic traps needed to prevent the escape of mixed alcohol/peroxide products to the more stable bisperoxides. Synthesis of β‐alkoxy‐β‐peroxylactones, a new type of organic peroxides, was accomplished by interrupting a thermodynamically driven peroxidation cascade. The higher energy β‐alkoxy‐β‐peroxylactones do not transform into the more stable bisperoxides due to the stereoelectronically imposed instability of a cyclic peroxycarbenium intermediate as a consequence of amplified inverse alpha‐effect. The practical consequence of this fundamental finding is the first three‐component cyclization/condensation of β‐ketoesters, H2O2, and alcohols that provides β‐alkoxy‐β‐peroxylactones in 15–80 % yields.
The C(sp³)-H peroxidation of 2-oxindole and barbituric acid derivatives using aliphatic peroxide under continuous flow and their antimalarial evaluation in vitro have been explored using magnetic iron oxide nanoparticles. This transformation uses less toxic, low cost, eco-friendly ethyl acetate as a solvent. To show the robustness, supported catalysis integrated with continuous-flow employed as a process development tool for the expeditious synthesis of quaternary peroxide derivatives with 7.9 minutes of residence time. Additionally, the explosive hazards of TBHP (tert-Butyl hydroperoxide) were also minimized during peroxidation in a continuous-flow process by controlled addition.
This research work describes the chemical synthesis of thirty-four newsulfanyl and sulfonyl chalcone derivatives, and thirty-four new metronidazolederivatives, as well as their biological assays as antimalarial and leishmanicidalagents. The antimalarial in vitro evaluation on the β-hematin formation showed thattwelve of these derivatives display an inhibitory activity higher than 80%. In vivo, twocompounds were found to decrease the parasitaemia by the fourth day after infectionand to increase significantly the survival time of mice. In the case of the in vitroleishmanicidal evaluation, three compounds showed an inhibitory activity on thegrowth of promastigotes of L. mexicana and L. braziliensis species. The most activecompounds are benzoate derivatives featuring hydroxyl substituents at the 3,4,5 and3,4 positions of the benzene ring.
The electrochemical behavior of phthaloyl peroxide C8H4O4 on an Au disk electrode in a 0.05 M aqueous solution of Na2SO4 was studied by cyclic voltammetry (CVA). It demonstrated a high activity in cathodic reduction with the formation of an irreversible peak on the CVA curve at E =–0.81 V. Additionally, during the anodic oxidation of C8H4O4, the surface of the Au electrode became passivated by compounds which prevented its oxidation during the registration of repeated cycles. Apparently, these compounds are surface complexes of phthaloyl peroxide with a gold cation.
A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20–28 showed IC50 values in the range of 0.019 µM to 0.192 µM against CCRF-CEM cells and between 0.345 µM and 7.159 µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019 ± 0.001 µM and 0.345 ± 0.031 µM, respectively. A relatively low cross resistance to hybrids 20–28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells.
The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2O2. The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.
The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2 O2 . The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2 O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.
The authors present a review on some recent developments on the synthesis, chemical reactivity and theoretical studies of Tetroxanes analysing their main physical chemistry properties. The authors examine the critical points of the PES of different conformers, and reaction paths at singlet ground state and triplet state of the tetroxane, leader member of the cyclic diperoxide compound family.
An easy and mild functionalization method of tetraoxane derivatives via olefin metathesis is reported. This reaction offers a new method to afford fully functionalized tetraoxanes in high yields. This method is also utilized in the functionalization of bioactive compounds.
An efficient route to the synthesis of potent antimalarial aryloxy 1,2,4,5-tetraoxanes is described that permits parallel synthesis for Structure–Activity Relationship (SAR) investigations. Brief details of the in vitro and in vivo antimalarial evaluation are included which enables identification of antimalarial leads for further development. Also described is an improved approach to the synthesis of a selected late-lead compound in just four or five synthetic steps from commercially available starting materials.
An efficient method for the synthesis of N-aryltetraoxazaspiroalkanes by ring transformation of pentaoxaspiroalkanes with arylamines catalyzed by Sm(NO3)3·6H2O has been developed.
We report the results obtained from the experimental determination and theoretical calculation of the diperoxide formaldehyde molecule. Experimental work was performed using a macrocalorimeter to get the combustion heat and sublimation enthalpy was determined measuring the equilibrium vapor pressure in equilibrium with the vapor phase at different temperatures through the Clapeyron-Claussius equation. Theoretical calculations were made resorting to the semiempirical AM1 procedure as well as via RHF ab initio and DFT B3LYP methods at the 3-21 G, 3-21+ G, 6-311 G(d, p) and 6-311 + G( d, p) basis set levels.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
For the first time, novel bicyclic 5a-h as well as tricyclic 9a-h aza-peroxides were synthesized using 1O2-mediated photo-oxygenation methodology as key step in 52-71% yields in which one of the oxygen atom of 1, 2, 4-trioxane ring has been replaced by nitrogen atom. The methodology is simple and is an efficient way to access 1,2-dioxa-4-aza six membered ring compounds. All these compounds were assessed for their in vitro antimalarial activity against Plasmodium falciparum. Compound 9a, 9c and 9f, the most active compound of the series, showed IC50 values of 9.43, 8.83 and 5.63 ng/ml, respectively which was found to be comparable to that of antimalarial drug Chloroquine (IC50 value 5.2 ng/ml). Compound 9f, the most active compound found in in vitro studies, provided 40% protection to the infected mice at the dose of 96 mg/kg × 4 days when screened for its antimalarial activity in vivo against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route. In this assay, -arteether and Chloroquine, showed 100% suppression of parasitaemia on day 4 and provided 100% and 80% protection, respectively, to the infected mice.
A cobalt-catalyzed peroxidation of styrenes with tert-butyl hydroperoxide gives 1-aryl-1,2-bis(tert-butylperoxy)ethanes in up to 53% yields.
A one-pot procedure was developed for the assembly of bicyclic compounds containing 1,2-dioxolane and tetrahydrofuran rings based on the reaction of 2-allyl-1,3-diketones with the I2 / H2O2 system. A fivefold molar excess of H2O2 and a twofold excess of I2 are required for the selective formation of tetrahydrofurodioxoles. The synthesis of these structurally complex molecules is unusual in that it does not produce the expected bridged tetraoxanes, products of the addition of several H2O2 molecules to a carbonyl group, or the products of double bond iodoperoxidation.
In the temperature range of 130-166 °C, the thermolysis of 3,6-diphenyl-1,2,4,5-tetroxane in toluene and methanol solutions in the initial concentration ranges of (1.1-15.6) · 10-3 mol kg-1 and (0.56-1.9) · 10-3 mol kg-1, respectively, follows first order kinetic laws. The activation parameters for the unimolecular reaction in toluene (ΔH#148 °C = 31.2 ± 0.6 kcal mol-1; ΔS#148 °C = -6.9 ± 1.5 cal mol-1 K-1; ΔG#148 °C = 34.1 ± 0.8 kcal mol-1), and in methanol (ΔH#148 °C = 25.3 ± 0.8 kcal mol-1; ΔS#148 °C = -15.3 ± 1.8 cal mol-1 K-1, ΔG#148 °C = 31.7 ± 0.8 kcal mol-1) indicate a significant solvent effect which support homolytic stepwise mechanisms of reaction instead of concerted processes. However, in both cases the main organic product is benzaldehyde which is partially oxidized in the solutions to benzoic acid.
We report the synthesis of 1,3-dibutanoic-1,2,4,5-tetroxane via a rather simple and direct method. The IR and UV spectra are given and the corresponding main assignments are made.
The thermal decomposition reaction of the cyclohexanone cyclic diperoxide has been studied in different solvent (2-butanol, acetic acid, chlorobenzene and 2-propanol/benzene) at 0.02 M initial concentration of diperoxide and in the temperature range of 40-165°C. The corresponding kinetic parameters have been compared with the literature data for the same reaction in other organic solvents. The enthalpy and entropy of activation of the reaction of this diperoxide in several organic solvents have been correlated through an "isokinetic relationship" to validate the existence of a genuine solvent effect on that reaction.
Different theoretical procedures are applied to make a conformational study of the 1,2,4,5-tetroxane molecule: AM1 semi-empirical method, ab initio RHF method at the 3-21+G and 6-311+G(d,p) basis set levels and B3LYP density functional method at the same basis set levels. The molecular stability is analyzed on the basis of different stereo-electronic and symmetry features. There is a general agreement between these methods and all of them predict the chair conformation to be the most stable conformer.
Reactions of beta-diketones and beta-keto esters with tert-butyl hydroperoxide under heterogeneous conditions using SiO2-supported copper(II) perchlorate as a catalyst give rise to alpha-peroxidation products in 65-82% yields. A possibility to reuse the catalyst was demonstrated.
Desethanoqinghaosu, a novel potential antimalarial qinghaosu analogue containing the unique C–O–O–C–O–C–O–CO (or cyclic peroxide lactone) moiety present in the natural product, has been synthesized from R-(+)-citronellal and its structure and stereochemistry have been verified from spectral data and a single-crystal X-ray analysis.
The ozonolysis of 1,2-dimethoxyethylene produces trans-3,6-dimethoxy-1,2,4,5-tetroxane which has a chair conformation with diaxial methoxy substituents and carbon–oxygen bond distances characteristic of anomeric and exo-anomeric interactions between the methoxy groups and the ring.
Treatment of qinghaosu (1) with acid yielded 1′,2′,4′-trioxanes (5 and 8), endoperoxides (6 and 9), and diketones (7 and 10). Structures of 5, 6, 7, 8, 9, and 10 were assigned based on their physical and spectral data. Structure-activity correlation among these compounds indicated the steric requirement of the 1′,2′,4′,-trioxane ring system as found in 1 for potent antimalarial activity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Verschieden substituierte Cyclohexanone (I) können entweder direkt mit 30 %igem Wasserstoffperoxid unter sauren Bedingungen (zunächst 2n Salzsäure, später .Eisessig und Perchlorsäure) bei Raumtemperatur in die Diperoxide (III) oder über die Zwischenstufe der 1-Hydroxy-1′-hydroperoxy-peroxide (II), die durch Umkristal = lisieren in Hexan gereinigt werden, in (III) verwandelt werden.
Dye-sensitized photooxygenation of 3-aryl-2-butenols furnishes 3-aryl-1-hydroxy-but-3-en-2-hydroperoxides which condense with aldehydes and ketones to give active antimalarial 1,2,4-trioxanes.
A multistep preparation is described for carboxyvinylsilane 6, which upon reaction with ozone initially gave dioxetane 8 as a transient intermediate in a highly stereoselective manner. Subsequent rearrangement at ambient temperature resulted in cyclization to (±)-hexahydroisochroman-3-one 2, whose relative stereochemistry was determined by X-ray crystallographic analysis and found to resemble the C.D-ring portion of the antimalarial artemisinin (1).
The chemistry and physiology of carbonic anhydrase are reviewed in relation to pharmacological progress in the development of sulfonamide inhibitors. The major organ systems are briefly dicussed. From the medical point of view, the major thrust is now for the treatment of glaucoma. The physiology of aqueous humor formation with respect to ion transport is discussed, and it is shown that a key event is the catalytic formation of HCO 3 ⁻ from CO 2 and OH ⁻ . The newly formed HCO 3 ⁻ is linked to NA ⁺ and fluid movement to produce aqueous humor. Inhibition of HCO 3 ⁻ sunthesis sulfonamides reduces aqueous formation and lowers pressure in normals and in glucoma.
Four sulfonamides have been used sytemically, the chief being acetazolamide. None of these works topically; they do not reach the ciliary process in adequate concetrations. New programs have begun, searching for sulfonamides of different properties that cross the cornea in effective concetrations to inhibit carbonic anhydrase in the ciliary porcess. The key to the problems seems to be to search for a balance between water and lipid solubility, maintaining high activity against the enzyme. This has been achieved, and new structures described from this and other laboratories lower pressure in the rabbit nearly as well as systemic sulfonamides.
Corneal permeabilities to test compounds (in vitro) in rabbit and man are similar, but accession to the auqeous (in vivo) is less in man. This may make the goal difficult, and the reasons for this difference are being explored.
The three dihydronaphtho[1,2,4]trioxines 9–11 have been synthesized and two of them converted to the five carbamate and ester derivatives 12–16 (Schemes 1 and 2). The resulting new trioxanes together with two already known and ascaridole (7) were tested for antimalarial activity against the sensitive N strain of Plasmodium berghei in mice. On comparison with artemisinin (1) and dihydroartemisinin (2), modest activity was found. The four most active compounds were some 12–18 times less potent than 1.
A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against
cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used
to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured
in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator
of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational
new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds
of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates
with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound
tested. The applications and expectations of this new test system within a drug development program are discussed.
We evaluated carbonic anhydrase inhibitors in a crossover study with a placebo and random allocation of treatment administration. Drugs evaluated included acetazolamide tablets and Sequels, dichlorphenamide, ethoxzolamide, methazolamide, and an ascorbic acid placebo. The best tolerated drug was acetazolamide Sequels. Methazolamide was next. The least tolerated drugs were ethoxzolamide, acetazolamide tablets, and dichlorphenamide.
The carbonic anhydrase inhibitor, Diamox, is an effective agent in lowering intraocular pressure in man when administered in oral doses of 500 to 1000 mg." This one sentence summarized a 2½ page initial article on this subject written by a single author, Bernard Becker, in 1954.1 A year later, Green and Leopold2 noted that acetazolamide given subconjunctivally to rabbits did not reduce intraocular pressure. Thus began a 35-year search for an active topically administered carbonic anhydrase inhibitor, a search characterized by stops and spurts, one that is reaching fruition thanks largely to the efforts of Thomas Maren of the University of Florida.
See also pp 46 and 50.
Systemically administered carbonic anhydrase inhibitors, even when properly utilized in the lowest dose possible to achieve the therapeutic goal in each patient with glaucoma, produce a well-known litany of side effects, including paresthesias, gastrointestinal upset, weight loss, fatigue, depression, impotence
A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- and thieno[3,2-b)thiophene-2-sulfonamides was prepared and evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase and water solubility. At the same time, these substituents were varied in order to obtain compounds with the appropriate pKa to minimize pigment binding in the iris. All of these variables were optimized in the best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl] amino]methyl]thieno[2,3-b]thiophene-2-sulfonamide hydrochloride (55).
Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compounds for clinical use was precluded by the observation that they cause dermal sensitization in guinea pigs. A correlation between electrophilicity, as assessed by in vitro reactivity with reduced glutathione, and dermal sensitization potential was further documented.
(+)-Deoxoartemisinin (2), a new and more active antimalarial agent, was successfully prepared from artemisinin in one step using NaBH4 and BF3.Et2O in THF. (-)-Deoxodeoxyartemisinin (5), a potential metabolite of deoxoartemisinin, was also prepared either from 2 or from artemisinic acid. 2 shows 8-fold increased antimalarial activity in vitro against chloroquine-resistant malaria as compared to artemisinin (1). Compound 2 possesses superior in vivo antimalarial activity to 1.
A number of 1,2,4-trioxanes were prepared and tested for antimalarial activity in search of a simplified analogue of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum. The most active compounds were methyl 2-(2,4a-epidioxy-4a,5,6,7,8,8a-hexahydro-5,5,8a-trimethyl-2H-1-benzop yra n-2-yl) acetate (3b), which showed IC20's of 96 and 39 ng/mL, respectively, and 2,4a-epidioxy-3,4,4a,5,6,7,8,8a-octahydro-2-[2-(benzoyloxy)propyl]-5,5,8 a- trimethyl-2H-1-benzopyran (12), which showed IC50's of 24 and 99 ng/mL, respectively. For comparison, qinghaosu exhibits an IC50 of 1 ng/mL for both strains.
The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution. To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage. The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature. All major condensation products are the beta isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding potassium salts, which were converted to free acids (8b-d) by acidification. The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed. In general, the new compounds are more effective against the W-2 than the D-6 strain. Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8b-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines. Artelinic acid, which is both soluble and stable in 2.5% K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.
The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria.
In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal
action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and,
unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully
in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains
of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate,
appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with
cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
Certain drugs that interfere with folate metabolism (sulfones, sulfonamides, and inhibitors of dihydrofolate reductase) play an important role in the chemotherapy and prophylaxis of malaria. The activities and mechanisms of action of these drugs are regarded as similar in most respects to their activities against procaryotic microorganisms. Believed incapable of utilizing intact exogenous folates, plasmodia have been regarded as dependent on de novo synthesis of required folate cofactors. The present investigation, conducted in pursuit of a method for testing the in vitro susceptibility of Plasmodium falciparum to antifol antimalarial drugs, produced evidence that earlier assumptions about the folate metabolism of this organism are not correct. Three of four isolates of P. falciparum were successfully maintained in a culture medium depleted of folic acid and p-aminobenzoic acid. The antimalarial activities of sulfonamides and dihydrofolate reductase inhibitors were, furthermore, variably antagonized by the presence of folic acid and p-aminobenzoic acid in the culture medium. Optimum conditions for assessment of antifol antimalarial activity in vitro therefore require precise control of these factors in the culture medium. Our results suggest that resistance to antifol antimalarial drugs involves a complex of factors related to both the de novo synthesis of active folate cofactors and the ability to utilize exogenous intact folates in various forms.
The antimalarial agent artemisinin has been converted to two new compounds, ISO-artemisitene and 9- EPI-artemisinin.
Replication in vitro
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Dirk Trauner and Anita Van Lierde for technical assis-tance and Hanspeter KMig for 400-MHz spectra
- Ann We
- Wolfgang Absillis
- Frieda Binder
- Martina Demeyer
- Judith Drescher
- Humpelstettar
We thank Ann Absillis, Wolfgang Binder, Frieda Demeyer, Martina Drescher, Judith Humpelstettar, Dirk Trauner and Anita Van Lierde for technical assis-tance and Hanspeter KMig for 400-MHz spectra. R e d s t w NO. 1, 30516-87-1; 2, 130481-61-7; 3, 136011-36-4;
Ordering information is given on any current masthead page. 130481-57-1; 19b, 14198@996, I%, 142036-W, 19d, 141981-00-2; 141981-02-4
- S Clc
- H Oc
ClC(S)OC,H,, 937-63-3; thymine, Supplementary Material Available: Full experimental details and 'H NMR data of compounds 8-11, 14,15, 16A-E, 17Aa/@-17Ea/@, and 20A-20E and 13C NMR data of 17Aa/@-17Ea/@ (8 pagea). Ordering information is given on any current masthead page. 130481-57-1; 19b, 14198@996, I%, 142036-W, 19d, 141981-00-2; 141981-02-4; 2Oc, 142036-38-2; 2od, 141981-03-5; 2b, 142128-33-4; 14198145-7; 21e,14203640-6; 22a, 130481-60-6; 22b, 142003-12-1;
Simplified analogues of the Antimalarial Artemisinin: Synthesis of 6,g-Desmethyl-artemismin. J. Org. C k m
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Antimalarial Activity of New Water-Soluble Dihydroartemisinii Derivatives. 2. Stereo-specificity of the Ether Side Chain Synthesis of Tricyclic Arteannuin-Like Compounds. Tetra-hedron Lett
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berghei) from WRAIR indicates that several 1,2,4,btetraoxanes derived from cyclic ketones are cu-rative, whereas thoee derived from acyclic ketones and aldeh-ydes are not
- ( P Antimalarial
Antimalarial data (P. berghei) from WRAIR indicates that several 1,2,4,btetraoxanes derived from cyclic ketones are cu-rative, whereas thoee derived from acyclic ketones and aldeh-ydes are not. Cyclic tripemxides (1,2,4,5,7,&hexaoxonanes) which are kinetic producta (Story, P. R; Lee, B.; Bishop, C. E.;
Macrocyclic Synthesis. 11. Cyclo-hexanone Peroxides3059-3062) of acid-catalyzed peroxyketalization between hydrogen peroxide and ketones are without activity
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Ketone-derived Peroxides. Part IV. Structural Studies of cyclic Di-and Tri-peroxides Derived from KetonesBond angles and distances, however, were not disclosed in the unpublished X-ray crystallographic analysis of 4
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Rodent Malaria Models In Handbook of Ex-perimental Parasitology: Antimalarial Drugs I. 6811 The % cure versus doee data from the Thompson test were fit to a Hill Equation using nonlinear regression (PCNONLIN SCI
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Thienothiopyran-2-sulfonamides. Novel Topically Active Carbonic Anhydrase Inhibitors for the Treatment of Glaucoma
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Topically Ac-tive Carbonic Anhydrase Inhibitors 4. [(Hydroxyalkyl)-sulfonyl] benzene and [ (Hydroxyalkyl)sulfonyl] thiophene-sulfonamides
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