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Antimalarial and anticancer activities of artemisinin-quinoline hybrid-dimers and pharmacokinetic properties in mice
Abstract and Figures
Malaria, one of the three most important life-threatening infectious diseases, is recommended to be treated with ACT (artemisinin combination therapy) against which Plasmodium falciparum already displayed resistance. Two artemisinin-4-amino-quinoline hybrid-dimers (1 and 2), previously synthesized, possessed low nanomolar in vitro antiplasmodial activity, while poorly toxic against mammalian cells. They are here investigated to ascertain whether this antimalarial activity would be carried on in vivo against Plasmodium vinckei. During the four day treatment, parasitemia of less than 1% were observed on day 5 after doses from 2.5mg/kgip and 50mg/kgpo for hybrid-dimer 1, and from 7.5mg/kgip and 25mg/kgpo for hybrid-dimer 2. Snapshot pharmacokinetic analysis demonstrated that the antiplasmodial activity of these C-10-acetal artemisinin dimers may be due to active metabolites, which were confirmed by in silico findings. Hybrid-dimer 1 also displayed potent in vitro activity against tumor cells and was found to be more active than etoposide against TK10, UACC62 and MCF7 cell lines (TGI values 3.45 vs. 43.33μM, 2.21 vs. 45.52μM and 2.99 vs. >100μM, respectively). The 1,3-diaminopropane linker, present in hybrid-dimer 1, was therefore identified as the optimum linker.
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... Artemisinin (CF: C 15 H 22 O 5 , MW: 282.34, (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-Benzodixepin-10-one) is mostly derived by direct extraction from Artemisia annua or by extracting artemisinic acid from Artemisia annua and then semi-synthetically obtaining it. Lombard and colleagues [39] synthesized two quinoline-artemisinin derivatives 43 and 44 ( Figure 11) (Table 8) and evaluated their antimalarial activity. The in vivo anti-plasma parasite activity of hybrid dimers 43 and 44 was stronger than the positive control, with in vitro IC 50 s of 8.7 and 29.5 µM against the 3D7 strain, respectively. ...
... Anti-plasma parasite IC50 = 29.5 µM synthetic [39] 45a ...
... Lombard and colleagues [39] synthesized two quinoline-coumarin derivatives 43-44 ( Figure 11) (Table 10) Tabbi and colleagues [59] synthesized the adamantane chalcone-quinoline derivatives 71a-b (Figure 15) ( Table 10) and evaluated their in vitro anticancer activity against human pancreatic cancer cells Mia Paka 2. The growth inhibitory activities of compounds 71a and 71b were 85% and 77%. Thus, compounds 71a-b possess some anticancer activity. ...
Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer’s disease, and others.
... However, the low cytotoxicity (IC50 > 100 M) prevents their application as anticancer drugs and encourages their use in developing novel anticancer hybrids [91,92]. Indeed, bile acids present different available positions suitable for chemical modifications and are able to improve bioavailability [93], oral adsorption, cellular selectivity and sitespecific delivery thanks to their amphiphilic properties and stability in dynamic pH vari- Breast [59,60] More potent than reference drugs Apoptotic cell death Diamine/piperazine Renal, melanoma and breast [61,62] More potent than reference drugs Lung, breast [85][86][87] Cytotoxic activity + Safety profile Ester Breast [88,89] Cytotoxic activity Artemisininsulfasalazine Ester Glioma [90] Apoptotic cell death Migration inhibition ...
... Hybrid 46 showed significantly higher cytotoxic activity with respect to parent artemisinin (1) as well as to standard drugs such as cisplatin and paclitaxel (Scheme 6). Quinoline-bis(dihydroartemisinin) hybrids 49 and 50 [61] were prepared as shown in Scheme 7 and tested in vitro against TK10 (renal), UACC62 (melanoma) and MCF7 (breast) cancer cell lines [62]. The cytotoxic activity was expressed as 50% growth inhibition (GI50) and drug concentration resulting in total growth inhibition (TGI). ...
... Hybrid 46 showed significantly higher cytotoxic activity with respe to parent artemisinin (1) as well as to standard drugs such as cisplatin and paclitax (Scheme 6). Quinoline-bis(dihydroartemisinin) hybrids 49 and 50 [61] were prepared as show in Scheme 7 and tested in vitro against TK10 (renal), UACC62 (melanoma) and MC (breast) cancer cell lines [62]. The cytotoxic activity was expressed as 50% growth inhib tion (GI50) and drug concentration resulting in total growth inhibition (TGI). ...
Artemisinin is a natural compound extracted from Artemisia species belonging to the Asteraceae family. Currently, artemisinin and its derivatives are considered among the most significant small-molecule antimalarial drugs. Artemisinin and its derivatives have also been shown to possess selective anticancer properties, however, there are several limitations and gaps in knowledge that retard their repurposing as effective anticancer agents. Hybridization resulting from a covalent combination of artemisinin with one or more active pharmacophores has emerged as a promising approach to overcome several issues. The variety of hybridization partners allows improvement in artemisinin activity by tuning the ability of conjugated artemisinin to interact with various molecule targets involved in multiple biological pathways. This review highlights the current scenario of artemisinin-derived hybrids with potential anticancer activity. The synthetic approaches to achieve the corresponding hybrids and the structure–activity relationships are discussed to facilitate further rational design of more effective candidates.
... There are reports of artemisinin-quinoline compounds with potent antimalarial activity ( Figure 24). Lombard et al. prepared artemisinin-quinoline compounds (45,46) and evaluated their in vitro antiplasmodial activity against P. falciparum CQ-S 3D7, D10, and CQ-R Dd2 strains, using CQ and dihydroartemisinin (DHA) as controls [60]. The compounds displayed promising antimalarial activity that was equivalent to CQ and DHA against all the strains of P. falciparum used in the study. ...
... The activity of the compounds was influenced by the length of the linker. Increasing the linker length resulted in a decrease in antimalarial activity [60]. Lombard et al. also prepared and evaluated the in-vitro and in-vivo activity of artemisinin-quinoline hybrid compounds 47 against P. vinckei. ...
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.
... Thus, compound (106) showed the most promising activity among the series of 4 compounds, with IC 50 values of 5.31 and 28.43 nM against D10 and Dd2 strains, respectively, in addition to Resistance index (RI) of 5 and Selectivity index (SI) of 128 (Fig. 24). Besides, compound (106) was subsequently investigated against 3D7 strain of P. falciparum, again showing promising activity (IC 50 value of 8.7 nM) [85], which suggests this hybrid-dimer as a model for the development of compounds that may be useful against resistant strains of this parasite. Fig. (24). ...
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 3 presents (1) a brief overview of botanical and pharmacological properties of alkaloids, (2) a summary of the synthesis of natural morphinans and related alkaloids, (3) caffeine-based compounds for the treatment of neurodegenerative disorders, (4) piperine derivatives, (5) noscapine-based anti-cancer agents, (6) biogenic amines and amino acid derivatives as carbonic anhydrase modulators and (7) antimalarial compounds on quinoline scaffolds.
The objective of this book is to fulfil gaps in current knowledge with updated information from recent years. It serves as a guide for academic and professional researchers and clinicians.
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.
One of the most fatal infectious diseases, malaria, still poses a threat to about half of the world's population and is the leading cause of death worldwide. The use of artemisinin-based combination therapy has helped to significantly reduce the number of deaths caused by malaria, but the emergence of drug resistance threatens to undo this gain. In a bid to boost adherence, several new combination therapies with effectiveness against drug-resistant parasites are currently being tested in clinical settings. Nevertheless, notwithstanding these gains, malaria must be completely eradicated by a concerted international effort on several fronts. Quinoline-based compounds were the cornerstone of malaria chemotherapy until recently when resistance to these drugs severely hampered efforts to achieve a "Zero Malaria" world. The inappropriate use of available antimalarials is one of the factors responsible for resistance development and treatment failure, warranting the search for new chemical entities and alternative approaches to combat this threat. A vast number of solutions have emerged and one of them, quinoline-hybridization, is an effective method for introducing structural diversity, resulting in molecules with improved biological activities, reduced drug resistance, fewer drug-drug interactions, and improved safety and pharmacokinetic profiles. Choosing the ideal target combination and achieving a balanced activity toward them while preserving drug-like properties are the key challenges in the development of molecular hybrids. This review examines the highlights of quinoline hybridization, with some of the hybrids exhibiting remarkable in vitro and in vivo activities, emphasizing that it is a useful method for developing new anti-malarial lead compounds.
Kemunculan strain parasit yang rintang terhadap hampir semua ubatan antimalaria telah mendorong para saintis mengkaji penggantian mekanisme tindakan alternatif yang lebih berkesan. Keberkesanan rawatan semasa antimalaria adalah terhad dari segi bio ketersediaan ubat yang rendah, ketoksikan ubat yang tinggi dan kadar keterlarutan dalam air yang rendah. Penghibridan adalah satu strategi menarik bagi mengembangkan konsep penemuan ubat antimalaria. Kerangka 4-aminokuinolina telah disasarkan dalam kebanyakan proses reka bentuk agen antiplasmodium kerana kos sintesisnya yang murah, selamat dan kurang toksik sejak 20 tahun yang lalu. Penemuan hibrid antiplasmodium menggunakan kerangka 4-aminokuinolina dan pelbagai moieti seperti artemisinin, piperidin, indolin, pirimidin telah menunjukkan aktiviti antiplasmodium yang baik. Walau bagaimanapun, sehingga kini penemuan hibrid ini masih tidak dapat dibangunkan dan memasuki ujian percubaan klinikal. Ulasan ini meringkaskan penemuan hibrid antiplasmodium yang telah diterbitkan dalam tempoh sebelas tahun ke belakang (2011-2021). Kelebihan dan kelemahan konsep penghibridan sebagai pengganti agen antiplasmodium sedia ada dibincangkan. Analisis kajian menunjukkan hibrid 4-aminokuinolina mempunyai aktiviti antiplasmodium yang setanding atau lebih baik secara in vitro berbanding rawatan profilaksis klorokuina. Hibrid kuinolina kelas IV adalah yang paling kerap dikaji dan diperoleh dalam kajian ini sepanjang tempoh sebelas tahun ke belakang. Kekurangan data praklinikal terperinci mengenai hibrid yang disintesis telah menghalang kajian lanjut dalam ujian klinikal.
Malgré des progrès significatifs dans la lutte contre le paludisme avec une nette réduction de la morbidité et de la mortalité au cours des dernières années, notamment grâce à un meilleur diagnostic, à l’utilisation croissante de moustiquaires et à un accès aux soins amélioré, le paludisme reste l'une des maladies infectieuses les plus mortelles au monde. Cependant, l’émergence de résistances aux insecticides et aux médicaments antipaludéens est une menace pour les efforts mondiaux de contrôle et d'élimination du paludisme. Ainsi, il est urgent de trouver de nouvelles cibles et de développer de nouveaux agents antipaludiques agissant via des mécanismes originaux. Dans ce contexte, nous nous sommes intéressés à un cluster prometteur de trois molécules basées sur un squelette de type quinazolinedione (MMV665916, MMV019066 et MMV665878). Outre leur simplicité et rapidité de synthèse, ces molécules possèdent des propriétés pharmacologiques intéressantes contre plusieurs stades du cycle de vie de l’agent pathogène responsable du paludisme, tout en ayant une faible toxicité envers des cellules humaines. Cependant, ces molécules souffrent d’un handicap majeur, eu égard à leur modeste profil pharmacocinétique avec notamment des problèmes de solubilité ou de stabilité métabolique. Pour pallier ces défauts, nous avons alors entamé une phase d'optimisation de ces « hits » qui consiste à les modifier pour améliorer leurs propriétés pharmacologiques. Le but de ce projet consiste au travers de notre partenariat multidisciplinaire, à mettre au point un composé phare administrable par voie orale et à en étudier son mécanisme d'action.
Novel artemisinin-quinoline hybrid-dimers were synthesized from dihydroartemisinin and different aminoquinolines at elevated temperatures (90-110°C). All compounds were obtained as the β-isomers and were tested against both chloroquine sensitive and resistant strains of Plasmodium falciparum. Hybrid-dimer 8 showed the highest antiplasmodial activity, inheriting the optimum chain length of three carbon atoms.
Artemisinin combination therapies are the first-line treatments for uncomplicated
Plasmodium falciparum malaria in most malaria-endemic countries. Recently, partial
artemisinin-resistant P. falciparum malaria has emerged on the Cambodia–Thailand
border. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic
doses for over 30 years, and the availability of substandard artemisinins, have probably
been the main driving force in the selection of the resistant phenotype in the region. A
multifaceted containment programme has recently been launched, including early diagnosis and
appropriate treatment, decreasing drug pressure, optimising vector control, targeting the
mobile population, strengthening management and surveillance systems, and operational
research. Mathematical modelling can be a useful tool to evaluate possible strategies for
containment.
Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38°C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. They have remained infective to Aotus.
Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI 50) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.
Artemisinin combination therapies are the first-line treatments for uncomplicated Plasmodium falciparum malaria in most malaria-endemic countries. Recently, partial artemisinin-resistant P. falciparum malaria has emerged on the Cambodia-Thailand border. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinins, have probably been the main driving force in the selection of the resistant phenotype in the region. A multifaceted containment programme has recently been launched, including early diagnosis and appropriate treatment, decreasing drug pressure, optimising vector control, targeting the mobile population, strengthening management and surveillance systems, and operational research. Mathematical modelling can be a useful tool to evaluate possible strategies for containment.
During the past decade, renewed global and national efforts to combat malaria have led to ambitious goals. We aimed to provide an accurate assessment of the levels and time trends in malaria mortality to aid assessment of progress towards these goals and the focusing of future efforts.
We systematically collected all available data for malaria mortality for the period 1980-2010, correcting for misclassification bias. We developed a range of predictive models, including ensemble models, to estimate malaria mortality with uncertainty by age, sex, country, and year. We used key predictors of malaria mortality such as Plasmodium falciparum parasite prevalence, first-line antimalarial drug resistance, and vector control. We used out-of-sample predictive validity to select the final model.
Global malaria deaths increased from 995,000 (95% uncertainty interval 711,000-1,412,000) in 1980 to a peak of 1,817,000 (1,430,000-2,366,000) in 2004, decreasing to 1,238,000 (929,000-1,685,000) in 2010. In Africa, malaria deaths increased from 493,000 (290,000-747,000) in 1980 to 1,613,000 (1,243,000-2,145,000) in 2004, decreasing by about 30% to 1,133,000 (848,000-1,591,000) in 2010. Outside of Africa, malaria deaths have steadily decreased from 502,000 (322,000-833,000) in 1980 to 104,000 (45,000-191,000) in 2010. We estimated more deaths in individuals aged 5 years or older than has been estimated in previous studies: 435,000 (307,000-658,000) deaths in Africa and 89,000 (33,000-177,000) deaths outside of Africa in 2010.
Our findings show that the malaria mortality burden is larger than previously estimated, especially in adults. There has been a rapid decrease in malaria mortality in Africa because of the scaling up of control activities supported by international donors. Donor support, however, needs to be increased if malaria elimination and eradication and broader health and development goals are to be met.
The Bill & Melinda Gates Foundation.
Nine dihydroartemisinin acetal dimers (6-14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC(50): 3.0-6.7 nM (D6) and 4.2-5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC(50): 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum. Compounds 10, 13 and 14 displayed enhanced anticancer activity in a number of cell lines compared to the control drug, doxorubicin. The antifungal activity of 7 and 12 against Cryptococcus neoformans (IC(50): 0.16 and 0.55 microM, respectively) was also higher compared to the control drug, amphotericin B. The antileishmanial and antibacterial activities were marginal. A number of dihydroartemisinin acetal monomers (15-17) and a trimer (18) were isolated as byproducts from the dimer synthesis and were also tested for biological activity.
Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity.