Promising Antimalarial Activity Research Articles

Synthesis of the decalin core of codinaeopsin via an intramolecular Diels–Alder reaction

We describe the synthesis of the decalin core of codinaeopsin (1), a tryptophan-polyketide hybrid natural product with promising antimalarial activity (IC50 4.7 μM, against Plasmodium falciparum), via an intramolecular Diels-Alder (IMDA) reaction. A convergent synthesis was developed to prepare the precursors for the IMDA reaction in 10 steps. The exo cycloadducts were derived from thermal, IMDA reactions of the substrates containing a Weinreb amide or ester conjugated dienophile, and the endo adducts were from Lewis acid promoted reactions of the substrates with a formyl group. Both exo and endo products of the IMDA were exclusively isolated and characterized by NMR spectroscopy. One endo cycloadduct was further confirmed with X-ray crystallography. Theoretical calculations reveal the influence of the substituents of the decalin core on the IMDA process.

Evaluation of Nepeta leavigata, Nepeta kurramensis and Rhynchosia reniformis on antimalarial and antileishmanial activities

The pharmacological investigation of methanolic extracts and different fractions of the Nepeta leavigata, Nepeta kurramensis and Rhynchosia reniformis were designed to assess the antimalarial and antileishmanial screening of medicinal plants for development of drugs. Materials and Methods: The shade-dried whole plant material of Nepeta leavigata was soaked in methanol for 10 days. The powdered drug was extracted with 80 % methanol three times and filtered at room temperature. The filtrate was evaporated in rotary to get a dark-greenish residue (extract), which was further suspended in water and partitioned successively with n -hexane, chloroform, ethyl acetate and n -butanol to obtain n -hexane-soluble, chloroform-soluble, ethyl acetate-soluble, n -butanol-soluble and aqueous fractions, respectively (Khan, et al ., 2010a). Same extraction and fractionation procedure was adopted for Nepeta kurramensis and Rhynchosia reniformis. The antimalarial / antileishmanial activity of crude extracts/fractions was determined through standard protocol (Kerharo & Adam, 1974/). Results: The crude extract, chloroform fraction of Nepeta leavigata and fractions chloroform and ethyl acetate of Nepeta kurramensis showed promising antileishmanial and antimalarial activity against parasites of leishmania and malaria (promistogetes and schizonts) by observing 1 or 0 number of parasites on slide field where ≤ 1 level is significant, while all fractions of Rhynchosia reniformis did not showed any action against promistigotes and schizonts. Conclusions: The bioassays guided isolation and phytochemical screening of active fractions against these activities will further enhance research in the field of pharmacology.

Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold

As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH2Cl2/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5–15). All compounds (1–15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC50 of 1.9μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC50 of 15.6μM.

In vitro Antimalarial Activity of 11 Terpenes Isolated from Ocimum gratissimum and Cassia alata Leaves. Screening of Their Binding Affinity with Haemin

Eleven terpenes extracted from Cassia alata and Ocimum gratissimum leaves were screened for in vitro antimalarial activity against Plasmodium falciparum and for their binding affinity with haemin in ethylene Glycol-water 3:7 solvent. Nine terpenes have promising antimalarial activity with IC50 values below 1µg/ml; two terpenes showed a good activity with IC50 values below 4µg/ml. All the terpenes bind strongly with haemin as shown by variation of absorbance of the haemin at ? 600nm in UV-Visible spectrum.

Stepwise MLR and PCR QSAR study of the pharmaceutical activities of antimalarial 3-hydroxypyridinone agents using B3LYP/6-311++G** descriptors

The quantitative relationship between molecular properties and pharmaceutical activities of 19 antimalarial 3-hydroxypyridinones is studied using B3LYP/6-311++G** structural, electronic, and thermochemical characteristics. In this QSAR study, stepwise-multilinear regression (MLR) and principle component regression (PCR) are utilized based on volume, HOMO, nCrH2, and nHDon descriptors selected from a number of descriptor sets calculated and examined. The MLR coefficients are evaluated by cross-validation and external test sets methods. Regression coefficients of R2 = 0.882 and R2 = 0.874 are obtained, respectively, for the MLR and PCR predicted pIC50 values as referenced to their experimental values. Results of PCR predict the same trend for the predicted IC50 approving validity of the MLR results. Based on the present MLR and PCR analyses, pIC50 value is calculated for six candidate antimalarial drugs designed in this work, two of which are found to have promising antimalarial activity as high as that of the two best already synthesized and examined drugs.

Curcuminoids-loaded liposomes in combination with arteether protects against Plasmodium berghei infection in mice

Curcuminoids are poorly water-soluble compounds with promising antimalarial activity. To overcome some of the drawbacks of curcuminoids, we explored the potential of liposomes for the intravenous delivery of curcuminoids in a model of mouse malaria. The curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy PC) by the thin-film hydration method. Antimalarial activity of curcuminoids-loaded liposomes alone and in combination with α/β arteether when administered intravenously, was evaluated in Plasmodium berghei infected mice. Animals treated with curcuminoids-loaded liposomes showed lower parasitemia and higher survival when compared to control group (no treatment). Importantly, the combination therapy of curcuminoids-loaded liposomes (40mg/kg body wt) along with α/β arteether (30mg/kg body wt) was able to not only cure infected mice but also prevented recrudescence. These data suggest that curcuminoids-loaded liposomes may show promise as a formulation for anti-malarial therapy.

ChemInform Abstract: Synthesis and Crystal Structure of 3‐[1‐Hydroxy‐3‐oxo‐3‐(4‐methylphenylpropyl)]quinolin‐2(1H)‐one Derivatives.

AbstractTitle compounds (III) possess very promising antimalarial activity both in vitro and in vivo.

Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: synthesis, characterization and in vitro antimalarial activity.

Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η(6)-cym)(L(1))Cl]Cl (1, cym = p-cymene, L(1) = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η(6)-cym)(L(2))Cl]Cl (2, L(2) = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η(6)-cym)(L(3))Cl] (3, L(3) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1-3 and ligands L(1), L(2) and L(3), as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L(4)), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L(2) also shows good activity against both the chloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR(50)) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR(50) properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L(3) to ruthenium, to give a metal complex (3) with promising antimalarial activity.

Pyrano[4,3-b]quinolines Library Generation via Iodocyclization and Palladium-Catalyzed Coupling Reactions

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity.

Antimalarial activity in Xylocarpus granatum (Koen)

The antimalarial activity of Xylocarpus granatum fruits and their active constituents gedunin and xyloccensin-I were investigated using an in vitro model in this study. The chloroform fraction of X. granatum fruits was found to show promising antimalarial activity using an in vitro model of Plasmodium falciparum. On purification of the active fraction, four pure compounds were isolated and characterised, namely gedunin, photogedunin, xyloccensin-I and palmitic acid. Out of these only gedunin and xyloccensin-I were found to show activity equivalent to the parent active fraction in vitro model.

Synthesis of 4‐aminoquinoline‐1,2,3‐triazole and 4‐aminoquinoline‐1,2,3‐triazole‐1,3,5‐triazine Hybrids as Potential Antimalarial Agents

We report herein synthesis of a series of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure-activity relationship of substituted 4-aminoquinoline-based hybrids, 34 structurally diverse compounds were synthesized and tested against D6 and W2 strains of P. falciparum. Some of the compounds have shown promising antimalarial activity without toxicity against Vero cells.

Estudo fitoquímico biomonitorado pelos ensaios de toxicidade frente à Artemia salina e de atividade antiplasmódica do caule de aninga (Montrichardia linifera)

Montrichardia linifera é uma planta aquática de amplo uso na medicina tradicional amazônica. Entretanto, muito pouco se conhece sobre a sua composição química, e sua atividade biológica ainda não foi comprovada. Na busca de substância(s) biologicamente ativa(s), este trabalho realizou um estudo fitoquímico biomonitorado no qual foram testados os extratos hexânico e etanólico obtidos do caule desta espécie, dos quais apenas o extrato etanólico foi selecionado para o fracionamento cromatográfico por ter apresentado toxicidade contra a Artemia salina e atividade contra o Plasmodium falciparum, parasita causador da malária. As atividades biológicas concentraram-se na fração diclorometânica que apresentou alta toxicidade contra A. salina (DL50<31μg mL-1) e alta atividade antiplasmódica (IC50<10 μg mL-1), mostrando promissora atividade antimalárica. Desta fração, o composto aromático p-hidroxibenzaldeído foi isolado pela primeira vez nesta planta.

Cryptolepine and development of new antimalarial agents

Natural product-derived drugs exemplified by quinine, isolated from South American Cinchona species and artemisinin discovered in China are of immense importance for the treatment of malaria. Although malaria parasites resistant to artemisinin have not yet been found in malaria patients, the need for new antimalarial agents remains. The burden of malaria is heaviest in Africa where over a million children die of the disease each year, but although many medicinal plants are used in African traditional medicines for the treatment of malaria, none has yet yielded and effective antimalarial compound. Cryptolepis sanguinolenta (Periplocaceae), is a West African climbing shrub used traditionally for the treatment of malaria. Cryptolepine, an indoloquinoline alkaloid is the major constituent of the roots of C. sanguinolenta and has potent activity against malaria parasites in vitro, but it is cytotoxic on account of its abilities to inhibit topoisomerase II and to intercalate into DNA and it is also toxic to mice in vivo. However, the antimalarial mode of action of cryptolepine appears to involve a quinine-like mechanism (inhibition of ?-haematin formation) that is independent of interactions with DNA. This opens up the possibility that it may be feasible to prepare analogues of cryptolepine that do not interact with DNA (and hence may be less cytotoxic) but that retain or have enhanced antiplasmodial activities. Using various synthetic routes, a number of substituted cryptolepine analogues have been made and evaluated for their potential as leads to new antimalarial agents. Compounds were assessed for in-vitro activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and for cytotoxic activities. Some compounds have been assessed for their abilities to interact with DNA and a number of compounds has also been assessed for antimalarial activity against P. berghei in mice. Several cryptolepine analogues were found to have potent antiplasmodial activities (IC50 < 0.1 µM) against chloroquine-resistant P. falciparum (IC50 for chloroquine = 0.44 µM), but they are generally of similar cytotoxicity to cryptolepine. However, while cryptolepine is toxic to mice, a number of analogues have been shown to have promising antimalarial activities in the mouse-malaria model with no apparent toxicity. In view of this, derivatives of cryptolepine appear to be worthy of further investigation as potential antimalarial agents. In this lecture, the current status of antimalarial cryptolepine research will be reviewed and the potential of cryptolepine as a lead to new antimalarial agents will be discussed.

Design, synthesis and antimalarial/anticancer evaluation of spermidine linked artemisinin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines

A series of artemisinin–spermidine conjugates designed to utilise the upregulated polyamine transporter found in cancer cells have been prepared. These conjugates were evaluated against human promyelocytic leukaemia HL-60 cells and chloroquine-sensitive 3D7 Plasmodium falciparum and several show promising anticancer and antimalarial activity. Although some limitations in this vector-based approach are apparent, a number of high potency Boc-protected analogues were identified with activity against malaria parasites as low as 0.21nM.

Synthesis, antimalarial activity and cytotoxicity of 4-aminoquinoline–triazine conjugates

A series of 4-aminoquinoline–triazine conjugates with different substitution pattern have been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum. Compounds 16, 19, 28 and 35 exhibited promising antimalarial activity against both strains of P. falciparum. Cytotoxicity of these compounds was tested against three cell lines. Several compounds did not show any cytotoxicity up to a high concentration (48 μM), others exhibited mild toxicities but selective index for antimalarial activity was high for most of these conjugates.

Antimalarial acridines: Synthesis, in vitro activity against P. falciparum and interaction with hematin

A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure–activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC 50 ⩽ 0.07 μM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC 50 ⩽ 0.3 μM. These acridine derivatives inhibited the formation of β-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains.

Synthesis, antimalarial activity and cytotoxicity of substituted 3,6-diphenyl-[1,2,4,5]tetraoxanes

Substituted tetraoxanes with different substitution pattern on the aromatic ring were synthesized in order to explore the influence of different substituents in the antimalarial activity. Antimalarial activity of these compounds improves by the introduction of ethyl, iso-propyl or n-propyl groups in the aromatic ring but substitution with n-butyl or t-butyl leads decrease in antimalarial activity. Some of these compounds exhibit promising antimalarial activity. None of the compounds shows any toxicity against vero cells and three compounds ( 2a– 2c) were tested against panel of six cell lines and none of these compounds showed any toxicity. X-ray crystal structure of compound 2w showed that tetraoxane ring is in the chair conformation with both the phenyl rings in the equatorial position. In addition, FeCl 3 mediated O–O bond scission of tetraoxanes ( 2a– 2c) was also examined.

Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of symmetrically and asymmetrically substituted 3,6-diphenyl[1,2,4,5]tetraoxanes

A novel iodine-catalyzed one-pot synthesis of symmetrically and asymmetrically substituted 3,6-diphenyl-[1,2,4,5]tetraoxanes is described. The synthetic protocol is general with substituted benzaldehydes and proceeds well under acidic conditions. Total 17 tetraoxanes have been prepared during this study and some of these compounds exhibit promising antimalarial activity. None of the compounds shows any toxicity against vero cells.

Antimalarial Activity of Cassiarin A from the Leaves of Cassia siamea

The extracts and cassiarin A from the leaves of Cassia siamea showed promising antimalarial activities. The ethanol and chloroform extracts, alkaloid fraction, cassiarin A, and chloroquine as a positive control exhibited the inhibition against Plasmodium falciparum (IC 50 : 7.06, 2.41, 0.24, 0.005, and 0.006 μg/mL, respectively). The in vivo antimalarial activity was assessed using the 4-day suppressive test procedure. The ethanol, chloroform extracts, and alkaloid fraction were found to give an ED 50 34.7, 19.59, and 0.47 mg/kg, respectively (p.o.). The ED 50 values of cassiarin A and chloroquine were 0.17 and 0.21 mg/kg, respectively (i.p.). The result showed that cassiarin A deserved further investigation toward development of a promising antimalarial drug.

Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents

Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure-activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.