High Antimalarial Activity Research Articles

High Antiplasmodial Activity of Golden Gamat (S.hermanni) Extract Through In Vitro Study

S.hermanni is a marine biota that contains active components that are anti-fungal, anti-bacterial, antioxidant, anti-inflammatory, and anti-cancer. The research focused on examining the antiplasmodial activity of an ethanol extract of S. hermanni on the proliferation of P. falciparum in vitro. The total sample size was 30 mediums, which included: (G1). No extract or chloroquine administration in the P.falciparum medium (G2). Chloroquine treatment administration on P. falciparum medium (G3). P. falciparum medium with S. hermanni extract. Parasitaemia, growth percentage, inhibitory rate, and IC50 were among the parameters evaluated. Administration of extract serial doses succeeds in reducing the percentage of parasite growth and parasitemia levels. G3 demonstrated an inhibitory rate of 88.51 % with a dose of 100 µg/ml and an IC50 of 2.86 µg/ml, indicating high antimalarial activity, although chloroquine had greater antimalarial activity than S. hermanni extract. In vitro studies on S hermanni, ethanol extract indicated that it contains bioactive components and can be an effective antiplasmodial agent.

Ligand Decorated Primaquine Loaded Nanocarriers for Liver Targeting for Triggered Anti-Malarial Activity.

The aim of the current research is to formulate a nano delivery system for effective delivery of primaquine for liver targeting to achieve the potential anti-malarial activity. Another objective of current development is to formulate a lactobionic acid conjugated polyphosphazene based nano delivery of primaquine for liver targeting to distinguish anti-malarial activity. The particle size, entrapment efficiency, in-vitro drug release pattern, hepatotoxicity, MTT assay, erythrocyte toxicity assay, histopathology study, HepG2 cell uptake study, anti-- malarial study, and organ-distribution was also carried out to estimate the activity and potential features of a nanoparticle system. The results obtained from the above analysis justify the efficiency and effectiveness of the system. The NMR studies confirm the conjugation pattern and the TEM represents the spherical morphological features of nanoparticles. The controlled release pattern from the in-vitro release study was observed and found to be 73.25% of drug release in 20 hrs and in the nano-size range (61.6± 1.56 nm) by particle size analysis.SGOT level, SGPT, ALP, and Parasitemia level of optimized drug-loaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles (FF) was found to lie in the safe range, showing that the formulation is non-toxic to the liver. Primaquine drug-loaded PEGylated lactobionic acid conjugated polyphosphazene polymeric nanoparticles showed higher cell uptake on HepG2 cell lines as compared to the drug-loaded in PEGylated polyphosphazene polymeric nanoparticles and plain drug.Percentage cell viability of drugloaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles was decreased by enhancing the concentration of prepared nanoparticle system accessed by MTT assay. From the studies, it can be concluded that the optimized formulation of drug-loaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles showed high liver targeting, least toxicity to the liver, controlled release of the drug, higher anti-malarial activity against hepatocytes at a low dose, more effectiveness, and can be treated as a potential candidate for anti-malarial therapy.

In vitro antimalarial activity of Garcinia parvifolia Miq. Stem extracts and fractions on Plasmodium falciparum lactate dehydrogenase (LDH) assay.

The rapid spread of antimalarial drug resistance is becoming a problem in the treatment of malaria. The fact was indicated the importance of finding new antimalarial drugs. The genus Garcinia is well known to be a rich source of bioactive prenylated xanthones and triterpenes reported for their antimalarial activity. Garcinia parvifolia is one of the Garcinia genera that can be explored for the search of new antimalarial drugs. This study was aimed to determine the antimalarial activities of G.parvifolia extracts and fractions. Garcinia parvifolia Miq. stem was collected fromBalikpapan Botanical Garden in East Kalimantan, Indonesia, was extracted gradually with n-hexane, dichloromethane, and methanol by ultrasonic assisted method. The most active extract was further separated using the open column chromatography method. All extracts and fractions were tested against Plasmodium falciparum 3D7 using lactate dehydrogenase (LDH) assay and followed by IC50 determination. The results showed that all extracts inhibit P.falciparum growth by LDH assay. The highest inhibition was showed by dichloromethane stem extract (BP12-S-D) with the IC50 value of 6.61±0.09μg/mL. Further fractionation of BP12-S-D has obtained 10 fractions. All of themwere identified by TLC, and a brownish-yellow spot (fraction-1) appears after spraying with 10% H2SO4. Fraction-1 (F1) performed the highest parasite growth inhibition with the IC50 value of 6.00±0.03μg/mL compared with other fractions. This fraction was classified as having a promising activity of antimalarial. The fraction-1 was identified using HPLC, and two major peaks were observed (A and B). The UV-Vis spectra showed the absorption at wavelengths 250 and 278 (A), 243, 281, and 317nm (B). Based on the profile of TLC, HPLC, and UV-Vis spectra of F1, it was expected that the active compounds are flavonoid (A)and xanthone (B). The fraction-1 of dichloromethane extract of G.parvifolia Miq. stem has the highest antimalarial activity. It might be a potential candidate for the new antimalarial drug.

Choline and PEG dually modified artemether nano delivery system targeting intra-erythrocytic Plasmodium and its pharmacodynamics in vivo

Objective The choline derivative (CD) and polyethylene-glycol (PEG) dually modified artemether (ARM) nanostructured lipid carriers (CD-PEG-ARM-NLC) have been designed to prolong the circulation of ARM in blood, as well as to develop targeting for new permeability pathways (NPPs) and erythrocyte choline carriers (ECCs) that are expressed on the Plasmodium-infected erythrocyte membrane. Significance The CD-PEG-ARM-NLC constructed in this study was found to be able to target endoerythrocytic Plasmodium by increasing the drug concentration and residence time in the infected erythrocytic microenvironment and minimizing toxicity and side effects. Methods CD-PEG-ARM-NLC was prepared using high-pressure homogenization followed by physicochemical characterization. The targeting ability of CD-PEG-NLC to infected erythrocytes probed by coumarin-6 was investigated by using fluorescence microscopy imaging. The SYBR Green I assay for parasite nucleic acid was adapted in order to assess the efficacy of inhibition against parasite growth in vitro. The antimalarial activity of ARM-loaded NLCs was evaluated by a Pearson four-day suppressive test in Pyy265BY-bearing mice. Results In vitro imaging indicated that the intracellular delivery of CD-PEG-ARM-NLC was efficiently taken up by the infected erythrocytes via ECCs and NPPs, which could be inhibited by addition of furosemide (an inhibitor of NPPs) and excessive choline (native substrate of ECCs). Moreover, in vitro and in vivo studies that evaluated antimalarial activity suggested that CD-PEG-ARM-NLC exhibited higher antimalarial activity in comparison to ARM-NLC and PEG-ARM-NLC. Conclusion These findings suggested that choline and PEG dually modified NLC could be promising preparations for the production of hydrophobic antimalarial drugs, particularly for ARM.

Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines

Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.

Supercritical carbon dioxide extraction of plant phytochemicals for biological and environmental applications – A review

Recently, supercritical fluid CO2 extraction (SFE) has emerged as a promising and pervasive technology over conventional extraction techniques for various applications, especially for bioactive compounds extraction and environmental pollutants removal. In this context, temperature and pressure regulate the solvent density and thereby effects the yield, selectivity, and biological/therapeutic properties of the extracted components. However, the nature of plant matrices primarily determines the extraction mechanism based on either density or vapor pressure. The present review aims to cover the recent research and developments of SFE technique in the extraction of bioactive plant phytochemicals with high antioxidant, antibacterial, antimalarial, and anti-inflammatory activities, influencing parameters, process conditions, the investigations for improving the yield and selectivity. In another portion of this review focuses on the ecotoxicology and toxic metal recovery applications. Nonpolar properties of Sc-CO2 create strong solvent strength via distinct intermolecular interaction forces with micro-pollutants and toxic metal complexes. This results in efficient removal of these contaminants and makes SFE technology as a superior alternative for conventional solvent-based treatment methods. Moreover, a compelling assessment on the therapeutic, functional, and solvent properties of SFE is rarely focused, and hence this review would add significant value to the SFE based research studies. Furthermore, we mention the limitations and potential of future perspectives related to SFE applications.

Quinolinotriazole antiplasmodials via click chemistry: synthesis and in vitro studies of 7-Chloroquinoline-based compounds

Malaria is nowadays one of the most serious health concerns in a global scale and, although there is an evident increase in research studies in this area, pointed by the vast number of hits and leads, it still appears as a recurrent topic every year due to the drug resistance shown by the parasite exposing the urgent need to develop new antimalarial medications. In this work, 38 molecules were synthesized via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) or “click” chemistry, following different routes to produce 2 different organic azides, obtained from a 4,7 dicholoquinoline, reacted with 19 different commercially available terminal alkynes. All those new compounds were evaluated for their in vitro activity against the chloroquine resistant malaria parasite Plasmodium falciparum (W2). The cytotoxicity evaluation was accomplished using Hep G2 cells and SI index was calculated for every molecule. Some of the quinoline derivatives have shown high antimalarial activity, with IC50 values in the range of 1.72-8.66 µM, low cytotoxicity, with CC50>1000 µM and selectivity index (SI) in the range of 20-100, with some compounds showing SI>800. Therefore, the quinolinotriazole hybrids could be considered a very important step on the development of new antimalarial drugs.

Antimalarial properties and preventive effects on mitochondrial dysfunction by extract and fractions of Phyllanthus amarus (Schum. and Thonn) in Plasmodium berghei-infected mice.

Broad spectrum antimalarial drugs without deleterious effects on mitochondria are scarce. It is in this regard that we investigated the potency of methanol extract and solvent fractions of Phyllanthus amarus on chloroquine-susceptible and resistant strains of Plasmodium berghei, toxicity and its consequential effects on mitochondrial permeability transition (mPT) pore opening. Malaria was induced in male Swiss mice with susceptible (NK 65) strain, divided into groups (n=5) and treated with 100, 200 and 400mg/kg of methanol extract, n-hexane, dichloromethane, ethylacetate and methanol fractions daily for seven days. Percentage parasitemia and parasite clearance were determined microscopically. The two most potent fractions were tested on resistant (ANKA) strains. Heme and hemozoin contents were determined spectrophotometrically. The mPT, mitochondrial ATPase (mATPase) and lipid peroxidation (mLPO) were determined spectrophotometrically. Similar groups of animals were used for toxicity studies. Dichloromethane fraction (400mg/kg) had the highest antimalarial curative effect via least parasitemia (0.49) and high clearance (96.63) compared with the negative control (10.08, 0.00, respectively), had the highest heme and least hemozoin contents (16.23; 0.03) compared with the negative control (8.2, 0.126, respectively). Malaria infection opened the mPT, caused significant increase in mLPO and enhanced mATPase; while dichloromethane fraction reversed these conditions. Serum ALT, AST, ALP, GGT, urea and creatinine of dichloromethane fraction-treated mice decreased relative tocontrol. No significant lesion was noticed in liver andkidney tissue sections. Dichloromethane fraction of Phyllanthus amarus had the highest antimalarial activity with the highest mito-protective effect and it was well tolerated without toxic effects.

Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline.

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum.

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 a-x) and 14 phthalimido-thiazoles (4 a-n) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50 =3.60 μM), 3 h (IC50 =3.75 μM), and 4 j (IC50 =4.48 μM), were more active than the control drug benznidazole (IC50 =14.6 μM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h, 3 t, and 4 j at IC50 concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarial activity were the phthalimido-thiazoles 4 l (IC50 =1.2 μM), 4 m (IC50 =1.7 μM), and 4 n (IC50 =2.4 μM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.

Theoretical design of novel antimalarial agents against P. falciparum strain, Dd2 through the QSAR modeling of synthesized 2′-substituted triclosan derivatives

In an attempt to design compounds with higher antimalarial activities, quantitative structure-activity relationship (QSAR) technique was utilized in the development of a molecular model for some synthesized 2′-substituted triclosan derivatives through a hybrid of the GA-MLR method. The model was found to have excellent statistical parameters (R2 = 0.8919, R2Adj = 0.8728, LOF = 0.2563). The descriptors mean effect (MF) revealed BCUTw-1l, which increases with an increase in molecular weight, to be the most contributive to the antimalarial activity. Consequently, compound 3, with the highest activities (pEC50 = 6.9586) was deployed as the design template. The molecular weight of the template was increasing through substitutions of its atoms at several positions with heavier atoms/groups to increases the descriptor (BCUTw-1l) value. Twelves (12) theoretical derivatives of the template were designed where six of the designed derivatives have better activity than the design template. The most active designed compound, 3L was found to have the highest antimalarial activity (pEC50 = 7.930) than that of the design template.

IN VITRO ANTIMALARIAL ACTIVITY AND TOXICITY STUDIES OF JOHAR (CASSIA SIAMEA) LEAVES FROM THREE DIFFERENT LOCATIONS.

Background:Antimalarial activity of Cassia siamea leaves has been proven by the active compound that has been found, i.e. Cassiarin A. It is known that the quantity of the content of a compound that has the potential as a raw material for medicine can be influenced by various factors including differences in plant origin. This study aims at comparing the antimalarial activity and toxicity of C.siamea leaves from three regions with different meters location values above sea level (asl), i.e Pariaman (1,000 m asl), Palu (60 m asl), and Surabaya (2 m asl).Materials and Methods:The materials used in this study were Johar leaves from Pariaman, Surabaya, and Palu extracted with n-hexane, and 90% ethanol containing 1% tartaric acid. The antimalarial activity test was done with Plasmodium falciparum 3D7. The toxicity test applied MTT ELISA method.Results:C.siamea leaf that had highest antimalarial activity came from Pariaman with IC50 value of 0.006μg/ml, then from Palu was 0.037μg/ml, and the lowest antimalarial activity was from Surabaya that was 0.09μg/ml . In testing the toxicity to get CC50, the highest toxicity came from Surabaya with CC50 value of 135.81μg/ml, Pariaman with CC50 value of 220.82 μg/ml, and the least toxic came from Palu with CC50 value of 235.52μg/ml .Conclusion:C.siamea leaf obtained from Pariaman had a selectivity index value that satisfies the requirements of a promising antimalarial effect.

Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds

BackgroundHerbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine (‘Kampo’) were examined for their potential anti-malarial activities.MethodsA comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity.ResultsOut of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride.ConclusionCoptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Effect of Formulated Artocarpus champeden Extract on Parasite Growth and Immune Response of Plasmodium berghei-Infected Mice.

Background The ethanol extract of Artocarpus champeden stem bark (ACEE) has been proven to exhibit antimalarial activity. Despite the antimalarial effects observed, mechanisms of immune response to explain the antimalarial activity of ACEE remain poorly characterized. Here, we show the production of pro- and anti-inflammatory cytokines T helper 1 (Th1: IFN-γ, TNF-α) and T helper 2 (Th2: IL-10) from Plasmodium berghei-infected mice treated with formulated ACEE in order to better characterize the mechanism behind ACEE's antimalarial activity. In addition, we have also determined the effect of formulated ACEE on parasite growth and liver function. Methods Balb/c mice were infected with P. berghei strain ANKA and then administered daily doses of ACEE at a dose of 20, 50, and 100 mg/kg BW, and survival time was recorded. We determined the presence of P. berghei strain ANKA and then administered daily doses of ACEE at a dose of 20, 50, and 100 mg/kg BW, and survival time was recorded. We determined the presence of P. berghei strain ANKA and then administered daily doses of ACEE at a dose of 20, 50, and 100 mg/kg BW, and survival time was recorded. We determined the presence of γ, TNF-α) and T helper 2 (Th2: IL-10) from Results We found that formulated ACEE inhibited parasite growth and showed the highest antimalarial activity at 100 mg/kg BW. AST and ALT levels were found to be in the normal range, and there was no significant difference among control and treatment groups (P > 0.05). Infected mice treated with formulated ACEE showed a significant increase in the production of IFN-γ, TNF-α) and T helper 2 (Th2: IL-10) from Conclusion This study suggests that the administration of ACEE was effective in inhibiting P. berghei strain ANKA and then administered daily doses of ACEE at a dose of 20, 50, and 100 mg/kg BW, and survival time was recorded. We determined the presence of γ, TNF-α) and T helper 2 (Th2: IL-10) from

Tomatoes’ skins as a rich source of natural pigments

Rhizome of Curcuma longa L. is rich in curcumin which is also an important natural pigment and has important biological activity. In order to obtain curcumin concentrated extracts, one-step and two-step processes were employed. The one step process involves supercritical carbon dioxide (scCO2) at 60 °C and 400 bar, ethanol at 25 °C and water at 60 °C, both at atmospheric pressure. Ethanol and/or water were used as solvents. In the two-step process, sequential extraction, using scCO2, was performed followed by ethanol or water extraction. All the extracts obtained were analyzed and results were reported for global extraction yield, the total phenolic content, total flavonoids, curcumin, antimalarial activity and antioxidant activity. The two-step process showed the highest global yield (23.4%) when water is used as solvent in the second step. However, high concentrations of curcumin and high antioxidant activity were obtained when ethanol is used as solvent. The supercritical extract presents low concentration of curcumin and high antimalarial activity; which shows that extracts of different compositions and functionality can be obtained from a sequential extraction.

In vitro and in vivo characterization of anti-malarial acylphenoxazine derivatives prepared from basic blue 3

BackgroundBasic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated.MethodsSix acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model.ResultsAll the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain.ConclusionsThe six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound.

Pharmacokinetic analysis of new synthetic antimalarial N-251

BackgroundWith the emergence and growing number of drug-resistant Plasmodium falciparum, a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice.ResultsPK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. Cmax was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability (F) was approximately 23%. Additionally, Tmax, Cmax, AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251.ConclusionsN-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251.

Kozupeptins, Antimalarial Agents Produced by Paracamarosporium Species: Isolation, Structural Elucidation, Total Synthesis, and Bioactivity.

Kozupeptins A and B, novel antimalarial lipopeptides, were isolated from the culture broths of Paracamarosporium sp. FKI-7019. They exhibited potent antimalarial activity against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. The structural elucidation was accomplished by a combination of spectroscopic analyses and chemical approaches including a total synthesis of kozupeptin A. Synthetic kozupeptin A demonstrated a therapeutic effect in vivo, and an intermediate exhibited much higher antimalarial activity than kozupeptin A.

Antimalarial activity of a novel series of artemisinin-derived 1, 2, 3-triazole dimers

Objective: To obtain suitable artimisinin-based drug candidates with high antimalarial activity. Methods: Three different reaction schemes were used to synthesize a total of 15 artemisinin-based compounds. The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin. The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds. Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2. Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane. The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields. Results: The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC50 value 0.066 μg/mL against chloroquine-sensitive and 0.865 μg/mL against chloroquine-resistant strains of Plasmodium falciparum. It suppressed 59.0% parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50 μg/kg body weight dosage. Molecular docking interactions of Plasmodium falciparum ATP6 (PfATP6) protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound. Conclusion: Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity. Of the two, GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study. Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.

Antimalarial Activity of Kaempferol and Its Combination with Chloroquine in Plasmodium berghei Infection in Mice.

The search for new antimalarial drugs has become an urgent requirement due to resistance to the available drugs and the lack of an effective vaccine. In this respect, the present study aimed to evaluate the antimalarial activity of kaempferol against Plasmodium berghei infection in mice as an in vivo model. Chronic toxicity and antimalarial activities of kaempferol alone and in combination with chloroquine were investigated in P. berghei ANKA infected ICR mice using standard procedures. The results showed that chronic administration of 2,000 mg/kg of kaempferol resulted in no overt signs of toxicity as well as no hepatotoxicity, nephrotoxicity, or hematotoxicity. Interestingly, kaempferol exerted significant (P < 0.05) chemosuppressive, chemoprophylactic, and curative activities in a dose-dependent manner. The highest antimalarial activity was found at a dose of 20 mg/kg which resulted in a significantly (P < 0.05) prolonged survival of infected mice. Moreover, combination treatment of chloroquine and kaempferol also presented significant (P < 0.05) antimalarial effects, although the effects were not significantly different from the chloroquine treated group. From the results of the present study, it can be concluded that kaempferol possesses acceptable antimalarial activities. However, further investigation should be undertaken on the mechanism responsible for the observed antimalarial activity.