Antimalarial Activity Of Compounds Research Articles

Discovery of new potential antimalarial compounds using virtual screening of ZINC database.

Falcipain-3 (FP-3) is a cysteine protease of the malaria parasite Plasmodium falciparum which is a promising and attractive target enzyme for antiparasitic chemotherapy. In this study, a support vector machine (SVM) model based on fingerprint-based descriptors was developed on a dataset of 239 FP-3 inhibitors to identify the most active antimalarial compounds among the active compounds provided from similarity search. The satisfactory classification performance achieved by the SVM model shows its ability to use it as a further filter to distinguish the most active compounds. The accuracy in prediction for the training, test and external validation sets were 97.39%, 94.74% and 90.6%, respectively. Furthermore, the performance of the model was examined by plotting the receiver operating characteristic (ROC) curve, and the area under the ROC curve was 0.96 for the modeling set. The ability of a virtual screening scheme to scaffold hopping or lead hopping is known as a key ability of an effective method for virtual screening. Three diverse reference FP-3 structures were chosen as active antimalarial compounds to search the lead-like database of ZINC and retrieve the most similar compounds. Compounds having Tanimoto similarity coefficient above 0.8 were extracted for further analysis by classification model. The SVM model rendered five most active compounds and they were also analyzed by ADME/Tox and diversity measures. Maximum property-based distance between extracted compounds was found to be 0.70, which shows the importance of applying multiple diverse reference compounds in the similarity searching.

English

Tanzania has over 12,000 plant species, some of which are endemic and have potential to yield useful medicines. This study seeks to document such plants used as traditional medicines for treatment of malaria in Kagera region of northwestern Tanzania and Lindi region in south eastern Tanzania. The study also reports on the antiplasmodial activity against chloroquine-resistant Plasmodium falciparum (Dd2) strain of some of the documented plants using the parasite lactate dehydrogenase method. A total of 108 plant species, among which the families Compositae (14; 12.96%), Fabaceae (12; 11.11%), Euphorbiaceae (8; 7.41%), Melastomataceae (6; 5.56%) and Myrtaceae (4; 3.70%) were documented. Sixteen (16; 44.4%) of 36 extracts from 31 plant species that were tested inhibited malaria parasites growth by more than 50%. Bersema abyssinica stem bark extract was the most active with 86.67% inhibition rate followed by Bridelia micrantha stem bark extract with 71.87% inhibition rate. These results confirm the potential for plants used in traditional medicine to yield active antimalarial compounds. Further in vitro and in vivo screening supported by bioassay-guided isolation of active compounds from plants showing good safety margin is suggested. Key words: Ethnobotanical survey, medicinal plants, malaria, treatment, in vitro antiplasmodial, Tanzania.

Antimalarial diterpene alkaloids from the seeds of Caesalpinia minax

Two new diterpene alkaloids, caesalminines A (1) and B (2), possessing a tetracyclic cassane-type furanoditerpenoid skeleton with γ-lactam ring, were isolated from the seeds of Caesalpinia minax. Their structures were determined by different spectroscopic methods and ECD calculation. The plausible biosynthetic pathway of caesalminines A and B was proposed. The anti-malarial activity of compounds 1 and 2 is presented with IC50 values of 0.42 and 0.79μM, respectively.

Antiplasmodial activity of compounds isolated from Elaeagnus umbellata

The study of the chemical constituents of the whole plant of Elaeagnus umbellata has resulted in the isolation and characterization of three coumarins, namely, 7-Hydroxy-chromen-2-one (1), 7, 8-Dihyroxy-chromen-2-one (2), 3-(2,2,3,4,5-Pentahydroxy-hexyloxy)-chromen-2-one (3) and an anthraquinone (4) together with β-sitosterol glucopyranoside (5) and lupeol (6). The structural elucidation of the isolated compounds was established based on spectroscopic studies. The in vitro antimalarial activity of compounds 1 to 4 againstPlasmodium falciparum shows partial suppression of parasitic growth. Key words: Elaeagnus umbellata, coumarins, anti-malarial activity.

In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon

Artemisinin is the active antimalarial compound obtained from the leaves of Artemisia annua L. Artemisinin, and its semi-synthetic derivatives, are the main drugs used to treat multi-drug-resistant Plasmodium falciparum (one of the human malaria parasite species). The in vitro susceptibility of P. falciparum K1 and 3d7 strains and field isolates from the state of Amazonas, Brazil, to A. annua infusions (5 g dry leaves in 1 L of boiling water) and the drug standards chloroquine, quinine and artemisinin were evaluated. The A. annua used was cultivated in three Amazon ecosystems (várzea, terra preta de índio and terra firme) and in the city of Paulínia, state of São Paulo, Brazil. Artemisinin levels in the A. annua leaves used were 0.90-1.13% (m/m). The concentration of artemisinin in the infusions was 40-46 mg/L. Field P. falciparum isolates were resistant to chloroquine and sensitive to quinine and artemisinin. The average 50% inhibition concentration values for A. annua infusions against field isolates were 0.11-0.14 μL/mL (these infusions exhibited artemisinin concentrations of 4.7-5.6 ng/mL) and were active in vitro against P. falciparum due to their artemisinin concentration. No synergistic effect was observed for artemisinin in the infusions.

Synthesis and antimalarial activity of urenyl Bis-chalcone in vitro and in vivo

Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, β-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3′,4′-N-(urenylphenyl)-3-(3″,4″,5″-trimethoxyphenyl)]-2-propen-1-one 5, with a percentage of inhibition of heme polymerization of 87.05 ± 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria.

Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

BackgroundDeveloping resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds.MethodsA set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design.ResultsStarting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM), with six being very effective (IC50 ≤ 1 μM), and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a therapeutic index of more than 6,900 for the most active compound.ConclusionsGradient's metric modelling approach and electron-density molecular representations can be powerful tools in the discovery and design of novel anti-malarial compounds. Since the quantum models are agnostic of the particular biological target, the technology can account for different mechanisms of action and be used for de novo design of small molecules with activity against not only the asexual phase of the malaria parasite, but also against the liver stage of the parasite development, which may lead to true causal prophylaxis.

An important role of intramolecular free radical reactions in antimalarial activity of artemisinin and its analogs

The kinetic schemes of intramolecular reactions of five analogs of artemisinin were built. The method of intersecting parabolas was used for the calculation of activation energies and rate constants of each elementary step of these schemes. The competition between monomolecular and bimolecular free radicals was taken into account. It was evidenced that the intramolecular oxidation of these compounds proceeds as a cascade of consecutive free radical reactions with the formation of hydroperoxide groups. The latter decompose via reactions with the Fe(II) complexes generating free radicals. Among the radicals formed, the hydroxyl radical was proved to play the key role. A correlation between the yield of hydroxyl radicals n(OH) and antimalarial activity of compounds (IC(50)) was observed. The dependence of index IC(50) on n(OH) is linear in the logarithmic coordinates: ln[IC(50)(Artemisinin)/IC(50)(Compound)] = -14.10 + 3.85 ×n(OH). The proposed scheme explains and demonstrates a strong dependence of the antimalarial effectiveness of a drug on the chemical structure.

Bis-alkylamine quindolone derivatives as new antimalarial leads

Quindolone derivatives, designed to target the malaria parasite digestive vacuole and heme detoxification pathway, have been synthesized by reaction with 2-chloro- N, N-diethylethanamine. This reaction gave N,O-, N,N- and O-alkylated products containing one or two basic side-chains. The compounds were evaluated for antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum W2 strain and for cytotoxicity in HepG2 A16 hepatic cells. By incorporating alkylamine side chains and chlorine atoms in the quindolone nucleus we transformed the inactive tetracyclic parent quindolones into moderate or highly active and selective antimalarial compounds. The most active and selective compound, 5c, showed an IC 50 = 51 nM for P. falciparum and a selectivity ratio of 98.

Evaluation of the potential of the marine sponges of the Zanzibar Island to yield antimalarial and antimicrobial active compounds

Background: Emergence of new and re-emergence of old infections continue to elude prospects of reducing morbidity and mortality caused by microbial infections. Trends of resistance to currently in use antimicrobials and antimalarials threaten to increase mortality caused by these infections. This study explores the potential of marine invertebrates as a source for new antimicrobials and antimalarials. Methods: The lactate dehydrogenase method was used to assay marine sponges for activity against Plasmodium falciparum, while the disc diffusion method was used to assay the extracts for antibacterial and antifungal activity. Results: Extracts of some marine sponges from the Zanzibar Island exhibited both antiplasmodial and antimicrobial activities. Among the 55 marine sponge extracts that were tested 23 (41.8%) inhibited Plasmodium falciparum W2 strain by more than 50% at both 250 and 50 µg/ml concentrations. Moderate polar extracts were more active against Plasmodium falciparum W2 strain than polar and non-polar extracts. None of the 12 extracts that were tested on Plasmodium falciparum strain D6 exhibited inhibitory activity reaching 50%. Among 18 marine sponge extracts that were tested for antimicrobial activity 12 (66.7%) showed activity against one or more of the bacteria and fungi used ranging from weak to strong on an arbitrary criterion. The ethyl acetate extracts of Agelas mauritania and Oceanopia sp. exhibited high activity against the fungi Candida albicans and Cryptococcus neoformans. The best antibacterial profile was exhibited by ethyl acetate extracts of Aplysinopsis sp., Halichondrida sp. 1 and Oceanopia sp. Conclusion: These results support the need for intensified efforts to search for active antimalarial and antimicrobial compounds from the Zanzibar marine sponges.

Antimalarial activity of compounds and mixed fractions of Cecropia pachystachya

AbstractExtracts from Cecropia pachystachya (Cecropiaceae), a medicinal plant used in Brazil, were tested for their antimalarial activity against Plasmodium falciparum and/or Plasmodium berghei in mice. The ethanol extracts of wood, root, and leaves reduce parasitemia of malaria‐infected mice from 35–66% in relation to nontreated control mice. The plant roots extracts, with stronger activity, were further analyzed and provided subfractions also active in vivo from which two compounds were isolated and chemically characterized as β‐sitosterol and tormentic acid. Although both compounds were active in mice malaria, only the tormentic acid inhibited P. falciparum chloroquine‐resistant parasites (W2) growth in cultures, reducing parasitemia dose‐responsively (IC50=11–15 µg/ml). The antimalarial activity of the plant extracts kept refrigerated 7 years after the initial isolation, when tested in parallel with new extracts freshly isolated from plants collected at the same geographical site, was similar, confirming the superiority of the plant roots and the stability of the active extracts. In these experiments, inhibition of parasite growth was measured by hypoxanthine incorporation and by immunoenzymatic assay (ELISA) with monoclonal antibodies against the P. falciparum histidine‐rich protein (HRP2), expressed by the erythrocytic forms. The plant roots showed the lowest IC50 value and displayed the lowest toxicity, thus having the best therapeutic index. C. pachystachya species is therefore a good candidate for phytotherapeutic use against malaria. Further studies are ongoing to isolate new active compounds through bioguided fractionation analysis, in an effort to develop a new drug prototype against P. falciparum erythrocytic parasites. Drug Dev Res 71: 82–91, 2010. © 2009 Wiley‐Liss, Inc.

Antiplasmodial activities of furoquinoline alkaloids from Teclea afzelii

The study of the chemical constituents of the stem bark of Teclea afzelii (Rutaceae) has resulted in the isolation and characterization of four furoquinoline alkaloids, namely kokusaginine (1), tecleaverdoornine (2), maculine (3) and montrifoline (4) together with lupeol (5) and beta-sitosterol glucopyranoside (6). The structures of the isolated compounds were elucidated based on spectroscopic studies. The antimalarial activity of compounds 1-4 against Plasmodium falciparum in vitro shows partial suppression of parasitic growth.

Antiplasmodial Activity of Lignans and Extracts fromPycnanthus angolensis

The dichloromethane, methanol and aqueous ethanol extracts of the stem bark of Pycnanthus angolensis were evaluated for their in vitro activity against the 3D7 Plasmodium falciparum strain. The CH (2)Cl (2) extract was the most active showing an IC (50) = 1.6 microg/mL. From this extract, a new dibenzylbutane lignan, threo-4,4'-dihydroxy-3-methoxylignan ( 1) named pycnantolol, together with the known lignans (-)-dihydroguaiaretic acid ( 2), heliobuphthalmin ( 3), talaumidin ( 4), hinokinin ( 5), the labdane-type diterpene ozic acid ( 6), and the steroids stigmast-4-en-6beta-ol-3-one ( 7), beta-sitosterol ( 8) and stigmasterol ( 9) were isolated. Their structures were established on the basis of physical and spectroscopic methods, including 2 D NMR experiments (COSY, HMQC, HMBC and NOESY). The antimalarial activity of compounds 1 - 7 was evaluated against 3D7 and Dd2 P. falciparum strains. Despite the significant activity displayed by the crude CH (2)Cl (2) extract, the isolated compounds showed weaker antiplasmodial activity. The lowest IC (50) value was obtained for talaumidin ( 4) (IC (50) = 20.7 microg/mL against the Dd2-chloroquine resistant P. falciparum strain).

Iron‐mediated degradation kinetics of substituted dispiro‐1,2,4‐trioxolane antimalarials

The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalarial activity.

Synthesis and evaluation of sulfonylurea derivatives as novel antimalarials

We have synthesized a series of sulfonylureas and have tested their antimalarial activities, including inhibition of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, in vitro hemoglobin hydrolysis, hemozoin formation, and development of Plasmodium berghei in murine malaria. The most active antimalarial compound was ( E)-1-[4′-(3-(2,4-difluorophenyl)acryloyl)phenyl]-3-tosylurea ( 22) with an IC 50 of 1.2 μM against cultured P. falciparum parasites. Biological results suggest a fairly potent antimalarial activity for this derivative, but also imply that its activity may arise from an unknown mechanism. Indeed, these compounds may act against malaria parasites through multiple mechanisms.

Newbouldiaquinone A: A naphthoquinone–anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from Newbouldia laevis

The study of the chemical constituents of the roots of Newbouldia laevis (Bignoniaceae) has resulted in the isolation and characterization of a naphthoquinone–anthraquinone coupled pigment named newbouldiaquinone A ( 1) together with 14 known compounds: apigenin, chrysoeriol, newbouldiaquinone, lapachol, 2-methylanthraquinone, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, oleanolic acid, canthic acid, 2-(4-hydroxyphenyl)ethyl triacontanoate, newbouldiamide, 5,7-dihydroxydehydroiso-α-lapachone, β-sitosterol, and β-sitosterol glucopyranoside. The structure elucidation of the isolated compounds was established based on spectroscopic studies, notably of the 2D NMR spectra. The antimalarial activity of compound ( 1) against Plasmodium falciparum in vitro shows moderate chemo suppression of parasitic growth. Its antimicrobial activity against a wide range of microorganisms was 13- and 24-fold more active against Candida gabrata and Enterobacter aerogens than the reference antibiotics nystatin and gentamycin.

Indoloquinazoline alkaloids from Araliopsis tabouensis

Three new indoloquinazolidine-type alkaloids, 2-methoxy-8-13-dihydro-7H-indolo[pyrido[2,1-b]quinazolin-5-one (1) , 2-methoxy-13-methyl-8-13-dihydro-7H-indolo[2',3',3,4]pyrido[2,1-b]quinazolin-5-one (2) , and 2-methoxy-14-methyl-7,8,13,14-tetrahydroindolo[2',3',4]pyrido[2,l-b]quinazolin-5-one (3) were isolated from Araliopsis tabouensis, together with three known compounds. The structures of the new compounds were determined primarily from 1D- and 2D-NMR spectroscopy. The antimalarial activities of compounds 1-5 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC 50 values in antimalarial bioassay for compounds 2-5 varied from 1.8 to 4.7 μg/ml. Nig. J. Pharm. Res. 3(1) 2004: 42-48

Synthesis and Evaluation of New Antimalarial Phenylurenyl Chalcone Derivatives

Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.

Indoloquinazoline Alkaloids from Araliopsis tabouensis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Indoloquinazoline Alkaloids from Araliopsis tabouensis

AbstractThree new indoloquinazolidine‐type alkaloids, 8,13‐dihydro‐2‐methoxyindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one (1), 8,13‐dihydro‐2‐methoxy‐13‐methylindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one (2), and 5,8,13,14‐tetrahydro‐2‐methoxy‐14‐methyl‐5‐oxo‐7H‐indolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolim‐6‐iun chloride (3) were isolated from Araliopsis tabouensis, together with three known compounds. The structures of the new compounds were determined primarily from 1D‐ and 2D‐NMR analysis. The antimalarial activities of compounds 1–5 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC50 values in antimalarial bioassay for compounds 2–5 varied from 1.8 to 4.7 μg/ml.