RESUMO

Glycyrrhiza glabra L., Fabaceae, or licorice has shown potential therapeutic effects on fever, gastric ulcers, hepatic disorders, and malaria. This study aimed to assess the antimalarial activity of different fractions of root extract from twelve ecotypes from Iran. In this regard, mice were then randomly divided into 8 groups of 5 mice. Four hours after mice were infected by Plasmodium berghei, they received methanolic plant extract by intraperitoneal injection. The treatment was continued for 4 consecutive days (every 24 h), then on the fifth and seventh days, blood samples were taken from the tails of the mice and the parasitic percentages were calculated by microscopy technique. In comparison to control, every analyzed ecotype has a remarkable parasite inhibitory effect, whereas the source of the root also has a drastic difference in its antimalarial effects. The highest percentage of inhibition on days 5 and 7 was subjected to the extract of Semirom ecotype with suppression of 86.37 and 83%, respectively. On the other hand, 13.21 and 9.19% parasite growth inhibition was shown in the extracts of Shahrbabak and Haji Abad, respectively. The significant difference between these 12 ecotypes was shown with Mann-Whitney U pairwise comparison to variable parasitemia day 5 and parasitemia day 7 (p < 0.001). Supplementary Information: The online version contains supplementary material available at 10.1007/s43450-022-00353-8.

RESUMO

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

Assuntos

Antimaláricos , Antimaláricos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindóis/farmacologia , Plasmodium falciparum , Relação Estrutura-Atividade

RESUMO

Abstract Morinda lucida leaves are largely used by Congolese traditional healers for the treatment of uncomplicated malaria. The antimalarial activity of their ethanolic extract has been confirmed both in vitro and in vivo. However, the development of relevant formulations for potential clinical application is hampered since the active ingredients contained in this extract exhibit poor water solubility and low oral bioavailability. Hence, this work aims not only to develop self-nanoemulsifying drug delivery systems (SNEDDSs) for oral delivery of the ethanolic extract of Morinda lucida (ML) but also to evaluate its oral antimalarial activity alone and in combination with other Congolese ethanolic plant extracts (Alstonia congensis, Garcinia kola, Lantana camara, Morinda morindoides or Newbouldia laevis). Based on the solubility of these different extracts in various excipients, SNEDDS preconcentrates were prepared, and 200 mg/g of each plant extract were suspended in these formulations. The 4-day suppressive Peter's test revealed a significant parasite growth inhibiting effect for all the extract-based SNEDDS (from 55.0 to 82.4 %) at 200 mg/kg. These activities were higher than those of their corresponding ethanolic suspensions given orally at the same dose (p<0.05). The combination therapy of MLSNEDDS with other extract-based SNEDDS exhibited remarkable chemosuppression, ranging from 74.3 % to 95.8 % (for 100 + 100 mg/kg) and 86.7 % to 95.5 % (for 200 + 200 mg/kg/day). In regard to these findings, SNEDDS suspension may constitute a promising approach for oral delivery of ML alone or in combination with other antimalarial plants.

Assuntos

Plantas/metabolismo , Preparações Farmacêuticas/administração & dosagem , Extratos Vegetais/administração & dosagem , Morinda/efeitos adversos , Antimaláricos/análise , Técnicas In Vitro/métodos , Sistemas de Liberação de Medicamentos , Dosagem , Malária/tratamento farmacológico

RESUMO

Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy.

Assuntos

Antimaláricos/síntese química , Antimaláricos/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética , Animais , Antimaláricos/toxicidade , Domínio Catalítico , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Feminino , Hemólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/química , Macrófagos Peritoneais/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/enzimologia , Estrutura Quaternária de Proteína , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Relação Estrutura-Atividade , Triazóis/toxicidade

RESUMO

Seven phenolic compounds (ferulic acid, caffeic acid, 4-methoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3-hydroxy-4-methoxybenzaldehyde, 3-methoxy-4-hydroxypropiophenone and 1-O,2-O-digalloyl-6-O-trans-p-coumaroyl-ß-D-glucopyranoside), a flavanonol (7-O-methylaromadendrin), two lignans (pinoresinol and matairesinol) and six diterpenic acids/alcohol (19-acetoxy-13-hydroxyabda-8(17),14-diene, totarol, 7-oxodehydroabietic acid, dehydroabietic acid, communic acid and isopimaric acid) were isolated from the hydroalcoholic extract of a Brazilian Brown Propolis and characterized by NMR spectral data analysis. The volatile fraction of brown propolis was characterized by CG-MS, composed mainly of monoterpenes and sesquiterpenes, being the major α-pinene (18.4 %) and ß-pinene (10.3 %). This propolis chemical profile indicates that Pinus spp., Eucalyptus spp. and Araucaria angustifolia might be its primary plants source. The brown propolis displayed significant activity against Plasmodium falciparum D6 and W2 strains with IC50 of 5.3 and 9.7 µg/mL, respectively. The volatile fraction was also active with IC50 of 22.5 and 41.8 µg/mL, respectively. Among the compounds, 1-O,2-O-digalloyl-6-O-trans-p-coumaroyl-ß-D-glucopyranoside showed IC50 of 3.1 and 1.0 µg/mL against D6 and W2 strains, respectively, while communic acid showed an IC50 of 4.0 µg/mL against W2 strain. Cytotoxicity was determined on four tumor cell lines (SK-MEL, KB, BT-549, and SK-OV-3) and two normal renal cell lines (LLC-PK1 and VERO). Matairesinol, 7-O-methylaromadendrin, and isopimaric acid showed an IC50 range of 1.8-0.78 µg/mL, 7.3-100 µg/mL, and 17-18 µg/mL, respectively, against the tumor cell lines but they were not cytotoxic against normal cell lines. The crude extract of brown propolis displayed antimicrobial activity against C. neoformans, methicillin-resistant Staphylococcus aureus, and P. aeruginosa at 29.9 µg/mL, 178.9 µg/mL, and 160.7 µg/mL, respectively. The volatile fraction inhibited the growth of C. neoformans at 53.0 µg/mL. The compounds 3-hydroxy-4-methoxybenzaldehyde, 3-methoxy-4-hydroxypropiophenone and 7-oxodehydroabietic acid were active against C. neoformans, and caffeic and communic acids were active against methicillin-resistant Staphylococcus aureus.

Assuntos

Antibacterianos/farmacologia , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Compostos Fitoquímicos/farmacologia , Própole/química , Animais , Antibacterianos/biossíntese , Antibacterianos/química , Antimaláricos/química , Antimaláricos/metabolismo , Antineoplásicos Fitogênicos/biossíntese , Antineoplásicos Fitogênicos/química , Abelhas , Brasil , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Compostos Fitoquímicos/biossíntese , Compostos Fitoquímicos/química , Plasmodium falciparum/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos

RESUMO

Malaria is still a life-threatening public health issue, and the upsurge of resistant strains requires continuous generation of active molecules. In this work, 35 sulfonylhydrazone derivatives were synthesized and evaluated against Plasmodium falciparum chloroquine-sensitive (3D7) and resistant (W2) strains. The most promising compound, 5b, had an IC50 of 0.22 µM against W2 and was less cytotoxic and 26-fold more selective than chloroquine. The structure-activity relationship model, statistical analysis and molecular modeling studies suggested that antiplasmodial activity was related to hydrogen bond acceptor count, molecular weight and partition coefficient of octanol/water and displacement of frontier orbitals to the heteroaromatic ring beside the imine bond. This study demonstrates that the synthesized molecules with a simple scaffold allow the hit-to-lead process for new antimalarials to commence.

Assuntos

Antimaláricos/farmacologia , Hidrazonas/química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Hidrazonas/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Aprendizado de Máquina , Malária/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/crescimento & desenvolvimento , Teoria Quântica , Relação Estrutura-Atividade

RESUMO

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

Assuntos

Técnicas In Vitro/instrumentação , Cloroquina/administração & dosagem , Malária/tratamento farmacológico , Antimaláricos/análise , Plasmodium falciparum/metabolismo , Pesquisa/classificação , Resistência a Medicamentos/efeitos dos fármacos , Quimera/anormalidades , Concentração Inibidora 50 , Química Click

RESUMO

A set of 23 steroidal 1,2,4,5-tetraoxane analogues were studied using quantum-chemical method (B3LYP/6-31 G*) and multivariate analyses (PCA, HCA, KNN and SIMCA) in order to calculate the properties and correlate them with antimalarial activity (log RA) against Plasmodium falciparum clone D-6 from Sierra Leone. PCA results indicated 99.94% of the total variance and it was possible to divide the compounds into two classes: less and more active. Descriptors responsible for separating were: highest occupied molecular orbital energy (HOMO), bond length (O1-O2), Mulliken electronegativity (χ) and Bond information content (BIC0). We use HCA, KNN and SIMCA to explain relationships between molecular properties and biological activity of a training set and to predict antimalarial activity (log RA) of 13 compounds (#24-36) with unknown biological activity. We apply molecular docking simulations to identify intermolecular interactions with a selected biological target. The results obtained in multivariate analysis aided in the understanding of the activity of the new compound's design (#24-36). Thus, through chemometric analyses and docking molecular study, we propose theoretical synthetic routes for the most promising compounds 28, 30, 32 and 36 that can proceed to synthesis steps and in vitro and in vivo assays.

Assuntos

Antimaláricos/química , Desenho de Fármacos , Plasmodium falciparum/efeitos dos fármacos , Tetraoxanos/química , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade

RESUMO

Acridines are considered an important class of compounds due to their wide variety of biological activities. In this work, we synthesized four acridine derivatives (1-4) and evaluated their biological activity against the Plasmodium falciparum W2 line, as well as studied the interaction with ctDNA and HSA using spectroscopic techniques and molecular docking. The acridine derivative 2 (IC50 = 0.90 ±â€¯0.08 µM) was more effective against P. falciparum than primaquine (IC50 = 1.70 ±â€¯0.10 µM) and similar to amsacrine (IC50 = 0.80 ±â€¯0.10 µM). In the fluorescence and UV-vis assays, it was verified that the acridine derivatives interact with ctDNA and HSA leading to a non-fluorescent supramolecular complex formation. The non-covalent binding constants ranged from 2.09 to 7.76 × 103 M-1, indicating moderate interaction with ctDNA. Through experiments with KI, fluorescence contact energy transfer and competition assays were possible to characterize the main non-covalent binding mode of the acridines evaluated with ctDNA as intercalation. The binding constants obtained showed a high linear correlation with the IC50 values against the antimalarial activity, suggesting that DNA may be the main biological target of these molecules. Finally, HSA interaction studies were performed and all evaluated compounds bind to the site II of the protein. The less active compounds (1 and 3) presented the highest affinity to HSA, indicating that the interaction with carrier protein can affect the (bio)availability of these compounds to the biological target.

Assuntos

Acridinas/síntese química , Antimaláricos/farmacologia , DNA/metabolismo , Albumina Sérica Humana/metabolismo , Acridinas/farmacologia , Sítios de Ligação , Humanos , Substâncias Intercalantes/farmacologia , Ligação Proteica , Relação Estrutura-Atividade

RESUMO

This paper provides a comparative account of the essential oil chemical composition and biological activities of five Brazilian species of Baccharis (Asteraceae), namely B. microdonta, B. pauciflosculosa, B. punctulata, B. reticularioides, and B. sphenophylla. The chemical compositions of three species (B. pauciflosculosa, B. reticularioides, and B. sphenophylla) are reported for the first time. Analyses by GC/MS showed notable differences in the essential oil compositions of the five species. α-Pinene was observed in the highest concentration (24.50%) in B. reticularioides. Other major compounds included α-bisabolol (23.63%) in B. punctulata, spathulenol (24.74%) and kongol (22.22%) in B. microdonta, ß-pinene (18.33%) and limonene (18.77%) in B. pauciflosculosa, and ß-pinene (15.24%), limonene (14.33%), and spathulenol (13.15%) in B. sphenophylla. In vitro analyses for antimalarial, antitrypanosomal, and insecticidal activities were conducted for all of the species. B. microdonta and B. reticularioides showed good antitrypanosomal activities; B. sphenophylla showed insecticidal activities in fumigation bioassay against bed bugs; and B. pauciflosculosa, B. reticularioides, and B. sphenophylla exhibited moderate antimalarial activities. B. microdonta and B. punctulata showed cytotoxicity. The leaves and stems of all five species showed glandular trichomes and ducts as secretory structures. DNA barcoding successfully determined the main DNA sequences of the investigated species and enabled authenticating them.

Assuntos

Antimaláricos/química , Baccharis/classificação , Inseticidas/química , Óleos Voláteis/química , Tripanossomicidas/química , Animais , Antimaláricos/farmacologia , Baccharis/química , Baccharis/genética , Percevejos-de-Cama/efeitos dos fármacos , Monoterpenos Bicíclicos , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Código de Barras de DNA Taxonômico , Cromatografia Gasosa-Espectrometria de Massas , Inseticidas/farmacologia , Limoneno/química , Limoneno/farmacologia , Sesquiterpenos Monocíclicos , Monoterpenos/química , Monoterpenos/farmacologia , Óleos Voláteis/farmacologia , Folhas de Planta/química , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Caules de Planta/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Tripanossomicidas/farmacologia

RESUMO

Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents. By a simple three-step procedure, five dehydroxy isoquines were prepared and subsequently examined on the inhibition of haemozoin formation, the main target of the 4-aminoquinolines. Four derivatives displayed significant inhibitory activities at low IC50 values from 1.66 to 1.86 µM comparable to CQ. On the basis of the results, these four compounds were subsequently tested against Plasmodium berghei ANKA model in mice, showing to be as active as CQ with significant curative responses and parasitemia suppression in mice infected. On the other hand, these four compounds showed an acceptable non specific cytotoxicity on murine peritoneal macrophague and human erythrocyte cells. Thus, the presented data indicate that the dehydroxy isoquines 4b, 4c and 4e constitute promising cost-effective leads for the development of new antiplasmodial targeted at blood-stage malaria parasites.

Assuntos

Antimaláricos/química , Plasmodium berghei/efeitos dos fármacos , Aminoquinolinas , Amodiaquina/análogos & derivados , Animais , Antimaláricos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Parasitemia/tratamento farmacológico

RESUMO

A new series of N-substituted 2-pyrazolines 9a-f, 10a-f, 11a-f, 12a-f and 13a-f were obtained from the cyclocondensation reaction of [(7-chloroquinolin-4-yl)amino]chalcones 8a-f with hydrazine hydrate and its derivatives. Fourteen of the synthesized compounds including the starting chalcones were selected by US National Cancer Institute (NCI) for testing their anticancer activity against 60 different human cancer cell lines, with the most important GI50 values ranging from 0.28 to 11.7 µM (0.13-6.05 µg/mL) and LC50 values ranging from 2.6 to > 100 µM (1.2 to > 51.7 µg/mL), for chalcones 8a,d and pyrazolines 10c,d. All compounds were assessed for antibacterial activity against wild type and multidrug resistant gram negative and gram positive bacteria, with MIC values ranging from 31.25 to 500 µg/mL. Additionally, the novel compounds were tested for antifungal and antiparasitic properties. Although these compounds showed mild activity against Candida albicans, chalcones 8a and 8e showed high activity against Cryptococcus neoformans with MIC50 = 7.8 µg/mL. For anti-Plasmodium falciparum activity the 2-pyrazoline 11b was the most active with EC50 = 5.54 µg/mL. Regarding the activity against Trypanosoma cruzi, compound 10a was highly active with EC50 = 0.70 µg/mL. Chalcone 8a had good activity against Leishmania panamensis amastigotes with EC50 = 0.79 µg/mL.

Assuntos

Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Quinolinas/química , Relação Estrutura-Atividade

RESUMO

BACKGROUND: In view of the wide variety of the flora of the Amazon region, many plants have been studied in the search for new antimalarial agents. Copaifera reticulata is a tree distributed throughout the Amazon region which contains an oleoresin rich in sesquiterpenes and diterpenes with ß-caryophyllene as the major compound. The oleoresin has demonstrated antiparasitic activity against Leishmania amazonensis. Because of this previously reported activity, this oleoresin would be expected to also have antimalarial activity. PURPOSE: In this study we evaluated the in vitro and in vivo antimalarial potential of C. reticulata oleoresin. METHODS: In vitro assays were done using P. falciparum W2 and 3D7 strains and the human fibroblast cell line 26VA Wi-4. For in vivo analysis, BALB/c mice were infected with approximately 106 erythrocytes parasitized by P. berghei and their parasitemia levels were observed over 7 days of treatment with C. reticulata; hematological and biochemical parameters were analyzed at the end of experiment. RESULTS: The oleoresin of C. reticulata containing the sesquiterpenes ß-caryophyllene (41.7%) and ß-bisabolene (18.6%) was active against the P. falciparum W2 and 3D7 strains (IC50 = 1.66 and 2.54 µg/ml, respectively) and showed low cytotoxicity against the 26VA Wi-4 cell line (IC50 > 100 µg/ml). The C. reticulata oleoresin reduced the parasitemia levels of infected animals and doses of 200 and 100 mg/kg/day reached a rate of parasitemia elimination resembling that obtained with artemisinin 100 mg/kg/day. In addition, treatment with oleoresin improved the hypoglycemic, hematologic, hepatic and renal parameters of the infected animals. CONCLUSION: The oleoresin of C. reticulata has antimalarial properties and future investigations are necessary to elucidate its mechanism of action.

Assuntos

Antimaláricos/uso terapêutico , Fabaceae/química , Malária/tratamento farmacológico , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Brasil , Linhagem Celular , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fitoterapia , Floresta Úmida

RESUMO

ABSTRACT The receptor protein PfATP6 has been identified as the common target of artemisinin and curcumin. The work was initiated to assess the antimalarial activity of six curcumin derivatives based on their binding affinities and correlating the in silico docking outcome with in vitro antimalarial screening results. A ligand library of thirty two Knoevenagel condensates of curcumin were designed and docked against PfATP6 protein and six compounds with the best binding scores were synthesized and screened for their antimalarial activity against the sensitive 3D7 strain of Plasmodium falciparum. ADME/Tox, pharmacokinetic and pharmacodynamic profiles of the designed compounds were analyzed and reported. 4-FB was found to have similar binding energy to the standard artemisinin (-6.75 and -6.73 respectively) while 4-MB, 3-HB, 2-HB, B, 4-NB displayed better binding energy than curcumin (-5.95, -5.89, -5.68, -5.35, -5.29 and -5.25 respectively). At a dose of 50 µg/mL all the six compounds showed 100% schizont inhibition while at 5µg/ml, five showed more than 75% inhibition and better results than curcumin. 4-FB showed the best activity with 97.8% schizonticidal activity. The in vitro results superimpose the results obtained from the in silico study thereby encouraging development of promising curcumin leads in the battle against malaria.

Assuntos

Curcumina/análise , Malária/prevenção & controle , Antimaláricos/análise , Simulação por Computador/estatística & dados numéricos

RESUMO

BACKGROUND: Ampelozizyphus amazonicus Ducke, a plant that is widely used by the population of the Amazonian region to prevent and treat malaria, was investigated in this work, which describes, for the first time, the antiplasmodial activity of its extracts and associates this activity with its isolated constituents. METHODS: Different extracts with solvents of increasing polarity (hexane, chloroform, ethanol, and water) were obtained of the root bark. This procedure resulted in extracts that were characterized for their constituents. The cytotoxicity and activity of the extracts against Plasmodium berghei (schizontocidal activity, liver stage) and Plasmodium falciparum (3D7 and Dd2 strains, erythrocyte stage) were assessed in vitro. RESULTS: Of the four extracts assayed against P. berghei, the chloroform extract showed the greatest activity, with an inhibitory concentration 50% (IC50) value of 30.1 µg/mL, followed by the aqueous extract (IC50 = 39.9 µg/mL). The chloroform extract exhibited the highest antiplasmodial activity in the erythrocyte stage of P. falciparum, with an IC50 value lower than 15 µg/mL. Fractionation of this more active extract led to the isolation and elucidation of pentacyclic triterpenes, lupeol, betulin and betulinic acid, which showed antiplasmodial activities with IC50 values ranging from 5.6 to 80.30 µM. The most active of these, betulinic acid, was further quantified in the extracts by high-performance liquid chromatography-photodiode array detector analyzes. The higher amount was found in the chloroform extract, which was the most active one against P. falciparum. CONCLUSION: The results obtained in this work may partly explain the popular intake of A. amazonicusas an antimalarial remedy in the Amazon region.

RESUMO

Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that of chloroquine.

Assuntos

Aminoquinolinas/química , Antimaláricos/síntese química , Hemeproteínas/antagonistas & inibidores , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cloroquina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hemeproteínas/metabolismo , Malária/tratamento farmacológico , Malária/patologia , Malária/veterinária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/efeitos dos fármacos , Relação Estrutura-Atividade

RESUMO

Based on the previously reported in vitro antiplasmodial activity of several xanthones from Garcinia mangostana, two xanthones, α-mangostin and a new compound, δ-mangostin, were isolated from mangosteen husk, and the in vitro antiplasmodial and cytotoxic effects were determined. α-Mangostin was more active against the resistant Plasmodium falciparum chloroquine-resistant (FCR3) strain (IC50 = 0.2 ± 0.01 µM) than δ-mangostin (IC50 = 121.2 ± 1.0 µM). Furthermore, the therapeutic response according to the administration route was evaluated in a Plasmodium berghei malarial murine model. The greatest therapeutic response was obtained with intraperitoneal administration; these xanthones reduced parasitemia by approximately 80% with a daily dose of 100 mg/kg administered twice a day for 7 days of treatment. Neither compound was effective by oral administration. Noticeable toxicological effects were not observed. In addition to the antimalarial effect of these xanthones isolated from G. mangostana husk, the availability of larger amounts of husk raw material to purify the bioactive xanthones is advantageous, permitting additional preclinical assays or chemical transformations to enhance the biological activity of these substances.

Assuntos

Antimaláricos/farmacologia , Garcinia mangostana/química , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Xantonas/farmacologia , Animais , Modelos Animais de Doenças , Eritrócitos/efeitos dos fármacos , Hemólise , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico , Células U937

RESUMO

Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 µM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 µM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained.

Assuntos

Alcinos/química , Antimaláricos/síntese química , Azidas/química , Triazóis/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Química Click , Reação de Cicloadição , Resistência a Medicamentos , Células Hep G2 , Humanos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Triazóis/toxicidade

RESUMO

Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanácea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of Costa Rica. Rev. Biol. Trop. 60 (2): 881-891. Epub 2012 June 01.

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El tratamiento con las drogas antimaláricas de uso común han inducido resistencia por parte del parásito, lo que obliga a buscar en las plantas de los bosques, componentes naturales con actividad en contra de esta enfermedad. Por lo tanto, decidimos buscar dichos componentes en plantas de una Reserva Forestal de Costa Rica. Extractos tanto frescos como secos de raíz, corteza, hojas, flores y frutos, de 25 plantas de la Reserva Biológica Alberto Manuel Brenes (REBAMB), fueron estudiados in vitro en busca de sustancias con actividad antimalárica. Las plantas estudiadas fueron: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) y Myriocarpa longipes (Urticaceae). Los extractos frescos y secos de las diferentes partes de las plantas fueron estudiadas y se determinó la IC50, el cual osciló entre 1-71.9mg/mL; los extractos frescos mostraron mayor actividad antimalárica. Las plantas que presentaron mayor actividad son muy comunes en Centroamérica y algunos géneros similares, aunque no las mismas especies, han sido encontrados positivos en América del Sur; por esta razón consideramos importante estos resultados como información y materia de discusión en este tema. Además este es el primer estudio sistemático de esta naturaleza realizado en un área boscosa circunscrita y protegida de Costa Rica.

Assuntos

Animais , Feminino , Masculino , Camundongos , Magnoliopsida/química , Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Magnoliopsida/classificação , Testes de Sensibilidade Parasitária

RESUMO

Introducción: Bixa orellana L. es una especie usada en la medicina tradicional de países de diversos continentes. Entre las propiedades medicinales que se le atribuyen se incluye su acción antimalárica. Objetivo: evaluar la actividad antimalárica in vitro e in vivo de un extracto de B. orellana cultivada en Cuba. Métodos: la actividad antimalárica del extracto hidroalcohólico de semillas de Bija se evaluó in vitro frente a la cepa Ghana de Plasmodium falciparum e in vivo utilizando un modelo de malaria de roedores, ratones Balb/c infectados con la cepa ANKA de Plasmodium berghei. La citotoxicidad se determinó frente a fibroblastos humanos de la línea MRC-5. Además, se caracterizó preliminarmente la composición fitoquímica del extracto estudiado. Resultados: el extracto exhibió un valor de concentración inhibitoria media de 11,6 µg/mL, concentración citotóxica media de 60,2 µg/mL e índice de selectividad de 5,1. La administración subcutánea del extracto a la dosis de 500 mg/kg causó una reducción de 50,3 ± 5,8 por ciento de la parasitemia en los animales infectados en comparación con la observada en los controles. El tamizaje fitoquímico fue consistente con la detección de triterpenoides y(o) esteroides, alcaloides, compuestos lactónicos, compuestos fenólicos, taninos y flavonoides. Conclusiones: el extracto hidroalcohólico de semillas de B. orellana cultivada en Cuba mostró actividad antimalárica moderada tanto in vitro como in vivo. El fraccionamiento guiado por bioensayos permitiría identificar las moléculas responsables de la actividad demostrada por este extracto y reevaluar sus potencialidades.

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Introduction: Bixa orellana L. is one species used in traditional herb medicine in several continents. Among the medicinal properties attributed to this plant, the antimalarial action has been included. Objective: to evaluate in vitro and in vivo antimalarial activity of extract from B. orellana grown in Cuba. Methods: the antimalarial activity of the hydroalcoholic extract fro Bija seeds was evaluated in vitro against Plasmodium falciparum Ghana strain and in vivo using a model of murine malaria, that is, Balb/c mice infected with Plasmodium berghei ANKA strain. Citotoxicity was determined against MRC-5 human fibroblasts. Additionally, phytochemical composition of the studied extract was preliminarily informed. Results: the extract exhibited IC50 (Medium Inhibitory Concentration) of 11.6 µg/mL, CC50 (Medium Citotoxic Concentration) of 60.2 µg/mL and SI (Selectivity Index) of 5.1. Subcutaneous administration of the extract at a 500 mg/kg dose caused parasitemia reduction of 50.3 ± 5.8 percent on infected animals compared with that of the controls. Phytochemical screening was consistent with detection of triterpenoids and/or steroids, alkaloids, lactonic compounds, phenols, tanins and flavonoids. Conclusions: the hydroalcoholic extract from B. orellana seeds grown in Cuba showed in vitro and in vivo moderate antimalarial activity. Bioassay-guided fractioning will allow identifying the molecules responsible for the exhibited extract activity and re-evaluating the potentialities of this extract.

Assuntos

Antimaláricos , Bixaceae , Extratos Vegetais , Etanol , Água