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1.
J Ethnopharmacol ; 235: 111-121, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30738118

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Annona muricata (Annonaceae) is a commonly used medicinal plants in Cameroonian traditional medicines to treat various diseases including malaria. Previous studies have shown that extracts from this plant have antiplasmodial activity. AIM OF THE STUDY: This study aimed to explore the endophyic fungi associated with some parts of this plant for their ability to produce antiplasmodial metabolites. MATERIALS AND METHODS: One hundred and fifty-two endophytic fungi isolated from twelve different organs of A. muricata were cultured and the ethyl acetate extracts of conditioned media screened for antiplasmodial activity using the 96-well microtiter plate format SYBR green florescence assay against Chloroquine-sensitive Pf3D7 and Chloroquine-resistant PfINDO/PfDd2 strains of Plasmodium falciparum. RESULTS: Twenty-seven (17.76%) of fungi tested were found to completely inhibit the growth of Plasmodium parasites at 10 µg/mL. The 5.8S rDNA sequencing data revealed the strongly active (IC50 < 2 µg/mL against at least 2 P. falciparum strains) isolates to be Trichoderma afroharzianum AMrb7, Penicillium citrinum AMrb11, Neocosmospora rubicola AMb22, Penicillium tropicum AMb3, Penicillium citrinum AMrb23, Aspergillus versicolor AMb7, and Fusarium sp AMst1. Of these, the extracts from Penicillium citrinum AMrb11 (IC50 0.84-0.93 µg/mL) and Neocosmospora rubicola AMb22 (IC50 0.39-1.92 µg/mL) showed the highest promise against all three plasmodial strains with selectivity indices ranging from 34.71 to 180.97. Dynamic head space GC-MS analysis of ethyl acetate extracts of promising fungi revealed broad-spectrum antimicrobial compounds such as Penicidin, Aromadendrene, Ethyl p-methoxycinnamate, 2-Coumaranone and 2-Methyl resorcinol. CONCLUSION: These results have opened new avenues for discovery of novel antimalarial lead compounds from endophytic fungi associated with Annona muricata - a medicinally important plant.


Assuntos
Annona/microbiologia , Antimaláricos/farmacologia , Fungos/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/administração & dosagem , Antimaláricos/isolamento & purificação , Camarões , Cloroquina/farmacologia , Descoberta de Drogas/métodos , Endófitos/isolamento & purificação , Cromatografia Gasosa-Espectrometria de Massas/métodos , Concentração Inibidora 50 , Medicina Tradicional Africana/métodos
2.
Medicines (Basel) ; 5(4)2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30380685

RESUMO

Background: In the midst of transient victories by way of insecticides against mosquitoes or drugs against malaria, the most serious form of malaria, caused by Plasmodium falciparum, continues to be a major public health problem. The emergence of drug-resistant malaria parasites facilitated by fake medications or the use of single drugs has worsened the situation, thereby emphasizing the need for a continued search for potent, safe, and affordable new antimalarial treatments. In line with this need, we have investigated the antiplasmodial activity of 66 different extracts prepared from 10 different medicinal plants that are native to Cameroon. Methods: Extracts were evaluated for their capacity to inhibit the growth of the chloroquine-sensitive (Pf3D7) and resistant (PfINDO) strains of P. falciparum using the SYBR green fluorescence method. The cytotoxicity of promising extracts against human embryonic kidney cells (HEK293T) mammalian cells was assessed by MTT assay. Results: The antiplasmodial activity (50% inhibitory concentration, IC50) of plant extracts ranged from 1.90 to >100 µg/mL against the two strains. Six extracts exhibited good activity against both Pf3D7 and PfINDO strains, including cold water, water decoction, and ethyl acetate extracts of leaves of Drypetes principum (Müll.Arg.) Hutch. (IC503D7/INDO = 4.91/6.64 µg/mL, 5.49/5.98 µg/mL, and 6.49/7.10 µg/mL respectively), water decoction extract of leaves of Terminalia catappa L. (IC503D7/INDO = 6.41/8.10 µg/mL), and water decoction extracts of leaves and bark of Terminalia mantaly H.Perrier (IC503D7/INDO = 2.49/1.90 µg/mL and 3.70/2.80 µg/mL respectively). These promising extracts showed no cytotoxicity against HEK293T up to 200 µg/mL, giving selectivity indices (SIs) in the range of >31.20⁻80.32. Conclusions: While providing credence to the use of D. principum, T. catappa, and T. mantaly in the traditional treatment of malaria, the results achieved set the stage for isolation and identification of active principles and ancillary molecules that may provide us with new drugs or drug combinations to fight against drug-resistant malaria.

3.
Med Chem ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30324888

RESUMO

BACKGROUND: Malaria remains a common life-threatening infectious disease across the globe due to the development of resistance by Plasmodium parasite against most antimalarial drugs. The situation demands new and effective drug candidates against Plasmodium. OBJECTIVES: The objective of this study is to design, synthesize and test novel quinoline based molecules against the malaria parasite. METHOD: C-2 and C-8 modified quinoline analogs obtained via C-H bond functionalization approach were synthesized and evaluated for inhibition of growth of P. falciparum grown in human red blood cells using SYBR Green microtiter plate based screening. Computational molecular docking studies were carried out with top fourteen molecules using Autodoc software. RESULT: The biological evaluation results revealed good activity of quinoline-8-acrylate 3f (IC50 14.2 µM), 2-quinoline-α-hydroxypropionates 4b (IC50 6.5 µM), 4j (IC50 5.5 µM) and 4g (IC50 9.5 µM), and against chloroquine sensitive pf 3D7 strain. Top fourteen molecules were screened also against chloroquine resistant Pf INDO strain and the observed resistant indices were found to lie between 1 and 7.58. Computational molecular docking studies indicated a unique mode of binding of these quinolines to Falcipain 2 and heme moiety, indicating these to be probable targets of their antiplasmodial action. CONCLUSION: An important finding of our work is the fact that unlike chloroquine which shows a resistance Index of 15, the resistance indices for the most promising molecules studied by us were about one indicating equal potency against drug sensitive and resistant strains of malaria parasite.

4.
ChemMedChem ; 13(23): 2581-2598, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30358112

RESUMO

A series of indolo[3,2-b]quinoline-C11-carboxamides were synthesized by incorporation of aminoalkyl side chains into the core of indolo[3,2-b]quinoline-C11-carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum led to the identification of a 2-(piperidin-1-yl)ethanamine-linked analogue {2-bromo-N-[2-(piperidin-1-yl)ethyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (3 g)} (IC50 =1.3 µm) as the most promising compound exhibiting good selectivity indices against mammalian cell lines. The kill kinetics on erythrocytic-stage parasites revealed that 3 g caused complete killing of only the trophozoite-stage parasites. Mechanistic studies showed that 3 g targets the food vacuole of the parasite and inhibits hemoglobin uptake, ß-hematin formation, and the basic endocytic processes of the parasite. Analogue 3 g was found to be orally bioavailable, and its curative antimalarial studies at 50 mg per kg p.o. against a Plasmodium berghei (ANKA)-infected mouse model revealed that mice treated with 3 g showed 27-35 % suppression of parasitemia with an increase in life span relative to untreated, control mice. Thus, the present work demonstrated a proof of concept for the oral efficacy of indolo[3,2-b]quinoline-C11-carboxamides.

5.
J Org Chem ; 83(20): 12702-12710, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30211555

RESUMO

Here, a facile and efficient protocol for the synthesis of 3-hydroxyquinolin-8-yl propanoates via Rh(III)-catalyzed C(8)-H activation of 2-substituted quinolines has been developed. The reaction proceeds via C(8)-H activation, functionalization with acrylates, followed by intramolecular migration of the oxygen atom from quinoline N-oxides to the acrylate moiety. In this approach, N-oxide plays a dual role of a traceless directing group as well as a source of an oxygen atom for hydroxylation. This catalytic method involves simultaneous formation of new C-C and C-O bonds and is applicable only for C2-substituted quinolines. A catalytically competent five-membered rhodacycle has been characterized, thus revealing a key intermediate in the catalytic cycle. In silico docking studies against Falcipan-2 have revealed that 3a, 3b, 3g, and 3m have better scores. In vitro evaluation of selected compounds against CQ-sensitive pf3D7 and CQ-resistant pfINDO strains provided evidence that 3d (IC50 13.3 µM) and 3g (IC50 9.5 µM) had good promise against Plasmodium falciparum in the in vitro culture. Compound 3g was found to be the most potent on the basis of both in vitro antiplasmodial activity [IC50 9.5 µM ( Pf3D7) and 11.9 µM ( PfINDO), resistance index 1.25] and in silico studies.

6.
J Org Chem ; 83(19): 11552-11570, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30160960

RESUMO

A convenient and eco-friendly synthesis of various fused N-heterocyclic compounds through catalyst and additive-free 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes in excellent yields and diastereoselectivities is reported. The thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imides and olefins provided cis-isomers at low temperature and trans-isomers at high temperature. A reaction between quinolinium imides with substituted maleimides gave four-ring-fused N-heterocyclic compounds in high yields as a single diastereomer. The aryne precursors also provided four-ring-fused N,N'-heterocyclic compounds in high yields. The in vitro antiplasmodial activity of selected molecules revealed that this class of molecules possesses potential for ongoing studies against malaria.

7.
Malar J ; 17(1): 304, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126436

RESUMO

BACKGROUND: Plasmodium enolase is a target for the growth neutralizing antibodies. Interestingly, the three invasive stages i.e. sporozoites, merozoites, and ookinetes express this protein on their cell surface. Polyclonal anti-Plasmodium falciparum enolase (Pfeno) antibodies disrupt traversal of ookinete through mosquito mid-gut wall as well as have inhibitory effect on parasite growth at erythrocytic stage. In a recent study, it was observed that immunization with a unique epitope of parasite enolase (EWGWS) could confer partial protection against mouse malaria. Further validation is needed for the protective potential of this unique epitope in otherwise highly conserved enolase. METHODS: In order to investigate the efficacy of growth inhibitory potential of the epitope of P falciparum enolase, a monoclonal antibody specific to EWGWS is generated. In vitro parasite growth inhibition assays and passive immunization of Plasmodium yoelii (or Plasmodium berghei) infected mice were used to assess the parasite growth neutralizing activity of the antibody. RESULTS: Screening a panel of monoclonal antibodies raised against recombinant Pfeno that were specific to EWGWS resulted in isolation of H12E1. This antibody recognized only EWGWS epitope containing enolases. H12E1 strongly inhibited parasite growth in culture. This inhibition was strain transcending. Passive infusion of this antibody in P. yoelii or P. berghei infected mice showed significant reduction in parasitemia as compared to controls (p < 0.001). Surface Plasmon Resonance measurements indicated high affinity binding of H12E1 to P. falciparum enolase (KD ~ 7.6 × 10-9M). CONCLUSIONS: A monoclonal antibody directed against EWGWS epitope of Pfeno was shown to inhibit the growth of blood stage malarial parasites. This inhibition was species/strain transcending and is likely to arise due to blockade of enolase on the surface of merozoites, functionally implicating Pfeno in invasion related events. Presence of enolase on the cell surface of merozoites and ookinetes could potentially result in inhibition of host cell invasions at erythrocytic and transmission stages in the parasite life cycle. It is suggested that antibodies against EWGWS epitope have the potential to confer dual stage, species and strain transcending protection against malaria.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antiprotozoários/imunologia , Malária/prevenção & controle , Fosfopiruvato Hidratase/imunologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antiprotozoários/administração & dosagem , Modelos Animais de Doenças , Imunização Passiva , Malária/imunologia , Masculino , Camundongos , Plasmodium berghei/imunologia , Plasmodium yoelii/imunologia
8.
Eur J Med Chem ; 155: 623-638, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29929118

RESUMO

The inherent affinity of natural compounds for biological receptors has been comprehensively exploited with great success for the development of many drugs, including antimalarials. Here the natural flavoring compound vanillin has been used as an economical precursor for the synthesis of a series of novel bischalcones whose in vitro antiplasmodial activities have been evaluated against erythrocytic stages of Plasmodium falciparum. Bischalcones 9, 11 and 13 showed promising antiplasmodial activity {Chloroquine (CQ) sensitive Pf3D7 IC50 (µM): 2.0, 1.5 and 2.5 respectively}but only 13 displayed potent activities also against CQ resistant PfDd2 and PfIndo strains exhibiting resistance indices of 1.4 and 1.5 respectively. IC90 (8 µM) of 13 showed killing activity against ring, trophozoite and schizont stages. Further, 13 initiated the cascade of reactions that culminates in programmed cell death of parasites including translocation of phosphatidylserine from inner to outer membrane leaflet, loss of mitochondrial membrane potential, activation of caspase like enzyme, DNA fragmentation and chromatin condensation. The combinations of 13 + Artemisinin (ART) exhibited strong synergy (ΣFIC50:0.46 to 0.58) while 13 + CQ exhibited mild synergy (ΣFIC50: 0.7 to 0.98) to mild antagonism (ΣFIC50: 1.08 to 1.23) against PfIndo. In contrast, both combinations showed marked antagonism against Pf3D7(ΣFIC50: 1.33 to 3.34). These features of apoptosis and strong synergy with Artemisinin suggest that bischalcones possess promising antimalarial drug-like properties and may also act as a good partner drugs for artemisinin based combination therapies (ACTs) against Chloroquine resistant P. falciparum.


Assuntos
Antimaláricos/farmacologia , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Benzaldeídos/farmacologia , Chalconas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Artemisininas/química , Benzaldeídos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Cloroquina/química , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Células HeLa , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
9.
J Fungi (Basel) ; 4(2)2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895768

RESUMO

There is continuing need for new and improved drugs to tackle malaria, which remains a major public health problem, especially in tropical and subtropical regions of the world. Natural products represent credible sources of new antiplasmodial agents for antimalarial drug development. Endophytes that widely colonize healthy tissues of plants have been shown to synthesize a great variety of secondary metabolites that might possess antiplasmodial benefits. The present study was carried out to evaluate the antiplasmodial potential of extracts from endophytic fungi isolated from Symphonia globulifera against a chloroquine-resistant strain of Plasmodium falciparum (PfINDO). Sixty-one fungal isolates with infection frequency of 67.77% were obtained from the bark of S. globulifera. Twelve selected isolates were classified into six different genera including Fusarium, Paecilomyces, Penicillium, Aspergillus, Mucor, and Bipolaris. Extracts from the 12 isolates were tested against PfINDO, and nine showed good activity (IC50 < 10 μg·mL−1) with three fungi including Paecilomyces lilacinus (IC50 = 0.44 μg·mL−1), Penicillium janthinellum (IC50 = 0.2 μg·mL−1), and Paecilomyces sp. (IC50 = 0.55 μg·mL−1) showing the highest promise. These three isolates were found to be less cytotoxic against the HEK293T cell line with selectivity indices ranging from 24.52 to 70.56. Results from this study indicate that endophytic fungi from Symphonia globulifera are promising sources of hit compounds that might be further investigated as novel drugs against malaria. The chemical investigation of active extracts is ongoing.

10.
Parasitol Res ; 117(8): 2473-2485, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29797084

RESUMO

Plasmodial resistance to artemisinin-based combination therapies emphasizes the need for new drug development to control malaria. This paper describes the antiplasmodial activity of metabolites produced by endophytic fungi of three Cameroonian plants. Ethyl acetate extracts of fungi cultivated on three different media were tested against Plasmodium falciparum chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains using the SYBR green florescence assay. Selected endophytes were further grown in potato dextrose broth supplemented with small organic elicitors and their extracts tested for activity. The effect of elicitors on de novo metabolite synthesis was assessed by reverse-phase HPLC. Activity screening of 81 extracts indicated that Aspergillus niger 58 (IC50 2.25-6.69 µg/mL, Pf3D7), Fusarium sp. N240 (IC50 1.62-4.38 µg/mL, Pf3D7), Phomopsis sp. N114 (IC50 0.34-7.26 µg/mL, Pf3D7), and Xylaria sp. N120 (IC50 2.69-6.77 µg/mL, Pf3D7) produced potent extracts when grown in all three media. Further culture of these endophytes in potato dextrose broth supplemented with each of the eight small organic elicitors and subsequent extracts screening indicated the extract of Phomopsis sp. N114 grown with 1% 1-butanol to be highly selective and extremely potent (IC50 0.20-0.33 µg/mL; SI > 666). RPHPLC profiles of extracts of Phomopsis sp. N114 grown with or without 1-butanol showed some peaks of enhanced intensities in the former without any qualitative change in the chromatograms. This study showed the ability of selected endophytes to produce potent and selective antiplasmodial metabolites in varied culture conditions. It also showed how the production of desired metabolites can be enhanced by use of small molecular weight elicitors.


Assuntos
Antimaláricos/farmacologia , Aspergillus niger/metabolismo , Cananga/microbiologia , Extratos Celulares/farmacologia , Fusarium/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Terminalia/microbiologia , Xylariales/metabolismo , Antimaláricos/metabolismo , Artemisininas/farmacologia , Aspergillus niger/isolamento & purificação , Agentes de Controle Biológico/metabolismo , Agentes de Controle Biológico/farmacologia , Camarões , Cloroquina/farmacologia , Meios de Cultivo Condicionados , Fusarium/isolamento & purificação , Malária/tratamento farmacológico , Testes de Sensibilidade Parasitária , Extratos Vegetais/farmacologia , Plantas Medicinais/microbiologia , Xylariales/isolamento & purificação
11.
Malar J ; 17(1): 142, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615047

RESUMO

BACKGROUND: The emergence and spread of malaria parasites resistant to artemisinin-based combination therapy stresses the need for novel drugs against malaria. Investigating plants used in traditional medicine to treat malaria remains a credible option for new anti-malarial drug development. This study was aimed at investigating the antiplasmodial activity and selectivity of extracts and fractions from Terminalia mantaly and Terminalia superba (Combretaceae) that are used in Cameroon to treat malaria. METHODS: Twelve methanolic (m) and water (w) extracts obtained by maceration of powdered dried leaves (l), stem bark (sb) and root (r) of Terminalia mantaly (Tm) and Terminalia superba (Ts) and 12 derived fractions of hexane, chloroform, ethyl acetate and 4 final residues of selected extracts were assessed for antiplasmodial potential in vitro against the chloroquine-resistant PfINDO and the chloroquine-sensitive Pf3D7 strains of Plasmodium falciparum using the SYBR green I-based fluorescence assay. The cytotoxicity of potent extracts and fractions was evaluated in vitro using the MTT assay on HEK239T cell line. RESULTS: The antiplasmodial IC50 of extracts from both plants ranged from 0.26 to > 25 µg/mL. Apart from the extracts Tmrm and Tsrw that exerted moderate antiplasmodial activities (IC50: 5-20 µg/mL) and Tmrw that was found to be non-active at the tested concentrations (IC50 > 25 µg/mL), all other tested crude extracts exhibited potent activities with IC50 < 5 µg/mL. The aqueous extracts from the stem bark of Terminalia mantaly (Tmsbw) and the leaf of Terminalia superba (Tslw) displayed the highest antiplasmodial activities (IC50: 0.26-1.26 µg/mL) and selectivity (SI > 158) on both resistant PfINDO and sensitive Pf3D7 strains. Four fractions upon further extraction with chloroform and ethyl acetate (TmlwChl, TmsbwChl, TmsbwEA, TsrmEA) afforded from three selected crude extracts (Tmlw, Tmsbw, Tsrm) exhibited highly potent activities against both P. falciparum strains (IC50 < 2 µg/mL) and high selectivity (SI > 109). CONCLUSIONS: The results achieved in this work validate the reported traditional use of Terminalia mantaly and Terminalia superba to treat malaria. Moreover, the highly potent and selective fractions warrant further investigation to characterize the active antiplasmodial principles and progress them to rodent malaria models studies if activity and selectivity are evidenced.

12.
Parasitol Res ; 117(5): 1473-1484, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29550997

RESUMO

The plant kingdom continues to hold great promise for the eradication of Malaria infection following the challenges of insecticide resistance by the vector mosquito, drug resistance by the parasite, and the development of a vaccine still being a mirage. Acalypha wilkesiana Muller Argoviensis, 1866 (family: Euphorbiaceae) leaves have the ethnopharmacological reputation for use as a remedy against dermal microbial infections in Nigeria. Here, we have studied the antiplasmodial potential of the extract of the leaves of this ornamental plant. Aqueous methanol crude extract (70%) and Prep reversed-phase high-performance liquid chromatography (RPHPLC) fractions were tested in vitro against blood stage Plasmodium falciparum 3D7 strain parasites for antiplasmodial activity using the SYBR Green assay. Results obtained were validated through Giemsa stained microscopic blood smeared slides. An IC50 of < 0.39 µg/ml for fractions of the RPHPLC together with TC50 of > 100 µg/ml against mammalian HUH-7 cell lines and a HC50 of > 100 µg/ml against red blood cells indicate a high selectivity of this plant against Plasmodium. This is the first report of the antiplasmodial activity of this plant and a GC-MS fingerprinting of the same, opening the possibilities of identifying novel pharmacophores against the malaria parasite.


Assuntos
Acalypha/química , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Linhagem Celular , Resistência a Medicamentos/efeitos dos fármacos , Etnofarmacologia , Cromatografia Gasosa-Espectrometria de Massas , Malária Falciparum/parasitologia , Nigéria , Folhas de Planta/química
13.
Pharm Biol ; 55(1): 1394-1400, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28320254

RESUMO

CONTEXT: Zea mays L. (Poacae) husk decoctions are traditionally used in the treatment of malaria by various tribes in Nigeria. OBJECTIVE: To assess the antimalarial and antiplasmodial potentials of the husk extract and fractions on malaria parasites using in vivo and in vitro models. MATERIALS AND METHODS: The ethanol husk extract and fractions (187-748 mg/kg, p.o.) of Zea mays were investigated for antimalarial activity against Plasmodium berghei using rodent (mice) malaria models and in vitro activity against chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using the SRBR green assay method. Median lethal dose and cytotoxic activities against HeLa and HEKS cells were also carried out. The GCMS analysis of the most active fraction was carried out. RESULTS: The husk extract (187-748 mg/kg, p.o.) with LD50 of 1874.83 mg/kg was found to exert significant (p < 0.05-0.001) antimalarial activity against P. berghei infection in suppressive, prophylactive and curative tests. The crude extract and fractions also exerted prominent activity against both chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with the ethyl acetate fraction exerting the highest activity with IC50 values of 9.31 ± 0.46 µg/mL (Pf 3D7) and 3.69 ± 0.66 µg/mL (Pf INDO). The crude extract and fractions were not cytotoxic to the two cell lines tested with IC50 values of >100 µg/mL against both HeLa and HEKS cell lines. DISCUSSION AND CONCLUSION: These results suggest that the husk extract/fractions of Zea mays possesses antimalarial and antiplasmodial activities and these justify its use in ethnomedicine to treat malaria infections.


Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Zea mays/química , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Etanol/química , Feminino , Células HEK293 , Células HeLa , Humanos , Concentração Inibidora 50 , Malária/parasitologia , Masculino , Camundongos , Testes de Sensibilidade Parasitária , Fitoterapia , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Plantas Medicinais , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Solventes/química , Fatores de Tempo
16.
Front Microbiol ; 6: 1368, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26696979

RESUMO

Visceral leishmaniasis (VL) is a life-threatening protozoal infection chiefly impinging the rural and poor population in the tropical and sub-tropical countries. The deadly affliction is rapidly expanding after its association with AIDS, swiftly defying its status of a neglected disease. Despite successful formulation of vaccine against canine leishmaniasis, no licensed vaccine is yet available for human VL, chemotherapy is in appalling state, and the development of new candidate drugs has been painfully slow. In face of lack of proper incentives, immunostimulatory plant preparations owing antileishmanial efficacy bear potential to rejuvenate awful antileishmanial chemotherapy. We have earlier reported profound leishmanicidal activity of Piper nigrum hexane (PNH) seeds and P. nigrum ethanolic (PNE) fractions derived from P. nigrum seeds against Leishmania donovani promastigotes and amastigotes. In the present study, we illustrate that the remarkable anti-promastigote activity exhibited by PNH and PNE is mediated via apoptosis as evidenced by phosphatidylserine externalization, DNA fragmentation, arrest in sub G0/G1 phase, loss of mitochondrial membrane potential and generation of reactive oxygen species. Further, P. nigrum bioactive fractions rendered significant protection to L. donovani infected BALB/c mice in comparison to piperine, a known compound present in Piper species. The substantial therapeutic potential of PNH and PNE was accompanied by elicitation of cell-mediated immune response. The bioactive fractions elevated the secretion of Th1 (INF-γ, TNF-α, and IL-2) cytokines and declined IL-4 and IL-10. PNH and PNE enhanced the production of IgG2a, upregulated the expression of co-stimulatory molecules CD80 and CD86, augmented splenic CD4(+) and CD8(+) T cell population, induced strong lymphoproliferative and DTH responses and partially stimulated NO production. PNH and PNE were devoid of any hepatic or renal toxicity. These encouraging findings merit further exploration of P. nigrum bioactive fractions as a source of potent and non-toxic antileishmanials.

18.
Parasit Vectors ; 8: 183, 2015 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-25884649

RESUMO

BACKGROUND: Exploration of immunomodulatory antileishmanials of plant origin is now being strongly recommended to overcome the immune suppression evident during visceral leishmaniasis (VL) and high cost and toxicity associated with conventional chemotherapeutics. In accordance, we assessed the in vitro and in vivo antileishmanial and immunomodulatory potential of ethanolic fractions of Azadirachta indica leaves (ALE) and seeds (ASE). METHODS: A. indica fractions were prepared by sequential extraction of the powdered plant parts in hexane, ethanol and water. Erythrosin B staining was employed to appraise the anti-promastigote potential of ALE and ASE. Cytostatic or cytocidal mode of action was ascertained and alterations in parasite morphology were depicted under oil immersion light microscopy. Study of apoptotic correlates was performed to deduce the mechanism of induced cell death and anti-amastigote potential was assessed in Leishmania parasitized RAW 264.7 macrophages. In vivo antileishmanial effectiveness was evaluated in L. donovani infected BALB/c mice, accompanied by investigation of immunomodulatory potential of ALE and ASE. Adverse toxicity of the bioactive fractions against RAW macrophages was studied by MTT assay. In vivo side effects on the liver and kidney functions were also determined. Plant secondary metabolites present in ALE and ASE were analysed by Gas chromatography-mass spectrometry (GC-MS). RESULTS: ALE and ASE (500 µg ml(-1)) exhibited leishmanicidal activity in a time- and dose-dependent manner (IC50 34 and 77.66 µg ml(-1), respectively) with alterations in promastigote morphology and induction of apoptosis. ALE and ASE exerted appreciable anti-amastigote potency (IC50 17.66 and 24.66 µg ml(-1), respectively) that was coupled with profound in vivo therapeutic efficacy (87.76% and 85.54% protection in liver and 85.55% and 83.62% in spleen, respectively). ALE exhibited minimal toxicity with selectivity index of 26.10 whereas ASE was observed to be non-toxic. The bioactive fractions revealed no hepato- and nephro-toxicity. ALE and ASE potentiated Th1-biased cell-mediated immunity along with upregulation of INF-γ, TNF-α and IL-2 and decline in IL-4 and IL-10 levels. GC-MS analysis revealed several compounds that may have contributed to the observed antileishmanial effect. CONCLUSION: Dual antileishmanial and immunostimulatory efficacy exhibited by the bioactive fractions merits their use alone or as adjunct therapy for VL.


Assuntos
Anti-Helmínticos/uso terapêutico , Apoptose , Azadirachta/química , Fatores Imunológicos/uso terapêutico , Leishmaniose/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Células Th1/imunologia , Animais , Anti-Helmínticos/efeitos adversos , Anti-Helmínticos/isolamento & purificação , Anti-Helmínticos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Leishmania/citologia , Leishmania/efeitos dos fármacos , Leishmania/fisiologia , Leishmaniose/parasitologia , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Microscopia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta/química , Sementes/química , Resultado do Tratamento
19.
Malar J ; 14: 65, 2015 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-25879738

RESUMO

BACKGROUND: Development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents. METHODS: Inspired by their ethnobotanical reputation for being effective against febrile diseases, antiplasmodial potential of ethyl acetate extracts (EAE) and methanol extracts (ME) of 17 medicinal plants collected from the Eastern Ghats of South India and Buchpora, North India were explored against Plasmodium falciparum in vitro using the SYBR Green assay. The results were validated both by confirmation that the fall in fluorescence signal was not due to quenching effects mediated by phytochemical extracts and by Giemsa-stained microscopy. RESULTS: Using EAE or ME, promising antiplasmodial activity (IC50 Pf3D7 ≤ 20 µg/ml), was seen in Aerva lanata (Whole aerial parts-EAE), Anisomeles malabarica (Leaf-EAE), Anogeissus latifolia (bark-EAE), Cassia alata (leaves-EAE), Glycyrrhiza glabra (root-EAE), Juglans regia (seed-ME), Psidium guajava (leaf-ME and EAE) and Solanum xanthocarpum (Whole aerial parts-EAE). EAEs from leaves of Couroupita guianensis, Euphorbia hirta, Pergularia daemia, Tinospora cordifolia and Tridax procumbens as also ME from Ricinus communis (leaf and seed) showed good antiplasmodial activity (Pf 3D7 IC50 21 - 40 µg/ml). Moderate activity (Pf 3D7 IC50: 40-60 µg/mL) was shown by the leaf EAEs of Cardiospermum halicacabum, Indigofera tinctoria and Ricinus communis while the remaining extracts showed marginal (Pf 3D7 IC50 60 to >100 µg/ml) activities. The promising extracts showed good resistance indices (0.41 - 1.4) against the chloroquine resistant INDO strain of P. falciparum and good selectivity indices (3 to > 22.2) when tested against the HeLa cell line. CONCLUSION: These results provide validity to the traditional medicinal usage of some of these plants and further make a case for activity-guided purification of new pharmacophores against malaria.


Assuntos
Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Eritrócitos/parasitologia , Células HeLa , Humanos , Índia , Extratos Vegetais/toxicidade
20.
J Ethnopharmacol ; 165: 152-62, 2015 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-25721804

RESUMO

BACKGROUND: The alarmingly increasing problem of drug resistance in treatment of malaria has led to an urgent need for identifying new anti-malarial drugs for both prophylaxis and chemotherapy. AIM OF THE STUDY: The present study presents a systematic exploration of the ex vivo blood stage antiplasmodial potential of medicinal plants to corroborate their traditional usage against malaria in Jharkhand, India. METHODS: An ethnobotanical survey in and around Ranchi was done to grasp the traditional knowledge of medicinal plants used by local healers for malaria, other fevers and for other medicinal purposes like, antiamoebic, antihelmenthic, antidote to poisons, etc. Following the survey, the selected 22 plant samples were extracted in ethanol for studying ex vivo SYBR Green I fluorescence assay based anti-plasmodial activity against both chloroquine-sensitive Pf3D7 and chloroquine resistant PfINDO strains of Plasmodium falciparum grown in human red blood cell cultures. Cytotoxicity was determined against HeLa and L929 cells using MTT assay. Further the most potent extract was chromatographed on reverse phase HPLC towards antiplasmodial activity guided purification of metabolites. RESULTS: Of the 22 plant species assayed, the highest antiplasmodial activity (Pf3D7IC50 ≤ 5 µg/ml) was seen in leaf ethanol extracts of Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson, Calotropis procera (Aiton) Dryand. and Annona squamosa L. and bark ethanol extract of Holarrhena pubescens Wall. ex G.Don. Leaf ethanol extract of H. pubescens, bark ethanol extract of Pongamia pinnata (L.) Pierre and whole plant ethanol extract of Partheniumhysterophorus L. showed promising activity (IC50 6-10 µg/ml). Good antiplasmodial activity (IC50: 11-20 µg/ml) was observed in leaf ethanol extract of Bryophyllum pinnatum (Lam.) Oken and whole plant ethanol extract of Catharanthus roseus (L.) G.Don. The extracts of plants showing highest to good antiplasmodial activity exhibited HeLa/Pf3D7 selectivity indices of the order of 20-45. Bioassay guided fractionation of P. hysterophorus led to fivefold enrichment of antiplasmodial activities (IC50 ~450 ng/ml) in some fractions. CONCLUSION: These results provide confirmation to the traditional usage of some medicinal plants against malaria in areas around Ranchi, Jharkhand.


Assuntos
Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Plasmodium falciparum/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa/efeitos dos fármacos , Humanos , Índia
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