RESUMO
After ethnobotanical surveys in central and western regions of Burkina Faso, five plants namely Lantana ukambensis (Verbenaceae), Xeoderris sthulmannii (Fabaceae), Parinari curatellifollia (Chrysobalanaceae), Ozoroa insignis (Anacardiaceae), and Ficus platyphylla (Moraceae) were selected for their traditional use in the treatment of parasitic diseases and cancer. Our previous studies have focused on the phytochemical, genotoxicity, antioxidant, and antiproliferative activities of these plants. In this study, the methanol extract of each plant was tested to reveal probable antileishmanial and antitrypanosomal activities. Colorimetric and spectrophotometric methods were used for the detection of antileishmanial and antitrypanosomal activities. Leishmania donovani (LV9 WT) and Trypanosoma brucei brucei GVR 35 were used to test the antileishmanial and antitrypanosomal activities, respectively. All extracts of tested plants showed a significant antitrypanosomal activity with minimum lethal concentrations between 1.5 and 25 µg/ml, the L. ukambensis extract being the most active. In the antileishmanial test, only the extract from L. ukambensis showed significant activity with an inhibitory concentration (IC(50)) of 6.9 µg/ml. The results of this study contribute to the promotion of traditional medicine products and are preliminary for the isolation of new natural molecules for the treatment of leishmaniasis and trypanosomiasis.
Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Plantas Medicinais/química , Trypanosoma brucei brucei/efeitos dos fármacos , Antiprotozoários/isolamento & purificação , Burkina Faso , Colorimetria , Viabilidade Microbiana/efeitos dos fármacos , Testes de Sensibilidade Parasitária , EspectrofotometriaRESUMO
2-n-propylquinoline is presently a drug-candidate for the treatment of visceral leishmaniosis in pre-clinical development. As this compound is in an oily state, it needs to be formulated and the objectives of this study are: to prepare a formulation; to demonstrate that the new salted formulation did not alter the activity of the active ingredient; and finally, that this activity was quite good compared to the reference oral drug, miltefosine. Therefore, a 2-n-propylquinoline formulation, as camphorsulfonic salt, was prepared and characterised. On the Leishmania donovani / Balb/c mice model, a treatment by oral route at 60 mmoles/kg/day for ten consecutive days with this formulation was compared to 2-n-propylquinoline alone and to miltefosine, the oral reference drug. The salt formulation did not alter the activity of the 2-n-propylquinoline. The formulation reduced the parasite burden of 76% compared to 89% for miltefosine (not significant). The characteristics of this formulation results in a suitable drugability of 2-n-propylquinoline for further studies.
Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Quinolinas/farmacologia , Administração Oral , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Química Farmacêutica , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Quinolinas/administração & dosagem , Quinolinas/químicaRESUMO
The in vitro activity of a new analogue of 2-alkenylquinoline (2-nitrilquinoline or NQ) against Leishmania donovani was compared to oral reference drug miltefosine (HePC). IC(50) of NQ was found at 38.6 microM against promastigotes and 2.4 microM against intramacrophage amastigotes. In vivo evaluation in the L. donovani Balb/c mice model indicated that oral treatments at 12.5 and 25 mg/kg for 10 consecutive days significantly reduced the parasite burden in the liver by 68.9 and 68.5%, respectively. This activity was similar to those of HePC at 7.5 mg/kg for 10 days which reduced the parasite burden in liver by 72.5%. The present study shows the positive contribution of a nitril substitute being added into the alkenyl chain branched at the 2-position of the quinoline ring to the antileishmanial activity. In addition, any apparent toxicological disorder was observed during the experiments.
Assuntos
Acrilonitrila/análogos & derivados , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Quinolinas/uso terapêutico , Acrilonitrila/efeitos adversos , Acrilonitrila/síntese química , Acrilonitrila/uso terapêutico , Administração Oral , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Leishmaniasis is an emergent orphan disease because of its co-infection with HIV AIDS. We report herein the in vitro biological evalution of five news quinolines, 2- or 3- substituted by an enyne group against Leishmania donovani (MHOM/ET/L82/LV9). PATIENTS AND METHODS: The quinolines has been synthesized by using a cross-coupling reaction between a chloroenyne and an organometallic coumpound in a presence of iron a "green" catalyst. Biological evalution is realized by a colorimetric method with the use of 3-(4,5-dimethylthiazol-2,5-diphényl)-tétrazolium bromide. RESULTS: Determination of the inhibitory concentrations as well as the minimal inhibitory concentrations has shown that the substitution by an enyne group made it possible to have a more important antileishmanial activity. In addition, we have seen that the -2 or the -3 position of the enyne group had no influence in the antileishmanial activity. CONCLUSION: Thus, we have shown the real interest of these quinolines which could be favourably compared with pentamidine, which is currently the reference product, and to consider the use of these quinolines in the treament of the leishmaniasis.
Assuntos
Leishmaniose/tratamento farmacológico , Quinolinas/síntese química , Quinolinas/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Leishmaniasis is an emergent orphan disease because of its co-infection with HIV AIDS. We report herein the in vitro biological evalution of five news quinolines, 2- or 3-substituted by an enyne group against Leishmania donovani (MHOM/ET/L82/LV9). PATIENTS AND METHODS: The quinolines has been synthesized by using a cross-coupling reaction between a chloroenyne and an organometallic coumpound in a presence of iron a "green" catalyst. Biological evalution is realized by a colorimetric method with the use of 3-(4,5-diméthylthiazol-2,5-diphényl)-tetrazolium bromide. RESULTS: Determination of the inhibitory concentrations as well as the minimal inhibitory concentrations has shown that the substitution by an enyne group made it possible to have a more important antileishmanial activity. In addition, we have seen that the -2 or the -3 position of the e nyne group h ad no influence in the antileishmanial activity. CONCLUSION: Thus, we have shown the real interest of these quinolines which could be favourably compared with pentamidine, which is currently the reference p roduct, and to consider the use of these quinolines in the treament of the leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Testes de Sensibilidade ParasitáriaRESUMO
The development of novel styryl lactone derivatives as bioactive compounds and the semisynthesis of both 4,5-dialkoxylated eight-membered-ring lactones with a heptolide skeleton (almuheptolide-A (1) type) and 7-alkoxylated delta-lactones with a saturated furanopyrone skeleton (etharvensin (8) type) have been successfully achieved from the chiral unsaturated alpha-pyrone altholactone (7). This new method is a direct and one-step enantiospecific alkoxylation of altholactone (7) in concentrated acid medium, followed by formation of the eight-membered-ring zeta-lactone. The reaction mechanism operating in the synthesis of the heptolide skeleton is postulated to be a direct Michael-type addition. Concerted opening of both the alpha-pyrone and tetrahydrofuran rings and subsequent intramolecular rearrangement with the ring closure lead to almuheptolide-A (1). This compound (1) and its diacetated derivative (1a) showed potent and selective inhibitory activity toward mammalian mitochondrial respiratory chain complex I. This mechanism of action, reported here for the first time, provides a possible explanation for the cytotoxic and antitumor activities previously described for related natural compounds.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Transporte de Elétrons/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Mitocôndrias Cardíacas/efeitos dos fármacos , NADH NADPH Oxirredutases/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Bovinos , Complexo I de Transporte de Elétrons , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Cinética , Mitocôndrias Cardíacas/enzimologia , Modelos Moleculares , Oxirredução , EstereoisomerismoRESUMO
Several glycosyl derivatives of squamocin (1) have been synthesized by glycosylation under Lewis acid catalysis with two different 1-O-acetyl sugars. Separation of these compounds has been achieved by HPLC and centrifugal partition chromatography (CPC). A detailed NMR, ESIMS, and LSIMS study allowed complete structural elucidations. The cytotoxic activity of the glycosyl derivatives was investigated and compared with that of squamocin and dihydrosquamocin against human epidermoid carcinoma cells (KB), African green monkey (Cercopithecus aethiops) kidney epithelial cells (VERO), and mouse lymphocytic leukemia cells (L1210). The antiproliferative effects of some derivatives were studied on cell cycles in mouse lymphocytic leukemia cells (L1210).
Assuntos
Antineoplásicos/síntese química , Furanos/síntese química , Lactonas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/farmacologia , Glicosilação , Humanos , Lactonas/química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Células Tumorais Cultivadas , Células VeroRESUMO
Aromatic side-chain analogues (arocalciferols 6-9) of the steroid hormone 1 alpha,25-dihydroxyvitamin D3 (1) were synthesized and biologically evaluated. The analogues were prepared by coupling the vitamin D A-ring enyne 14 with the appropriate enol triflate of a modified CD steroid fragment of the type 22. The resulting dienyne 23 was then transformed in three steps to the vitamin D analogues 6-9. Biological evaluation of these analogues have provided information concerning side-chain topographical effects on in vivo and in vitro activity.
Assuntos
Calcitriol/análogos & derivados , Animais , Ligação Competitiva , Calcitriol/síntese química , Calcitriol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Fenômenos Químicos , Química , Galinhas , Humanos , Mucosa Intestinal/metabolismo , Leucemia Promielocítica Aguda , Conformação Molecular , Estrutura Molecular , Receptores de Calcitriol , Receptores de Esteroides/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína de Ligação a Vitamina D/metabolismoRESUMO
The antiproliferative activities of six medicinal plant extracts from Burkina Faso were evaluated in order to justify their traditional use for the treatment of cancer. The SOS chromotest method was used in vitro on Escherichia coli PQ37 to evaluate the mutagenic effect of the plant extracts. The DPPH method was used to evaluate the antioxidant activity of each plant. The antiproliferative activity was evaluated by MTS method on normal cells (Vero and MCR5) and cancer cells (KB) in contact with the extracts for 72 h. The results showed that the studied plants are not genotoxic. Lantana ukambensis and Acacia macrostachya induced a very significant antiproliferative effect against cancer cells with 94% and 95%, respectively. They also developed a strong antioxidant activity. The IC50 values were 5.96 ± 0.40 µg mL⻹ for L. ukambensis and 4.30 ± 0.26 µg mL⻹ for A. macrostachya. These two plants are therefore potential sources for isolating new antioxidant and anticancer molecules.
Assuntos
Antineoplásicos/análise , Antioxidantes/análise , Magnoliopsida/química , Mutagênicos/análise , Plantas Medicinais/química , Animais , Burkina Faso , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Plantas Medicinais/toxicidadeRESUMO
Dopamine and serotonin are important neurotransmitters in the mammalian central nervous system (CNS) involved in numerous physiological and behavioural disorders such as schizophrenia, major depression, anxiety, Parkinson's and Huntington's diseases, and attention deficit hyperactivity disorder. Several natural and synthetic benzylisoquinoline derivatives have displayed affinity for dopamine and serotonin receptors in nanomolar or micromolar ranges. This review covers the last three decades of dopaminergic and serotonergic activities, and especially focuses on structure-activity relationships of natural and synthetic benzylisoquinoline derivatives. We have included aporphines, 1-benzyltetrahydroisoquinolines, bis-benzylisoquinolines, protoberberines, cularines and other structural analogues. Further molecular modelling calculations have been considered as important tools to not only obtain structural information of both neurotransmitter receptors, but to also identify their pharmacophore features. The development of selective potential ligands like benzylisoquinoline derivatives may help in the therapy of diseases related to CNS dysfunction.
Assuntos
Benzilisoquinolinas/química , Antagonistas de Dopamina/química , Neurotransmissores/química , Antagonistas da Serotonina/química , Benzilisoquinolinas/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Antagonistas de Dopamina/farmacologia , Humanos , Neurotransmissores/farmacologia , Receptores Dopaminérgicos/química , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Fifteen bisbenzylisoquinoline alkaloids (BBIQ) with one ether bridge (thaligrisine [1], berbamunine [2], dimethylgrisabine [3], pampulhamine [4], and methyl-dauricine [5]), with two ether bridges (homoaromoline, isotetrandrine, and obaberine), with one ether bridge and one biphenyl bridge (oxandrine, dimethylpseudoxandrine, pseudoxandrine, and antioquine) or secoderivatives (secoobaberine, secoantioquine, and secolucidine), were tested for their ability to displace 3H-raclopride or 3H-SCH 23390 from their specific dopaminergic binding sites to rat striatal membranes. The most active compounds were found in the group of BBIQs with one ether bridge. Inactive or weakly active compounds were found in this group of BBIQs with one ether bridge and in the other groups. Analysis of tridimensional representations indicates that the differnt activities among the BBIQs with one ether bridge could be related to strong differences between the spatial occupancy of these compounds according to their stereochemistry.
Assuntos
Alcaloides/farmacologia , Corpo Estriado/metabolismo , Isoquinolinas/farmacologia , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Ligação Competitiva/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , França , Técnicas In Vitro , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Racloprida , Ratos , Ratos Wistar , Salicilamidas/farmacologia , Relação Estrutura-AtividadeRESUMO
Semisynthetic derivatives were prepared from two natural annonaceous acetogenins, rolliniastatin-1 and squamocin, and their cytotoxicity was evaluated. Amino derivatives show decreased bioactivity. Isorolliniastatin-1 was found to be much less toxic than rolliniastatin-1 after intraperitoneal administration to mice, although the in vitro cytotoxicity of both compounds was comparable.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Furanos/síntese química , Furanos/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Furanos/administração & dosagem , Furanos/química , Humanos , Injeções Intraperitoneais , Lactonas/administração & dosagem , Lactonas/química , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células Tumorais CultivadasRESUMO
The first synthesis of the methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate (desmethyltrimebutine) I is described. This compound is the main bioactive metabolite of trimebutine II (Debridat, CAS 39133-31-8), an antispasmodic widely used for intestinal diseases since 1969. It was used for pharmacokinetic and bioequivalence studies.
Assuntos
Benzoatos/síntese química , Fármacos Gastrointestinais/síntese química , Trimebutina/farmacocinética , Benzoatos/farmacocinética , Biotransformação , Cromatografia em Camada Fina , Fármacos Gastrointestinais/farmacocinética , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Three new bistetrahydrofuran acetogenins, carolins A-C (1-3), were isolated from the MeOH extract of Annona spinescens in addition to the known compound, squamocin (4). The structures of 1, 2, and 3 were elucidated by spectroscopic methods including LSIMS/MS technique and confirmed by a chemical transformation, The cytotoxic activity of the new compounds 1-3 is reported and discussed in comparison with 4 and the previously isolated spinencin (5).