RESUMEN
Covering mainly from 2013 up to 2023 with relevant references to work done before 2013First reported in 1995, the dichapetalins and analogous compounds constitute a novel class of natural dammarane-type merotriterpenoids characterized by their unique 2-phenylpyrano moiety annellated to ring A of the dammarane skeleton. They have been reported from only two genera: Dichapetalum (Dichapetalaceae) and Phyllanthus (Phyllanthaceae). About 100 novel dichapetalins and dichapetalin-type compounds, including the acutissimatriterpenes and their antitumour and other bioactivities have been reported. In the present review, we cover the distribution, ethnobotanical and medicinal importance and the diversity of secondary metabolites reported from the two genera Dichapetalum and Phyllanthus from 2013 to date, with appropriate reference to relevant information prior to 2013. We also propose and discuss possible biosynthetic pathways, antitumour activity against a broad range of human and murine cancer cell lines, structure activity relationships, and other biological activities and mechanisms of action. Finally, the review deals with future perspectives which include expansion of the structural diversity and bioactivity scope, possible simplification of the structural complexity of the compounds to enhance their drug-likeness, in silico studies, and continuation of the search for new dichapetalins and dichapetalin-type compounds from the over 200 Dichapetalum and over 1200 Phyllanthus species yet to be investigated. It is envisaged that the present review will stimulate further multidisciplinary and interdisciplinary studies.
RESUMEN
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa , Antimaláricos , Hemoproteínas , Naftiridinas , Plasmodium falciparum , Pez Cebra , Plasmodium falciparum/efectos de los fármacos , Animales , Naftiridinas/farmacología , Naftiridinas/química , Naftiridinas/síntesis química , Naftiridinas/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Humanos , Relación Estructura-Actividad , Hemoproteínas/antagonistas & inhibidores , Hemoproteínas/metabolismo , Ratones , Ratas , Malaria Falciparum/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis químicaRESUMEN
In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.
Asunto(s)
Antimaláricos , Artemisininas , Plasmodium falciparum , Artemisininas/farmacología , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Resistencia a Medicamentos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Humanos , Pruebas de Sensibilidad Parasitaria , Animales , Peróxidos/farmacologíaRESUMEN
Drug metabolism is generally associated with liver enzymes. However, in the case of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), Mtb-mediated drug metabolism plays a significant role in treatment outcomes. Mtb is equipped with enzymes that catalyse biotransformation reactions on xenobiotics with consequences either in its favour or as a hindrance by deactivating or activating chemical entities, respectively. Considering the range of chemical reactions involved in the biosynthetic pathways of Mtb, information related to the biotransformation of antitubercular compounds would provide opportunities for the development of new chemical tools to study successful TB infections while also highlighting potential areas for drug discovery, host-directed therapy, dose optimization and elucidation of mechanisms of action. In this Review, we discuss Mtb-mediated biotransformations and propose a holistic approach to address drug metabolism in TB drug discovery and related areas.
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Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Humanos , Xenobióticos/metabolismo , Antituberculosos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis Latente/tratamiento farmacológicoRESUMEN
Pyrido[1,2-a]benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparumin vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.
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Antimaláricos , Antagonistas del Ácido Fólico , Malaria , Aminoquinolinas/química , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Animales , Antimaláricos/química , Antimaláricos/farmacología , Antiparasitarios/farmacología , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Cloroquina/farmacología , Antagonistas del Ácido Fólico/farmacología , Hemo , Malaria/tratamiento farmacológico , Malaria/parasitología , Ratones , Plasmodium falciparumRESUMEN
Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome of this chemical modification is to produce a new hybrid compound with improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization was used to generate new molecular hybrids which were tested against the chloroquine sensitive (NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to produce a total of twenty-two molecular hybrids in 11%-96% yield. The synthesized compounds displayed good antiplasmodial activity with IC50 values ranging at 0.10-4.45 µM.
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Antimaláricos/síntesis química , Antimaláricos/farmacología , Chalconas/química , Descubrimiento de Drogas , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinolinas/química , Humanos , Malaria Falciparum/parasitología , Relación Estructura-ActividadRESUMEN
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores the importance of a continuous pipeline of new anti-TB agents. Drug repurposing has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, is one such candidate for repurposing. The present study aimed to understand the mechanism of action of FA and its selected analogs in M. tuberculosis. By using chemical biology and genetics, we identified elongation factor G as the target of FA in M. tuberculosis. We showed essentiality of its encoding gene fusA1 in M. tuberculosis by demonstrating that the transcriptional silencing of fusA1 is bactericidal in vitro and in macrophages. Thus, this work validated a novel drug target FusA1 in M. tuberculosis.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Antituberculosos/farmacología , Ácido Fusídico/farmacología , Genes Esenciales , Humanos , Mycobacterium tuberculosis/genética , Tuberculosis/tratamiento farmacológicoRESUMEN
A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
Asunto(s)
Antimaláricos/química , Bencimidazoles/química , Hemoproteínas/metabolismo , Bases de Mannich/química , Microtúbulos/metabolismo , Administración Oral , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Modelos Animales de Enfermedad , Diseño de Fármacos , Resistencia a Medicamentos/efectos de los fármacos , Estabilidad de Medicamentos , Semivida , Hemoproteínas/efectos de los fármacos , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Microtúbulos/efectos de los fármacos , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Relación Estructura-ActividadRESUMEN
The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.
Asunto(s)
Malaria Falciparum , Parásitos , Animales , Bencimidazoles/farmacología , Humanos , Estadios del Ciclo de Vida , Malaria Falciparum/tratamiento farmacológico , Masculino , Plasmodium falciparumRESUMEN
Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and in vivo efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIß while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity in vitro. Using in silico docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both Plasmodium PI4K and PKG. While several derivatives showed low nanomolar antiplasmodium activity (IC50 < 100 nM), some compounds, including piperazine analogue 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of early- and late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa , Plasmodium , Proteínas Quinasas Dependientes de GMP Cíclico , Guanidina , Fosfatidilinositoles , Plasmodium falciparum , Proteínas QuinasasRESUMEN
Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 µM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice.
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Esquistosomiasis mansoni , Esquistosomicidas , Animales , Bencimidazoles/farmacología , Cricetinae , Ratones , Fenetilaminas , Schistosoma mansoni , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomicidas/farmacologíaRESUMEN
Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Further studies have led to the identification of 16-deacetoxy-16ß-ethoxyfusidic acid (58), an analog which exhibited comparable activity to FA with an in vitro MIC99 value of 0.8 µM. Preliminary SAR studies around the FA scaffold suggested that the hydrophobic side chain at C-20, like the C-11 OH group, was required for activity. The C-3 OH group, however, can be functionalized to obtain more potent compounds.
Asunto(s)
Antibacterianos/química , Ácido Fusídico/química , Mycobacterium/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Cricetulus , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Ácido Fusídico/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Fusidic acid (FA) has previously been shown to be rapidly metabolized in rodents to its C-3 epimer, which has significantly lower antimycobacterial activity relative to FA. This was in part hypothesized to account for FA's lack of in vivo efficacy in a mouse model of tuberculosis despite potent in vitro antimycobacterial activity. In the current work, we hypothesized that C-3 alkyl ester prodrugs of FA would deliver higher levels of the drug and prevent the rapid metabolism observed upon administration of FA in its original form. Pharmacokinetic analysis of FA and its 3-ketofusidic acid metabolite as well as novel C-3 alkyl ester prodrugs of FA revealed that FA has low exposure in mice due to rapid metabolism to a species-specific metabolite, 3-epifusidic acid. The C-3 alkyl ester prodrugs showed improved absorption and tissue distribution in pharmacokinetic and organ distribution experiments. These results support the original objective of the FA C-3 ester prodrugs to improve drug concentrations and tissue distribution.
Asunto(s)
Antibacterianos/farmacocinética , Ésteres/farmacocinética , Ácido Fusídico/farmacocinética , Profármacos/farmacocinética , Alquilación , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Globally, schistosomiasis threatens more than 700 million lives, mostly children, in poor localities of tropical and sub-tropical areas with morbidity due to acute and chronic pathological manifestations of the disease. After a century since the first antimonial-based drugs were introduced to treat the disease, anti-schistosomiasis drug development is again at a bottleneck with only one drug, praziquantel, available for treatment purposes. This review focuses on promising chemotypes as potential starting points in a drug discovery effort to meet the urgent need for new schistosomicides.
RESUMEN
Fusidic acid is a natural product antibiotic used clinically, primarily against staphylococcal infections. It has also exhibited antimycobacterial activity against Mycobacterium species, including Mycobacterium tuberculosis (Mtb). Novel C-21 fusidic acid amides were synthesized and evaluated for antimycobacterial activity in a drug repositioning approach for tuberculosis. The synthesized compounds exhibited good potency in MB7H9/CAS medium albeit showing low to no activity in MB7H9/ADC medium. The fusidic acid ethanamides were, generally, the most potent of the analogues evaluated for antimycobacterial activity (MIC90 < 10 µM) in the MB7H9/CAS medium. The lack of activity in the MB7H9/ADC medium was supported by strong binding interactions in the fusidic acid binding site of the human serum albumin (HSA) protein. The most potent antimycobacterial analogue was the N-(4-sulfamoylbenzyl)fusidic acid amide (1.26) with an MIC90 value of 2.71 µM.
RESUMEN
Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharmacokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metabolism of FA and semisynthesized ester derivatives in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and derivative molecules with a free C-3 OH underwent species-specific metabolism to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These additional routes of metabolism may contribute to the more rapid clearance of FA observed in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compounds were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.
Asunto(s)
Ésteres/síntesis química , Ácido Fusídico/química , Mycobacterium tuberculosis/crecimiento & desarrollo , Silicatos/síntesis química , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Técnicas Bacteriológicas , Células CHO , Cricetulus , Reposicionamiento de Medicamentos , Ésteres/química , Ésteres/farmacocinética , Ésteres/farmacología , Microsomas Hepáticos/química , Mycobacterium tuberculosis/efectos de los fármacos , Plasma/química , Ratas , Silicatos/química , Silicatos/farmacocinética , Silicatos/farmacologíaRESUMEN
A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.
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Antimaláricos/administración & dosificación , Antimaláricos/química , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Malaria/tratamiento farmacológico , Bases de Mannich/química , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Evaluación Preclínica de Medicamentos , Humanos , Malaria/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Plasmodium berghei , Plasmodium falciparum/fisiología , Relación Estructura-ActividadRESUMEN
Two new bisbibenzyls, heudelotol A (1) and B (2), along with the known bibenzyls, (E)-combretastatin A-1 (3) and combretastatin B-1 (4) have been isolated from the ethyl acetate extract of the roots of Dichapetalum heudelotii. Structure elucidation of all four isolated compounds was achieved using UV, IR, 1D and 2D NMR spectroscopy and HR-Mass Spectrometry. The compounds exhibited varying antiproliferative activity against six cancer cell lines using the CellTiter-Glo® Luminiscent Cell Viability Assay. Compound 3 was found to be the most active with sub-micromolar growth inhibition concentrations against all the cell lines (GI50 0.03-0.72µM). However, it was about ten-fold less active than the positive control, taxol. The new bisbibenzyls heudelotol A and B exhibited good activity against human pancreatic adenocarcinoma (GI50 9.04µM) and Burkitt's lymphoma (GI50 4.67µM) respectively, and average activity against the other cancer cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Bibencilos/farmacología , Magnoliopsida/química , Estilbenos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Bibencilos/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Raíces de Plantas/química , Estilbenos/aislamiento & purificaciónRESUMEN
As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification of the roots of a hitherto unexamined species, Dichapetalum pallidum, led to the isolation of the newly occurring 7-hydroxydichapetalin P (1) and the known dichapetalins A (2) and X (3). Also isolated were the known compounds friedelin-2,3-lactone (4), friedelan-3-one (6), friedelan-3ß-ol (7) and pomolic (8), as well as the dipeptide aurantiamide acetate (5). The compounds were characterized by direct interpretation of their IR, 1D NMR and 2D NMR spectral data and by comparison of their physico-chemical data, including their chromatographic profiles, with the literature and authentic samples in our compound library for the genus Dichapetalum. The compounds were assayed for their anti-proliferative activities against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines. Overall, dichapetalin X showed the strongest (3.14 µM) and broadest cytotoxic activities against all the leukemic cell lines tested, exhibiting even stronger activities than the standard compound, curcumin.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Magnoliopsida/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Células Jurkat , Estructura Molecular , Extractos Vegetales/química , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
CONTEXT: Dichapetalum filicaule Breteler (Dichapetalaceae) is a rare species occurring only in Côte d'Ivoire and Ghana. Although research on several species of the genus has produced interesting bioactive compounds, particularly the Dichapetalins, a novel class of triterpenoids with antineoplastic properties, there is virtually no information on the ethnobotanical uses and chemical constituents of D. filicaule. OBJECTIVE: The phytochemical and anthelminthic activities of the constituents of D. filicaule were investigated. MATERIALS AND METHODS: Chemical constituents of the petroleum ether, chloroform-acetone, and methanol root extracts of D. filicaule were isolated by column chromatography and characterized by their physico-chemical properties, 1-D and 2-D NMR spectroscopy and mass spectrometry. In vitro anthelminthic activity of the extracts and compounds against the human hookworm, Necator americanus, Stiles 1902 (Nematoda: Ancylostomatidae) was determined within a concentration range of 2500-250 µg/ml using the Egg Hatch Inhibition (EHI) Assay. The hookworm species were identified using a published polymerase chain reaction (PCR) method. RESULTS: A new dichapetalin, dichapetalin X (1), together with the known dichapetalin A (2), pomolic acid (3), glycerol monostearate (4), D:A-friedooleanan-3ß-ol (5), and D:A-friedooleanan-3-one (6) were isolated. Compounds 1, 2, and 4 exhibited EHI with IC50 values of 523.2, 162.4, and 306.0 µg/ml, respectively, against the hookworm. The positive control albendazole gave an IC50 value of 93.27 µg/ml. DISCUSSION AND CONCLUSION: This is the first report of the phytochemical investigation of D. filicaule. The study has yielded a new dichapetalin and also demonstrated the potential anthelminthic properties of the constituents.