RESUMO
A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.
Assuntos
Diterpenos , Quinonas , Extratos Vegetais , Quinonas/farmacologiaRESUMO
To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.
Assuntos
Antimaláricos , Artemisininas , Antimaláricos/farmacologia , Artemisininas/farmacologia , Peróxidos/farmacologiaRESUMO
7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive Plasmodium falciparum strains (K1 and FCR3, respectively). In addition, the time-dependent changes of the addition reactions of the BNTX derivatives with 1-propanethiol were examined by 1H-NMR experiments to estimate their thiol group-trapping ability. The relative chemical reactivity of the BNTX derivatives to trap the thiol group of 1-propanethiol was correlated highly with the antimalarial activity. Therefore, the measurements of the thiol group-trapping ability of the BNTX derivatives with a Michael acceptor is expected to become an alternative method for in vitro malarial activity and related assays.
Assuntos
Compostos de Benzilideno , Morfinanos , Naltrexona/análogos & derivados , Plasmodium falciparum/crescimento & desenvolvimento , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Humanos , Morfinanos/química , Morfinanos/farmacologia , Naltrexona/química , Naltrexona/farmacologia , Ressonância Magnética Nuclear Biomolecular , Relação Estrutura-AtividadeRESUMO
Twelve new furanocassane diterpenoids, sucupiranins A-L (1-12), and three known compounds (13-15) were isolated from the seeds of Bowdichia virgilioides. The structures of the compounds were elucidated via 1H and 13C NMR analysis, including 2D NMR (1H-1H COSY, HSQC, HMBC, and NOESY); HRMS data; and X-ray crystallographic analysis. The absolute configurations were defined using their electronic circular dichroism (ECD) spectra by applying the exciton chirality method to the bis-p-bromobenzoate of compound 13. Sucupiranin J (10) inhibited lipopolysaccharide-induced nitric oxide production (IC50 30.6 µM), whereas sucupiranins J (10), K (11), and 13 exhibited weak antimalarial activity against Plasmodium falciparum K1 with IC50 values of 32.2, 23.5, and 22.9 µM and selectivity indices of 4.3, 1.9, and >12.0 (MRC-5/K1), respectively.
Assuntos
Diterpenos/química , Fabaceae/química , Sementes/química , Antimaláricos/química , Antimaláricos/farmacologia , Cristalografia por Raios X/métodos , Diterpenos/farmacologia , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Óxido Nítrico/metabolismo , Plasmodium falciparum/efeitos dos fármacosRESUMO
The present study evaluated the growth-inhibitory effects of clofazimine, currently used for treating leprosy, against Babesia bovis, B. bigemina, B. caballi, and Theileria equi in in vitro culture and against Babesia microti in mice. The 50% inhibitory concentrations (IC50s) of clofazimine against the in vitro growth of B. bovis, B. bigemina, B. caballi, and T. equi were 4.5, 3, 4.3, and 0.29 µM, respectively. In mice infected with B. microti, treatment with 20 mg/kg of body weight of clofazimine administered orally resulted in a significantly lower peak parasitemia (5.3%) than that in the control group (45.9%), which was comparable to the subcutaneous administration of 25 mg/kg diminazene aceturate, the most widely used treatment for animal piroplasmosis. Although slight anemia was observed in both clofazimine- and diminazene aceturate-treated infected mice, the level and duration of anemia were lower and shorter, respectively, than those in untreated infected mice. Using blood transfusions and PCR, we also examined whether clofazimine completely killed B. microti On day 40 postinfection, when blood analysis was performed, parasites were not found in blood smears; however, the DNA of B. microti was detected in the blood of clofazimine-treated animals and in several tissues of clofazimine- and diminazene aceturate-treated mice by PCR. The growth of parasites was observed in mice after blood transfusions from clofazimine-treated mice. In conclusion, clofazimine showed excellent inhibitory effects against Babesia and Theileria in vitro and in vivo, and further study on clofazimine is required for the future development of a novel chemotherapy with high efficacy and safety against animal piroplasmosis and, possibly, human babesiosis.
Assuntos
Antimaláricos/uso terapêutico , Babesia/efeitos dos fármacos , Babesia/patogenicidade , Clofazimina/uso terapêutico , Theileria/efeitos dos fármacos , Theileria/patogenicidade , Animais , Eritrócitos/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Reação em Cadeia da PolimeraseRESUMO
Janadolide, a new cyclic polyketide-peptide hybrid possessing a tert-butyl group, was isolated from an Okeania sp. marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configurations of the amino acid moieties were determined by acid hydrolysis and chiral-phase HPLC analyses. The absolute configuration of the two stereogenic centers in the polyketide moiety was elucidated based on a combination of degradation reactions and spectroscopic analyses including the phenyl-glycine methyl ester method. Janadolide showed potent antitrypanosomal activity with an IC50 value of 47 nM without cytotoxicity against human cells at 10 µM.
Assuntos
Cianobactérias/química , Peptídeos Cíclicos/isolamento & purificação , Policetídeos/isolamento & purificação , Trypanosoma/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Policetídeos/química , Policetídeos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
During the search for new antitrypanosomal drug leads, four antitrypanosomal compounds, of three depsipeptides and one nortriterpenoid, were isolated from cultures of the mutant strain IU-3 of the insect pathogenic fungus Ophiocordyceps coccidiicola NBRC 100683. Their structures were identified by the analysis of high resolution-electron ionization (HR-EI)-MS and HR-FAB-MS, and (1)H- and (13)C-NMR spectra, including extensive two dimensional (2D)-heteronuclear NMR experiments, and comparison with literature data for destruxin A (1), destruxin B (2), destruxin E chlorohydrin (3) and helvolic acid (4). Compounds 1-4 showed in vitro antitrypanosomal activity against Trypanosoma brucei brucei GUTat3.1 with IC50 values of 0.33, 0.16, 0.061 and 5.08 µg/mL, respectively.
Assuntos
Antiprotozoários/farmacologia , Ascomicetos/química , Trypanosoma brucei brucei/efeitos dos fármacos , Antiprotozoários/química , Antiprotozoários/metabolismo , Ascomicetos/metabolismo , Relação Dose-Resposta a Droga , Conformação Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrinâ A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two-pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)-dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated through our total synthesis. In addition, we evaluated the bioactivity, especially the anti-infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.
RESUMO
A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.
Assuntos
Extratos Vegetais/síntese química , Extratos Vegetais/farmacologia , Salvia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Trypanosoma brucei brucei/fisiologiaRESUMO
Herein, we describe the first asymmetric total synthesis and determination of the relative and absolute stereochemistry of naturally occurring 16-hydroxy-16,22-dihydroapparicine. The key steps include 1)â a novel phosphinimine-mediated cascade reaction to construct the unique 1-azabicyclo[4.2.2]decane core, including a pseudo-aminal-type moiety; 2)â a highly stereospecific 1,2-addition of 2-acylindole or a methylketone through a Felkin-Anh transition state for the construction of a tetrasubstituted carbon center; and 3)â an intramolecular chirality-transferring Michael reaction of the ketoester, with neighboring-group participation, to introduce a chiral center at C15 in the target molecule. In addition, we evaluated the antimalarial activity of synthetic (+)-(15S,16R)-16-hydroxy-16,22-dihydroapparicine and its intermediate against chloroquine-resistant Plasmodium falciparum (K1 strain) parasites.
Assuntos
Antimaláricos/síntese química , Alcaloides Indólicos/síntese química , Aldeídos/química , Antimaláricos/química , Antimaláricos/farmacologia , Compostos Aza/química , Ésteres , Alcaloides Indólicos/química , Oxirredução , Plasmodium falciparum/efeitos dos fármacos , EstereoisomerismoRESUMO
Borrelidin, a structurally unique 18-membered macrolide, was found to express antimalarial activity against drug-resistant Plasmodium falciparum malaria parasites, with IC50 value of 0.93 ng/mL. However, it also displays strong cytotoxicity against human diploid embryonic MRC-5 cells. To investigate the issue of the cytotoxicity of borrelidin, borrelidin-based analogues were synthesized and their anti-Plasmodium properties were evaluated. In this communication, we report that a novel borrelidin analogue, bearing the CH2SPh moiety via a triazole linkage, was found to retain a potent antimalarial activity, against drug-sensitive and drug-resistant parasite strains, but possess only weak cytotoxicity against human cells.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Linhagem Celular , Álcoois Graxos/síntese química , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure-activity relationship (SAR) studies were also undertaken.
RESUMO
To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp(3) ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine.
Assuntos
Sesquiterpenos/síntese química , Tripanossomicidas/síntese química , Artemisininas/síntese química , Artemisininas/química , Artemisininas/farmacologia , Linhagem Celular , Humanos , Estrutura Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
A fungal metabolite, diatretol, has shown to be a promising antimalarial agent. Diatretol displayed potent in vitro antiparasitic activity against the Plasmodium falciparum K1 strain, with an IC50 value of 378 ng ml-1, as well as in vivo efficacy in a Plasmodium berghei-infected mice model, with ca. 50% inhibition at 30 mg/kg (p.o.).
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Animais , Antimaláricos/química , Dicetopiperazinas/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/parasitologia , Humanos , Malária/parasitologia , Camundongos Endogâmicos ICR , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Plasmodium berghei/parasitologia , Plasmodium falciparum/efeitos dos fármacosRESUMO
Kozupeptins A and B, novel antimalarial lipopeptides, were isolated from the culture broths of Paracamarosporium sp. FKI-7019. They exhibited potent antimalarial activity against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. The structural elucidation was accomplished by a combination of spectroscopic analyses and chemical approaches including a total synthesis of kozupeptin A. Synthetic kozupeptin A demonstrated a therapeutic effect in vivo, and an intermediate exhibited much higher antimalarial activity than kozupeptin A.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Cloroquina/química , Estrutura Molecular , Plasmodium falciparum/químicaRESUMO
The aim of the present study was chemical clarification of in vitro Peyer's patch-immunomodulating polysaccharides in sugar cane molasses, and evaluation of in vivo modulating activity on immune function of T lymphocytes in Peyer's patches and on microenvironment of hemopoietic system. Five kinds of glucans, comprising of dextranase-sensitive and activity-related d-glucosyl moieties, were purified as in vitro Peyer's patch-immunomodulating polysaccharides from the molasses. Oral administration of a glucan-enriched subfraction induced IL-2 and GM-CSF-producing T lymphocytes in Peyer's patches, resulting in enhancement of IL-6 production in a hemopoietic microenvironment to boost neutrophil numbers in the peripheral blood stream. Oral administration of purified glucan or glucan-enrich sub-fraction of sugar cane reduced the number of Plasmodium berghei- or P. yoelii-infected erythrocytes in a murine infection model, using polysaccharide alone or via co-administration with the antimalarial drug, artesunate. These results suggested that Peyer's patch-immunomodulating glucans enhanced protective immunity through axis of Peyer's patches-hemopoietic system.
Assuntos
Glucanos/farmacologia , Hematopoese/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Malária/tratamento farmacológico , Nódulos Linfáticos Agregados/efeitos dos fármacos , Saccharum/química , Administração Oral , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Feminino , Expressão Gênica/efeitos dos fármacos , Glucanos/química , Glucanos/isolamento & purificação , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hematopoese/imunologia , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Nódulos Linfáticos Agregados/imunologia , Extratos Vegetais/química , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Five pregnane glycosides were isolated from Caralluma tuberculata (1-5), in addition to a known one (russelioside E, 6). The structures of the isolated compounds were elucidated by the analysis of NMR data and FAB-MS experiments. All the isolated compounds were tested for their antimalarial and antitrypanosomal activities as well as their cytotoxicity against human diploid embryonic cell line (MRC5).
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Apocynaceae/química , Glicosídeos/química , Glicosídeos/farmacologia , Pregnanos/química , Acilação , Animais , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A new lycorine derivative LT1 (4) was isolated from the aerial part and bulbs of Lycoris traubii Hayward (Amaryllidaceae). Its structure including absolute configuration was established by spectroscopic analysis and semi-synthesis to be 1-O-(3'S)-hydroxybutanoyllycorine. Some lycorine ester derivatives including LT1 were examined for their inhibitory activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against Plasmodium falciparum, the causative agent of malaria. Among them, 2-O-acetyllycorine (6) showed the most potent activity against parasitic T. b. brucei, and LT1 (4), 1-O-(3'R)-hydroxybutanoyllycorine (8), 1,2-di-O-butanoyllycorine (11), and 1-O-propanoyllycorine (12) showed significant activity against P. falciparum in an in vitro experiment.
Assuntos
Alcaloides/farmacologia , Alcaloides de Amaryllidaceae/química , Antimaláricos/química , Antimaláricos/farmacologia , Liliaceae/química , Fenantridinas/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides de Amaryllidaceae/isolamento & purificação , Animais , Antimaláricos/isolamento & purificação , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Fenantridinas/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Tripanossomicidas/isolamento & purificaçãoRESUMO
Simaomicin alpha shows potent antimalarial activity in vitro and is known to be a cell-cycle effector. As erythrocytic schizogony of Plasmodium correlates with cell cycle events, we investigated the effect of simaomicin alpha on stage development of the malaria parasite Plasmodium falciparum. Simaomicin alpha interferes with normal parasite development in a time and concentration dependent manner. Parasites exposed to 2.5 nM simaomicin alpha at the ring stage or trophozoite stage showed disrupted development and immature schizont-like and segmenter-like forms were observed. However, schizont stage parasites were not affected by 2.5 nM simaomicin alpha. It is unclear whether mitosis involved in sequential parasite development occurred when parasites were exposed to simaomicin alpha at the ring or trophozoite stage. At a concentration of 5.0 nM, simaomicin alpha inhibited merozoite-trophozoite development. This concentration curtails p-LDH activity at all parasite stages, although its impact on the schizont stage is delayed for 24 hours.
Assuntos
Antimaláricos/farmacologia , Isoquinolinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Plasmodium falciparum/citologia , Plasmodium falciparum/crescimento & desenvolvimentoRESUMO
More than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the Kitasato Institute for Life Sciences, were screened against African trypanosomes. Ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin A, echinomycin, hedamycin, irumamycin, LL-Z 1272beta, O-methylnanaomycin A, venturicidin A and virustomycin A. Results of the in vitro assays using the GUTat 3.1 strain of Trypanosomal brucei brucei and the STIB900 strain of T. b. rhodesiense are presented. Cytotoxicity was determined using a human MRC-5 cell line. This is the first report of antitrypanosomal activities of the 10 microbial metabolites listed above.