Subjective biosafety assessment of bisdemethoxycurcumin from the rhizomes of Curcuma longa.

Introduction/Background: Curcuma longa, a plant native to the Indian subcontinent has a variety of biological activities. Curcumin is the most abundant and biologically active compound with many therapeutic properties. Demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) - the two other bioactive components present in Curcuma longa, besides curcumin, are collectively termed curcuminoids. Apart from the well-known curcumin, BDMC also has been reported to possess promising biological and pharmacological effects, but very little scientific evidence on its safety assessment has been published.Objective: The present study was undertaken to determine the safety of pure BDMC from Curcuma longa extract in rodents which comprises of general toxicity (both four weeks and three months duration), reproductive/developmental toxicity and genotoxicity studies.Methods: The Good Laboratory Practice studies were carried out in accordance with the test guidelines established by the Organization for Economic Cooperation and Development.Results: No treatment-related adverse findings were seen in general toxicity testing and a no observed adverse effect level (NOAEL) of 1000 mg/kg/day was established after four weeks (sub-acute) and three-months (sub-chronic) dosing. Evaluation of fertility, embryo-fetal, and post-natal reproductive and developmental parameters also showed no adverse findings with a NOAEL of 1000 mg/kg/day established. The results of genotoxicity as evaluated by in vitro reverse mutation assay, and in vivo micronucleus test in mice indicate that BDMC did not induce any genotoxic effects.Conclusion: Oral administration of BDMC is safe in rodents and non-mutagenic, with no adverse effects under experimental conditions.

Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1ß, acetylcholinesterase, and ß-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.

Demethoxycurcumin Suppresses Human Brain Glioblastoma Multiforme GBM 8401 Cell Xenograft Tumor in Nude Mice In Vivo.

Demethoxycurcumin (DMC), a derivate of curcumin, has been shown to induce apoptotic cell death in human glioblastoma multiforme GBM 8401 cells via cell cycle arrest and induction of cell apoptosis. However, there is no report showing DMC suppresses glioblastoma multiforme cells in vivo. In the present study, we investigated the effects of DMC on GBM8401 cells in vivo. At first, we established a luciferase-expressing stable clone named GBM 8401/luc2. Second, mice were inoculated subcutaneously with GBM 8401/luc2 cells to generate a xenograft tumor mice model. After inoculation, tumor volume reached 100-120 mm3, and all mice were randomly divided into three groups: Group I was treated with 110 µL phosphate-buffered solution (PBS) containing 0.1% dimethyl sulfoxide, Group II with 30 mg/kg of DMC, and Group III with 60 mg/kg of DMC. Mice from each group were given the oral treatment of DMC by gavage for 21 days. The body weight and tumor volume were recorded every 3 days. DMC significantly decreased the tumor volumes, and 60 mg/kg treatment showed a higher decrease in tumor volumes than that of 30 mg/kg, However, DMC did not affect the body weights. The photons emitted from mice tumors were detected with Xenogen IVIS imaging system, DMC at both doses decreased the total photon flux and 60 mg/kg treatment of DMC has low total photon flux than that of 30 mg/kg. The tumor volumes and weights in 60 mg/kg treatment of DMC were lower than that of 30 mg/kg. Immunohistochemical analysis was used to measure protein expression of tumors and results showed that DMC treatment led to lightly staining with anti-Bcl-2 and -XIAP and 60 mg/kg treatment of DMC has lighter staining with anti-Bcl-2 and -XIAP than that of 30 mg/kg. The higher dose (60 mg/kg) of DMC has higher signals of cleaved-caspase-3 than that of the lower dose (30 mg/kg). Furthermore, the hematoxylin and eosin (H&E) staining of liver tissues showed no significant difference between DMC-treated and control-groups. Overall, these observations showed that DMC suppressed tumor properties in vivo and DMC may be used against human glioblastoma multiforme in the future.

Bioprospection of novel synthetic monocurcuminoids: Antioxidant, antimicrobial, and in vitro cytotoxic activities.

The irrational use of medications has increased the incidence of microbial infections, which are a major threat to public health. Moreover, conventional therapeutic strategies are starting to become ineffective to treat these infections. Hence, there is a need to develop and characterize novel antimicrobial compounds. Phytochemicals are emerging as a safe and accessible alternative to conventional therapeutics for treating infectious diseases. Curcumin is extracted from the dried rhizome of the spice turmeric (Curcuma longa (Zingiberaceae)). However, the bioavailability of curcumin is low owing to its lipophilic property and thus has a low therapeutic efficacy in the host. A previous study synthesized structural variants of curcumin, which are called monocurcuminoids (CNs). CNs are synthesized based on the chemical structure of curcumin with only one methyl bridge. The biological activities of four previously synthesized CNs (CN59, CN63, CN67, and CN77), curcumin, and turmeric powder were examined in this study. Gas chromatography-tandem mass spectrometry analysis of curcumin and turmeric powder revealed similar peaks, which indicated the presence of curcumin in turmeric powder. The antioxidant activity of the test compounds was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays. The ABTS radical scavenging activities of the test compounds were similar to those of vitamin C. The minimum inhibitory concentration (MIC) values of the test compounds against seven microbial strains were in the range of 4.06-150 µg/mL. The MIC value was equal to minimum bactericidal concentration value for CN63 (150 µg/mL) and CN67 (120 µg/mL) against Staphylococcus aureus. The treatment combination of CN77 (8.75 or 4.37 µg/mL) and turmeric powder (9.37 or 4.68 µg/mL) exerted synergistic growth-inhibiting effects on Aeromonas hydrophila, Candida albicans, and Pseudomonas aeruginosa. Photodynamic therapy using 2X MIC of CN59 decreased the growth of Enterococcus faecalis by 4.18-fold compared to the control group and completely inhibited the growth of Escherichia coli. The results of the hemolytic assay revealed that the test compounds were not cytotoxic with half-maximal inhibitory concentration values ranging from 49.65-130.9 µM. The anticoagulant activity of most compounds was comparable to that of warfarin but higher than that of heparin. This indicated that these compounds target the intrinsic coagulation pathway. These results demonstrated that these CNs are a safe and promising alternative for curcumin.

Demethoxycurcumin analogue DMC-BH inhibits orthotopic growth of glioma stem cells by targeting JNK/ERK signaling.

Glioma stem cells (GSCs) play an important role in glioblastoma resistance to conventional therapies and disease recurrence. Here, we assessed the therapeutic effect of a demethoxycurcumin analogue, DMC-BH, on GSCs, and investigated the underlying mechanisms. Our in vitro data demonstrate that DMC-BH inhibits GSC proliferation, and induces apoptosis and autophagy in GSCs. In addition, our results show that DMC-BH effectively crosses the blood-brain barrier to inhibit the growth of intracranial GSC tumors in vivo. DMC-BH significantly increased phosphorylation levels of JNK, ERK and c-Jun in GSCs. Inhibition of JNK and ERK activities reversed the pro-apoptotic effect of DMC-BH in GSCs, indicating that the DMC-BH-induced apoptosis in GSCs is mediated via the JNK/ERK signaling pathway. These results suggest that DMC-BH could potentially serve as a effective therapy against GSCs that acts by targeting the JNK/ERK signaling pathway.

Bisdemethoxycurcumin promotes apoptosis in human platelets via activation of ERK signaling pathway.

Curcumin, a major bioactive component of turmeric (Curcuma longa), is known for its multiple health benefits. Curcumin as such is a mixture of its analogs: bisdemethoxycurcumin (BDMC)-3%, and demethoxycurcumin (DMC)-17%. Although the effect of curcumin on platelets is documented, the effect of BDMC and DMC on platelets is less studied. Considering the indispensable role played by platelets in hemostasis, thrombosis, inflammation, and immunity, the present study evaluates the effect of curcumin, DMC and BDMC on platelet apoptosis. The components of curcumin were purified by silica-gel column chromatography. The purity and mass analysis of the purified curcuminoids was determined by RP-HPLC and LC-MS respectively. When analyzed for platelet apoptotic markers, only BDMC demonstrated increased incidence of platelet apoptotic markers including increase in intracellular Ca2+, decrease in ∆ψm, alteration in BCl-2 family proteins, the release of cytochrome c, caspase activation, and PS externalization via activation of ERK activation. ERK inhibitor PD98059 significantly alleviated BDMC induced decrease in ∆ψm, alteration in BCl-2, caspase-8 activation and PS externalization. Our results demonstrate that curcumin, DMC and BDMC differentially act on platelet in inducing apoptosis and the study highlights that the toxicity associated with curcumin therapy might be attributed to BDMC in the mammalian system.

Bactericidal and cytotoxic activity of a diarylheptanoid (etlingerin) isolated from a ginger (Etlingera pubescens) endemic to Borneo.

AIMS: The aim of this study was to investigate the antimicrobial activities of Etlingera pubescens, and to isolate and identify the antimicrobial compound. METHODS AND RESULTS: The crude extracts of E. pubescens were obtained through methanol extraction, and evaluated for antimicrobial activities. From this extract, 1,7-bis(3,4-dihydroxyphenyl)heptan-3-yl acetate (etlingerin) was isolated. When compared to curcumin (a compound with a similar chemical structure), etlingerin showed twofold lower minimum inhibitory concentration values while also being bactericidal. Through time kill assay, etlingerin showed rapid killing effects (as fast as 60 min) against the Gram-positive bacteria (Staphylococcus aureus ATCC 43300 and Bacillus subtilis ATCC 8188). Further assessment revealed that etlingerin caused leakage of intracellular materials, therefore suggesting alteration in membrane permeability as its antimicrobial mechanism. Cytotoxicity study demonstrated that etlingerin exhibited approximately 5- to 12-fold higher IC50 values against several cell lines, as compared to curcumin. CONCLUSIONS: Etlingerin isolated from E. pubescens showed better antibacterial and cytotoxic activities when compared to curcumin. Etlingerin could be safe for human use, though further cytotoxicity study using animal models is needed. SIGNIFICANCE AND IMPACT OF THE STUDY: Etlingerin has a potential to be used in treating bacterial infections due to its good antimicrobial activity, while having potentially low cytotoxicity.

The mechanistic antitumor study of myricanol 5-fluorobenzyloxy ether in human leukemic cell HL-60.

AIM: The aim of the study was to explore the growth inhibitory effect of myricanol 5-fluorobenzyloxy ether (5FEM) and the underlying mechanism in human leukemic cells HL-60. MATERIALS & METHODS: 5FEM was obtained by chemical modification of myricanol with fluorobenzyloxy ether at the OH(5) position. The cytotoxicity, cell apoptosis, cell cycle and the expression of key apoptosis-related genes in HL-60 were evaluated. RESULTS & CONCLUSION: 5FEM can significantly inhibited growth of HL-60 cells, increased the G2/M population and upregulated the expression of Bax, Fas, FasL, caspase-9 and p21 and downregulated that of Bcl-2 and survivin. The results enhance our understanding of 5FEM and aid the discovery of novel myricanol derivatives as potential antitumor agents.

Diarylheptanoid from Curcuma comosa Roxb. suppresses RANKL-induced osteoclast differentiation by decreasing NFATc1 and c-Fos expression via MAPK pathway.

Osteoporosis is caused by a functional imbalance between osteoblasts and osteoclasts. The increased activation of osteoclasts that is a hallmark of osteoporosis results in the progressive loss of bone mass and therefore in an increased susceptibility to bone fractures. Diarylheptanoids are a group of phytoestrogens that have been isolated from a number of plant species, including the rhizomes of Curcuma comosa Roxb. In this study, the effect of one of diarylheptanoids, (3S)-1-(3,4-dihydroxyphenyl)-3-hydroxy-7-phenyl-(6E)-6-heptene (DHPH), was investigated for anti-inflammatory and anti-osteoclastogenic activity. DHPH significantly inhibited nitric oxide production in RAW264.7 cell line following their activation by lipopolysaccharide and interferon-γ, with no cytotoxicity. In primary mouse bone-marrow-derived macrophage precursors, DHPH suppressed osteoclastogenesis induced by receptor activator of nuclear factor-κB (RANK) ligand at an inhibitory concentration 50 of 325±1.37nM. DHPH treatment delayed and reduced the expression of master regulators of osteoclast differentiation, NFATc1 and c-Fos. Consistent with this result, the mRNA level of cathepsin K, associated with osteoclast differentiation, was decreased whereas the reduction in the mRNA of irf8, a negative regulator of osteoclast differentiation, was similar to that measured in the vehicle-treated control cells. DHPH reduced the phosphorylation of p38 MAPK, ERK (p44/42). Furthermore, DHPH suppressed the bone absorption activity of osteoclasts and enhanced osteoblast differentiation. Taken together, DHPH interrupts the immediate downstream signaling cascade of RANK and interferes with osteoclast differentiation and its function while enhances osteoblast differentiation. These results demonstrate the potential of this diarylheptanoid as a new therapeutic agent in osteoporosis.

Protective effect of diarylheptanoids from Curcuma comosa on primary rat hepatocytes against t-butyl hydroperoxide-induced toxicity.

CONTEXT: Curcuma comosa Roxb. (Zingiberaceae) has traditionally been used as an anti-inflammatory agent in liver, and recent study has shown its hepatoprotective effect against CCl4-induced liver injury in vivo. OBJECTIVE: This study further assesses the protective effect of C. comosa extracts and its isolated compounds against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in isolated primary rat hepatocytes. MATERIALS AND METHODS: Isolated primary hepatocytes were pretreated with either ethanol (5-50 µg/ml) or hexane extract (1-50 µg/ml), or two diarylheptanoids (4-35 µM): compound D-91 [1-(4-hydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol] and compound D-92 [(3S)-1-(3,4-dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol], from C. comosa for 2 h prior to exposure to 1.5 mM t-BHP for 15 and 30 min. Their hepatoprotective activities were then determined. RESULTS: t-BHP markedly caused the formation of MDA and ALT leakage from the hepatocytes. Pretreatment with the C. comosa ethanol extract showed greater protective effect than the hexane extract, and the effect was concentration related. Treating the hepatocytes with compound D-92 provided greater protective effect than compound D-91. IC50 values of compounds D-91, D-92, and silymarin for the protection of ALT leakage at 30 min were 32.7 ± 1.1, 9.8 ± 0.7, and 160 ± 8 µM, respectively. Further investigation showed that compound D-92 was more effective in maintaining the intracellular glutathione content in the t-BHP treated group, whereas the reduction in antioxidant enzymes, glutathione peroxidase and glutathione-S-transferase activities, were not improved. DISCUSSION AND CONCLUSION: Results suggest that diarylheptanoids are the active principles that provide protection against t-BHP-induced injury. Their ability to maintain intracellular glutathione content is the main mechanisms underlying the protective action.

Development of phenotypic and transcriptional biomarkers to evaluate relative activity of potentially estrogenic chemicals in ovariectomized mice.

BACKGROUND: Concerns regarding potential endocrine-disrupting chemicals (EDCs) have led to a need for methods to evaluate candidate estrogenic chemicals. Our previous evaluations of two such EDCs revealed a response similar to that of estradiol (E2) at 2 hr, but a less robust response at 24 hr, similar to the short-acting estrogen estriol (E3). OBJECTIVES: Microarray analysis using tools to recognize patterns of response have been utilized in the cancer field to develop biomarker panels of transcripts for diagnosis and selection of treatments most likely to be effective. Biological effects elicited by long- versus short-acting estrogens greatly affect the risks associated with exposures; therefore, we sought to develop tools to predict the ability of chemicals to maintain estrogenic responses. METHODS: We used biological end points in uterine tissue and a signature pattern-recognizing tool that identified coexpressed transcripts to develop and test a panel of transcripts in order to classify potentially estrogenic compounds using an in vivo system. The end points used are relevant to uterine tissue, but the resulting classification of the compounds is important for other sensitive tissues and species. RESULTS: We evaluated biological and transcriptional end points with proven short- and long-acting estrogens and verified the use of our approach using a phytoestrogen. With our model, we were able to classify the diarylheptanoid D3 as a short-acting estrogen. CONCLUSIONS: We have developed a panel of transcripts as biomarkers which, together with biological end points, might be used to screen and evaluate potentially estrogenic chemicals and infer mode of activity.

Diterpenoids and a diarylheptanoid from Hedychium coronarium with significant anti-angiogenic and cytotoxic activities.

Two new labdane diterpenoids, namely hedycoronals A and B (1 and 2, resp.), were isolated from the rhizomes of Hedychium coronarium, together with eight known diterpenoids, 4-11, and a known diarylheptanoid, 3. The structures of 1 and 2 were established by detailed interpretation of their 1D- and 2D-NMR spectra and HR-ESI-MS data. Inhibitory activities against human umbilical vein endothelial cells (HUMECs) proliferation and cytotoxic activities against four cancer cell lines were assessed for all the isolates. Most of these metabolites showed moderate or potent cytotoxic activities against four cancer cell lines. Moreover, compounds 3 and 8 exhibited promising inhibitory activities against HUMECs with the IC(50) values of 6.4 to 3.3 µM.

Anti-inflammatory activities, triterpenoids, and diarylheptanoids of Alnus acuminata ssp. arguta.

CONTEXT: The main use of stem bark infusions of Alnus acuminata ssp. arguta (Schlecht.) Furlow (Betulaceae) includes treatments for acute inflammation in Mexican traditional medicine. OBJECTIVE: n-Hexane (CHE), chloroform (CCE), and methanol (CME) extracts of the stem bark were investigated for anti-inflammatory activity and its safety. MATERIALS AND METHODS: The anti-inflammatory effects of the orally administered CME, CCE, and CHE extracts, using carrageenan-induced rat hind paw edema model, and acute oral toxicity in mice, using Lorke's method, were determined. RESULTS AND DISCUSSION: The column chromatographic fraction (CME-3) showed a higher anti-inflammatory activity (92.2%) (IC(50): 60.8 mg/mL) as compared with CME (76.9%); both were in the same order of magnitude as that of indomethacin, the positive control drug. Safety parameters for acute oral toxicity test showed that CME was not toxic (LD(50): >5000). Several triterpenoids (1-7) from hexane extracts and diarylheptanoids (10-14) from methanol extracts of A. acuminata ssp. arguta were isolated and characterized. CONCLUSIONS: These results confirm the traditional uses of A. acuminata in acute inflammatory conditions and its safety for consumption.

Diarylheptanoid 7-(3,4 dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene from Curcuma comosa Roxb. protects retinal pigment epithelial cells against oxidative stress-induced cell death.

Chronic exposure to oxidative stress causes damage to retinal pigment epithelial cells which may lead to the development of age-related macular degeneration, the major cause of vision loss in humans. Anti-oxidants provide a natural defense against retinal cell damage. The present study was designed to evaluate the potential anti-oxidant activity and protective effect of two diarylheptanoids isolated from a medicinal herb Curcuma comosa; 7-(3,4 dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound A), and 1,7-diphenyl-4(E),6(E)-heptadien-3-ol (compound B) against oxidative stress (H(2)O(2))-induced human retinal pigment epithelial (APRE-19) cell death. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay indicated that the anti-oxidant activity (IC(50)) of compound A was similar to that of vitamin C. Pre-treatment of ARPE-19 cells with 20 µM compound A for 4h afforded greater protection against the insult from 500 µM H(2)O(2), compared to a similar protection period for compound B. Compound A lowered H(2)O(2)-induced lipid peroxidation, malondialdehyde formation and intracellular reactive oxygen species. Furthermore, compound A ameliorated the H(2)O(2)-induced decrease in anti-oxidant enzyme activities and subsequent apoptotic cell death in ARPE-19 cells in a dose and time-dependent manner. These results suggest that compound A protects ARPE-19 cells against oxidative stress, in part, by enhancing several anti-oxidant defense mechanisms. Therefore, compound A may have therapeutic potential for diseases associated with oxidative stress, particularly degenerative retinal diseases.

[Antioxidative and cytotoxic properties of diarylheptanoids isolated from Zingiber officinale].

OBJECTIVE: To investigate the antioxidant and cytotoxic properties of five diarylheptanoids (1-5) isolated from the rhizomes of Zingiber officinale. METHOD: Various models such as scavenging superoxide anions and 1,1-diphenyl-2- picrylhydrazyl (DPPH) radicals, inhibiting lipid peroxidation, as well as protecting of rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H2O2) were employed to assay the antioxidative effects of the diarylheptanoids. The cytotoxicities of compounds 1-5 were measured with MTT assays. RESULT: The test compounds (1-5) showed promising DPPH inhibitory activities, and compound 5 exhibited the strongest DPPH scavenging activity with an IC50 value of (22.6+/-2.4) micromol x L(-1). Compounds 1, 3 and 4 showed potential anti-peroxidative effects with inhibitory rates of (66.3+/-15.4)%, (68.7+/-15.8)% and (72.2+/-10.6)%, respectively, at 100 microg x mL(-1). It could be observed that compounds 1, 3 and 4 demonstrated significant neuroprotective activities in a dose-dependent manner. Moreover, compound 3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR) with IC50 values of (34.9+/-0.6), (50.6+/-23.5) micromol x L(-1), respectively. CONCLUSION: In vitro results demonstrated that five diarylheptanoids (1-5) isolated from the roots of Z. officinale were capable of scavenging radicals, inhibiting lipid peroxidation and protecting PC12 cells against the insult by H2O2. Additionally, compound 3 could inhibit the growth of K562 and K562/ADR cells.

An effective diaryl derivative against Leishmania amazonensis and its influence on the parasite X macrophage interaction.

The activity of several diarylheptanoid derivatives (curcuminoids) was previously evaluated against Leishmania amazonensis promastigotes and among them the most active compound was 5-hydroxy-7- (4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl)-1,4,6-heptatrien-3-one. This study was carried out to investigate the influence of this diaryl derivative on the infective promastigotes and Balb/c mice peritoneal macrophage interaction. The potential in vitro toxicity was also evaluated. Promastigotes pretreated for 24 hours with the compound had their infective capacity significantly decreased. When the infection of Balb/c macrophage by L. amazonensis promastigotes was already installed, addition of the drug resulted in a diminishing of the infection rate. It was demonstrated that the compound was not toxic to the host macrophage in a concentration equivalent to the LD50/24h from the previous in vitro experiment.

Estudo de compostos diarílicos como potenciais agentes leishmanicidas: avaliação do efeito na biossíntese de esteróides / Study of diarylic compounds as potents leishmanicidal agents: evaluation of the effect in biosynthesis of steroids

Compostos diarílicos derivados da curcumina vêm sendo estudados pelo nosso grupo contra algumas espécies de Leishmania com resultados bastante promissores. Dando continuidade a este projeto, no presente trabalho foram estudados in vitro e in vivo derivados diarílicos sintéticos: diarilheptanóides e diarilpentanóides, contra contra promastigotas de L. braziliensis, L. chagasi e L. amazonensis e amastigotas axênicas de L. amazonensis. Nossos resultados in vitro mostraram que de uma maneira geral, os diarilheptanóides foram mais ativos que os diarilheptanóides contra as três espécies de Leishmania estudadas, e que funções oxigenadas nos anéis e uma cadeia alifática de maior número de carbonos são importantes para a atividade leishmanicida. O diarilheptanóide l (5-hidroxi-7-(4-hidroxi-3-metoxifenil)-1-4-metoxifenil)-1,4,6-heptatrien-3-ona), que foi o mais ativo nos experimentos in vitro, foi escolhido para dar continuidades aos experimentos. Nos ensaios de toxicidade in vitro utilizando-se macrófagos peritoniais de camundongos Balb/c, este composto não se mostrou deletério paras as células do hospedeiro, mesmo em concentrações 10 vezes maior que o equivalente ao seu IC50/24h=0,514mM. O efeito sobre a infecção de macrófagos por L. amazonensis, sugere uma toxicidade seletiva contra as amastigotas intracelulares. Além disto, foi observado um efeito no processo de interiorização dos parasitas nos macrófagos, possivelmente indicando alterações em moléculas de superfície do parasita. O estudo in vivo, mostrou que o composto foi eficaz, diminuindo o tamanho das patas dos camundongos Balb/c tratados experimentalmente com até três doses, quando comparados aos animais que não receberam tratamento ou que foram tratados com a Pentamidina, que foi a droga de referência em todos os experimentos. A análise do efeito do composto no metabolismo de ergosterol de L. amazonensis, mostrou mudanças significativas na biossíntese deste esteLmetilados e a inibição completa de sua síntese, permitindo supor ser esta via metabólica um potencial alvo para os compostos diarílicos.