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1.
Nat Prod Res ; 35(17): 2972-2976, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31631695

RESUMO

In the current study, chemical composition of cultivated Salvia canariensis L was determined. Carnosol was the main product isolated. We prepared more lipophilic derivatives from carnosol, and both isolated and semisynthetic abietane diterpenes were evaluated in vitro as inhibitors of squalene synthase. Among the compounds tested, carnosol was the most potent inhibitor (IC50 = 17.6 µM). These results highlight the great potential of this species for the production of new ingredients in nutritional supplements for the treatment of hyperlipidemia.


Assuntos
Abietanos/farmacologia , Diterpenos , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Salvia , Abietanos/isolamento & purificação , Animais , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Fígado/enzimologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Ratos , Salvia/química
2.
Antimicrob Agents Chemother ; 59(10): 6402-18, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26239973

RESUMO

Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Ergosterol/antagonistas & inibidores , Itraconazol/farmacologia , Leishmania mexicana/efeitos dos fármacos , Piridinas/farmacologia , Quinuclidinas/farmacologia , Triazóis/farmacologia , Tripanossomicidas/farmacologia , Animais , Meios de Cultura/química , Sinergismo Farmacológico , Quimioterapia Combinada , Ergosterol/biossíntese , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Farnesil-Difosfato Farnesiltransferase/metabolismo , Humanos , Leishmania mexicana/isolamento & purificação , Leishmania mexicana/metabolismo , Leishmania mexicana/ultraestrutura , Leishmaniose Tegumentar Difusa/parasitologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/ultraestrutura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Esterol 14-Desmetilase/metabolismo
3.
Parasitol Res ; 113(6): 2185-97, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24752367

RESUMO

Trichomonas vaginalis causes trichomoniasis in humans, a sexually transmitted disease commonly treated with metronidazole (MTZ), a drug that presents some toxicity, causing undesirable side effects. In addition, an increase in metronidazole-resistant parasites has been reported. Thus, the development of alternative treatment is recommended. To date, the search for antiparasitic drugs has been based on different approaches: identification of active natural products, identification of parasite targets, and the use of available compounds active against other pathogenic microorganisms. Here, we analyzed the in vitro antiproliferative and ultrastructural effects on T. vaginalis of BPQ-OH, a hydroxiquinuclidine derivative that inhibits squalene synthase and is active against several protozoa and fungi. We also compared the effects of BPQ-OH on T. vaginalis and mammalian cells with those of MTZ. We found that BPQ-OH inhibits in vitro proliferation of T. vaginalis, with an IC50 of 46 µM after 24 h. Although this IC50 is 16 times higher than that of MTZ (1.8 µM), BPQ-OH is less toxic for human cell lines than MTZ, with LC50 values of 2,300 and 70 µM, and selective indexes of 50 and 39, respectively. Ultrastructural analyses demonstrated that BPQ-OH induced alterations in T. vaginalis, such as rounded and wrinkled cells, membrane blebbing and intense vacuolization, leading to cell death, whereas MTZ also caused significant changes, including a decrease in hydrogenosomes size and endoflagellar forms. Our observations identify BPQ-OH as a promising leading compound for the development of novel anti-T. vaginalis drugs and highlight the need for further testing this molecule using experimentally infected animals.


Assuntos
Antiprotozoários/farmacologia , Metronidazol/farmacologia , Quinuclidinas/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Animais , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Células HeLa , Humanos , Organelas/efeitos dos fármacos , Trichomonas vaginalis/citologia , Trichomonas vaginalis/ultraestrutura
4.
J Infect Chemother ; 17(4): 563-70, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21264486

RESUMO

Three quinuclidine-based squalene synthase (SQS) inhibitors (BPQ-OH, E5700, and ER-119884) were evaluated against five Candida tropicalis strains with different susceptibility profiles to fluconazole (FLC), itraconazole (ITC), terbinafine (TRB), and amphotericin B (AMB). Although the quinuclidine derivatives were inactive against most C. tropicalis strains tested at concentrations up to 16 µg/ml, E5700 and ER-119884 showed antifungal activity against C. tropicalis ATCC 28707, a strain resistant to FLC, ITC, and AMB, with IC(50) and IC(90) values (i.e., the minimum inhibitory concentrations of the drugs determined as the lowest drug concentrations leading to a 50 and 90% of reduction in turbidity at 492 nm, respectively, after 48 h of incubation) of 1 and 4 µg/ml, respectively. Analysis of free sterols showed that non-treated C. tropicalis ATCC 28707 cells contained only 14-methylated sterols and that treatment with E5700 or ER-119884 led to a marked reduction of squalene content and the complete disappearance of the endogenous sterols. The fatty acid and phospholipid profiles in C. tropicalis ATCC 28707 cells grown in the presence of E5700 and ER-119884 were also markedly altered, with a large increase in the content of linolenic acid (C18:3), associated with a reduction in the content of linoleic (C18:2) and oleic (C18:1) acids. Treatment of C. tropicalis ATCC 28707 with E5700 or ER-119884 IC(50) values induced several ultrastructural alterations, including a marked increase in the thickness of the cell wall and the appearance of a large number of electron-dense vacuoles. In conclusion, our results indicated that E5700 and ER-119884 inhibited the growth and altered the lipid prolife and the ultrastructure of a multiple drug-resistant C. tropicalis strain. Therefore, such compounds could act as leads for the development of new treatment options against multidrug resistant Candida species.


Assuntos
Candida tropicalis/efeitos dos fármacos , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Ácidos Graxos/metabolismo , Piridinas/farmacologia , Quinuclidinas/farmacologia , Anfotericina B/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Candida tropicalis/química , Candida tropicalis/citologia , Candida tropicalis/metabolismo , Proliferação de Células/efeitos dos fármacos , Farmacorresistência Fúngica Múltipla , Ácidos Graxos/química , Ácidos Graxos/classificação , Fluconazol/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Histocitoquímica , Concentração Inibidora 50 , Itraconazol/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Piridinas/química , Quinuclidinas/química
5.
Ann Clin Microbiol Antimicrob ; 10: 3, 2011 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-21255433

RESUMO

BACKGROUND: Sterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14α-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains. METHODS: Ten arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy. RESULTS: The most potent arylquinuclidine derivative (3-[1'-{4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 µg/ml for all species tested and MIC90 varying from 4 µg/ml to 8 µg/ml. Ultrathin sections of C. albicans treated with 1 µg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei. CONCLUSION: Taken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Quinuclidinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Candida/enzimologia , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/enzimologia , Candidíase/microbiologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Proteínas Fúngicas/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Quinuclidinas/síntese química , Quinuclidinas/química
6.
Antimicrob Agents Chemother ; 52(11): 4098-114, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18765694

RESUMO

ER-119884 and E5700, novel arylquinuclidine derivatives developed as cholesterol-lowering agents, were potent in vitro growth inhibitors of both proliferative stages of Leishmania amazonensis, the main causative agent of cutaneous leishmaniasis in South America, with the 50% inhibitory concentrations (IC(50)s) being in the low-nanomolar to subnanomolar range. The compounds were very potent noncompetitive inhibitors of native L. amazonensis squalene synthase (SQS), with inhibition constants also being in the nanomolar to subnanomolar range. Growth inhibition was strictly associated with the depletion of the parasite's main endogenous sterols and the concomitant accumulation of exogenous cholesterol. Using electron microscopy, we identified the intracellular structures affected by the compounds. A large number of lipid inclusions displaying different shapes and electron densities were observed after treatment with both SQS inhibitors, and these inclusions were associated with an intense disorganization of the membrane that surrounds the cell body and flagellum, as well as the endoplasmic reticulum and the Golgi complex. Cells treated with ER-119884 but not those treated with E5700 had an altered cytoskeleton organization due to an abnormal distribution of tubulin, and many were arrested at cytokinesis. A prominent contractile vacuole and a phenotype typical of programmed cell death were frequently found in drug-treated cells. The selectivity of the drugs was demonstrated with the JC-1 mitochondrial fluorescent label and by trypan blue exclusion tests with macrophages, which showed that the IC(50)s against the host cells were 4 to 5 orders of magnitude greater that those against the intracellular parasites. Taken together, our results show that ER-119884 and E5700 are unusually potent and selective inhibitors of the growth of Leishmania amazonensis, probably because of their inhibitory effects on de novo sterol biosynthesis at the level of SQS, but some of our observations indicate that ER-119884 may also interfere with other cellular processes.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , Piridinas/farmacologia , Quinuclidinas/farmacologia , Animais , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Humanos , Técnicas In Vitro , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/metabolismo , Esteróis/metabolismo , Tubulina (Proteína)/metabolismo
7.
Vet Parasitol ; 146(1-2): 25-34, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17367936

RESUMO

Leishmaniasis is an important disease in widely dispersed regions of the world. In South America, visceral leishmaniasis (VL) is mainly caused by Leishmania chagasi. The morbidity associated with the infection is high, and death may occur in some untreated patients. Treatment has been based upon pentavalent antimonial drugs for more than half a century and problems, including development of resistance to antimonials and lack of efficacy against VL/HIV co-infections, have emphasized the need for new drugs. Squalene synthase (SQS) is an essential enzyme for the biosynthesis of protozoal sterol molecules. In this work, nineteen synthetic quinuclidines, potentially inhibitors of SQS, were tested against promastigote forms of L. chagasi and the IC50 values of the compounds were determined. The most active compounds had IC50 values of around 30 nM and induced complete growth arrest and cell lysis at sub-micromolar concentrations. We analyzed the morphological structure of the parasites treated with these compounds by transmission electron microscopy of thin sections. Treated parasites showed significant ultrastructural changes, which varied from discrete alterations to total destruction of the cells, depending on the drug concentration and the time of incubation. One important change observed was a typical swelling of the unique and highly branched mitochondrion, where the inner membrane lost its organization. There was an increase in the number of autophagosomal structures. Changes in the organization of the nuclear chromatin and alterations in the flagellar pocket and flagellar membrane were also observed.


Assuntos
Antiprotozoários/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Leishmania/crescimento & desenvolvimento , Leishmania/ultraestrutura , Animais , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Leishmania/efeitos dos fármacos , Estrutura Molecular , Fatores de Tempo
8.
Exp Parasitol ; 111(4): 230-8, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16198340

RESUMO

Parasites of the Leishmania genus require for the growth and viability the de novo synthesis of specific sterols as such as episterol and 5-dehydroepisterol because cholesterol, which is abundant in their mammalian hosts, does not fulfill the parasite sterol requirements. Squalene synthase catalyzes the first committed step in the sterol biosynthesis and has been studied as a possible target for the treatment of high cholesterol levels in humans. In this work we investigated the antiproliferative and ultrastructural effects induced by 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a specific inhibitor of squalene synthase, on promastigote and amastigote forms of Leishmania amazonensis. BPQ-OH had a potent dose-dependent growth inhibitory effect against promastigotes and amastigotes, with IC(50) values 0.85 and 0.11 microM, respectively. Ultrastructural analysis of the treated parasites revealed several changes in the morphology of promastigote forms. The main ultrastructural change was found in the plasma membrane, which showed signs of disorganization, with the concomitant formation of elaborated structures. We also observed alterations in the mitochondrion-kinetoplast complex such as mitochondrial swelling, rupture of its internal membrane and an abnormal compaction of the kinetoplast. Other alterations included the appearance of multivesicular bodies, myelin-like figures, alterations of the flagellar membrane and presence of parasites with two or more nuclei and kinetoplasts. We conclude that the BPQ-OH was a potent growth inhibitor of L. amazonensis, which led to profound changes of the parasite's ultrastructure and might be a valuable lead compound for the development of novel anti-Leishmania agents.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Leishmania mexicana/efeitos dos fármacos , Quinuclidinas/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura
9.
Int J Antimicrob Agents ; 24(1): 72-8, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15225865

RESUMO

Squalene synthase (SQS) catalyses the first committed step of sterol biosynthesis; a blockade of this enzyme does not affect the production of other essential isoprenoids. In the present study, 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH) and ER27856, two specific inhibitors of SQS, were tested against epimastigote forms of Trypanosoma cruzi. Both compounds inhibited parasite multiplication with IC(50) values of 24.3 and 4.5 microM, respectively and induced marked morphological changes. These changes included: (a) detachment of the plasma membrane from the cell body, forming blebs; (b) detachment of the membrane lining the cell body and the flagellum from the sub-pellicular and axonemal microtubules; (c) enlargement of the flagellar pocket; (d) enlargement of a vacuole localised close to the flagellar pocket, which may correspond to a contractile vacuole; (e) mitochondrial swelling, with the appearance of concentric structures formed by invaginations of the inner mitochondrial membrane; (f) alterations in the nucleus of some cells, where the chromatin appears in clumps, as described for apoptotic cells; and (g) blockage of cytokinesis. These alterations are interpreted as a consequence of the depletion of essential parasite sterols induced by the experimental compounds and the concomitant alteration of the physical properties of the parasite membranes.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Trypanosoma cruzi/efeitos dos fármacos , Animais , Microscopia Eletrônica , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
10.
Antimicrob Agents Chemother ; 48(7): 2379-87, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15215084

RESUMO

Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K(i) values in the low nanomolar to subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Piridinas/farmacologia , Quinuclidinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Animais , Divisão Celular/efeitos dos fármacos , Farnesil-Difosfato Farnesiltransferase/isolamento & purificação , Feminino , Cinética , Metabolismo dos Lipídeos , Camundongos
11.
Mol Biochem Parasitol ; 125(1-2): 35-45, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12467972

RESUMO

Trypanosoma cruzi and Leishmania parasites have a strict requirement for specific endogenous sterols (ergosterol and analogs) for survival and growth and cannot use the abundant supply of cholesterol present in their mammalian hosts. Squalene synthase (SQS, E.C. 2.5.1.21) catalyzes the first committed step in sterol biosynthesis and is currently under intense study as a possible target for cholesterol-lowering agents in humans, but it has not been investigated as a target for anti-parasitic chemotherapy. SQS is a membrane-bound enzyme in both T. cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular localization, being almost evenly distributed between glycosomes and mitochondrial/microsomal vesicles. Kinetic studies showed that the parasite enzymes display normal Michaelis-Menten kinetics and the values of the kinetic constants are comparable to those of the mammalian enzyme. We synthesized and purified 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a potent and specific inhibitor of mammalian SQS and found that it is also a powerful non-competitive inhibitor of T. cruzi and L. mexicana SQS, with K(i)'s in the range of 12-62 nM. BPQ-OH induced a dose-dependent reduction of proliferation the extracellular stages of these parasites with minimal growth inhibitory concentrations (MIC) of 10-30 microM. Growth inhibition and cell lysis induced by BPQ-OH in both parasites was associated with complete depletion of endogenous squalene and sterols, consistent with a blockade of de novo sterol synthesis at the level of SQS. BPQ-OH was able to eradicate intracellular T. cruzi amastigotes from Vero cells cultured at 37 degrees C, with a MIC of 30 microM with no deleterious effects on host cells. Taken together, these results support the notion that SQS inhibitors could be developed as selective anti-trypanosomatid agents.


Assuntos
Antiprotozoários/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Leishmania mexicana/efeitos dos fármacos , Quinuclidinas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/metabolismo , Antiprotozoários/uso terapêutico , Chlorocebus aethiops , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Farnesil-Difosfato Farnesiltransferase/química , Farnesil-Difosfato Farnesiltransferase/isolamento & purificação , Cinética , Leishmania mexicana/enzimologia , Leishmania mexicana/crescimento & desenvolvimento , Estágios do Ciclo de Vida , Modelos Moleculares , Infecções por Protozoários/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/crescimento & desenvolvimento , Células Vero
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