Publications by authors named "Sérgio de Albuquerque"

62 Publications

Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets.

Eur J Pharm Sci 2021 Apr 4;162:105834. Epub 2021 Apr 4.

Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Universidade Federal do Triângulo Mineiro, Uberaba, Brazil. Electronic address:

Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, [AuClL] (1, L: (E,Z)-N-ethyl-N'-(3-nitroso-kN)butan-2-ylidene)carbamohydrazonothioato-kN,S) and [Au(Hdamp)L]Cl (2, L: N-(N'',N''-diethylaminothiocarbonyl)-N'(N''', N'''-dimethylcarbothioamide)benzamidineto-kN,kS and Hdamp: 2-(N,N-dimethylaminomethyl)-phenyl-C), and their affinities to possible biological targets were investigated. Three different tumor cell lines were used to perform the cytotoxicity assays, including one cisplatin-resistant model, and the results showed lower EC for 1 over 2 in every case: B16F10 (4.1 μM and 15.6 μM), A431 (4.0 μM and >50 μM) and OVCAR3 (4.2 μM and 24.5 μM). However, a lower toxicity to fibroblast 3T3 cell line was observed for 2 (30.58 μM) when compared to 1 (7.17 μM), resulting in comparable therapeutic indexes. Both complexes presented strong affinity to HSA: they distorted the secondary structure of the protein, as verified by circular dichroism, but 1 additionally presented the apparent fluorescence quenching constant (K) ten times greater than 2, which was probably due to the fact of 1 being able to denature HSA. The ethidium bromide displacement assay showed that neither 1 nor 2 are strong DNA intercalators, which is in agreement with what was observed through the UV-vis titration. In both cases, the 260 nm band presented hyperchromism, which can indicate ionic interactions or DNA damage. In fact, 1 was able to damage the pGEM plasmid, similarly to cisplatin, as verified by agarose gel electrophoresis and Atomic Force Microscopy. Biophysical studies in cancer cells model membranes were also performed in order to investigate the interaction of the gold complexes to lipid bilayers and revealed that the compounds interact with the membranes by exhibiting partition coefficients of 10 order of magnitude. Overall, both complexes were found to be promising candidates for the development of a future anticancer drug against low sensitive or cisplatin resistant tumors.
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http://dx.doi.org/10.1016/j.ejps.2021.105834DOI Listing
April 2021

Melatonin decreases circulating Trypanosoma cruzi load with no effect on tissue parasite replication.

Can J Physiol Pharmacol 2020 Dec 9. Epub 2020 Dec 9.

Universidade de São Paulo, 28133, Ribeirão Preto, São Paulo, Brazil;

Cardiac damage during the acute phase of Chagas disease (CD) is associated with an increase in pro-inflammatory markers and oxidative stress. Melatonin has emerged as a promising therapy for CD due to its antioxidant and immunomodulatory properties. However, the protective action of melatonin in the cardiac tissue as well as its direct action on the parasite cycle is not fully understood. We investigated the effects of melatonin on heart parasitism in mice infected with Trypanosoma cruzi (T. cruzi) and also its effects on the parasitic proliferation in vitro. Our in vivo study showed that melatonin reduced circulating parasitemia load, but did not control tissue (heart, liver and spleen) parasitism in mice. Melatonin did not prevent the redox imbalance in the left ventricle of infected mice. Our in vitro findings showed that melatonin did not inhibit parasites replication within cells, but rather increased their release from cells. Melatonin did not control parasitism load in the heart or prevented the cardiac redox imbalance induced by acute T. cruzi infection. The hormone controlled the circulating parasitic load, but in cells melatonin accelerated parasitic release, a response that can be harmful.
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http://dx.doi.org/10.1139/cjpp-2020-0473DOI Listing
December 2020

Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies.

Bioorg Med Chem 2021 01 6;29:115855. Epub 2020 Nov 6.

Universidade Federal Fluminense, Faculdade de Farmácia, Laboratório de Química Medicinal, RJ, Brazil. Electronic address:

Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
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http://dx.doi.org/10.1016/j.bmc.2020.115855DOI Listing
January 2021

Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection.

Exp Parasitol 2020 Dec 1;219:108032. Epub 2020 Nov 1.

Medicinal & Biological Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP), São Carlos, São Paulo, Brazil. Electronic address:

Chagas disease affects several countries around the world with health and sanitation problems. Cysteine proteases are essential for the virulence and replication of the Trypanosoma cruzi, being modulated by dipeptidyl nitriles and derivatives. Here, four dipeptidyl nitrile derivatives were assayed in three T. cruzi morphologies and two strains (Tulahuen and Y) using a set of assays: (i) analysis of the inhibitory activity against cysteine proteases; (ii) determination of the cytotoxic activity and selectivity index; (iii) verification of the inhibition of the trypomastigote invasion in the host cell. These compounds could inhibit the activity of cysteine proteases using the selective substrate Z-FR-MCA for the trypomastigote lysate and extracellular amastigotes. Interestingly, these compounds did not present relevant enzymatic inhibition for the epimastigote lysate. Most of the substances were also cytotoxic and selective against the trypomastigotes and intracellular amastigotes. The best compound of the series (Neq0662) could reduce the enzymatic activity of the cysteine proteases for the trypomastigotes and amastigotes. It was equipotent to the benznidazole drug in the cytotoxic studies using these two parasite forms. Neq0662 was also selective for the parasite, and it inhibited the invasion of the mammalian host cell in all conditions tested at 10 μM. The stereochemistry of the trifluoromethyl group was an important factor for the bioactivity when the two diastereomers (Neq0662 and Neq0663) were compared. All-in-all, these results indicate that these compounds could move further in the drug development stage because of its promising bioactive profile.
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http://dx.doi.org/10.1016/j.exppara.2020.108032DOI Listing
December 2020

Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment.

Chem Biol Drug Des 2020 09;96(3):948-960

LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.

Cruzain is an established target for the identification of novel trypanocidal agents, but how good are in vitro/in vivo correlations? This work describes the development of a random forests model for the prediction of the bioavailability of cruzain inhibitors that are Trypanosoma cruzi killers. Some common properties that characterize drug-likeness are poorly represented in many established cruzain inhibitors. This correlates with the evidence that many high-affinity cruzain inhibitors are not trypanocidal agents against T. cruzi. On the other hand, T. cruzi killers that present typical drug-like characteristics are likely to show better trypanocidal action than those without such features. The random forests model was not outperformed by other machine learning methods (such as artificial neural networks and support vector machines), and it was validated with the synthesis of two new trypanocidal agents. Specifically, we report a new lead compound, Neq0565, which was tested on T. cruzi Tulahuen (β-galactosidase) with a pEC of 4.9. It is inactive in the host cell line showing a selectivity index (SI = EC /EC ) higher than 50.
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http://dx.doi.org/10.1111/cbdd.13663DOI Listing
September 2020

Anticancer and antitrypanosomal activities of trinuclear ruthenium compounds with orthometalated phenazine ligands.

Dalton Trans 2020 Nov;49(45):16440-16452

LABIQSC2 (Laboratório de Atividade Biológica e Química Supramolecular de Compostos de Coordenação), Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, 14040-901, Ribeirão Preto, SP, Brazil.

Trinuclear ruthenium complexes with orthometalated phenazines of general formula [Ru3(μ3-O)(μ2-OAc)5(L)(py)2]PF6 (L = dppn, benzo[i]dipyrido[3,2-a:2',3'-c]phenazine, 1; dppz, dipyrido[3,2-a:2',3'-c]phenazine, 2; CH3-dppz, 7-methyldipyrido[3,2-a:2',3'-c]phenazine, 3; Cl-dppz, 7-chlorodipyrido[3,2-a:2',3'-c]phenazine, 4) were investigated for their cytotoxic activity toward the B16F10 murine melanoma and the L929 non-cancer cell lines and against Trypanosoma cruzi (2-4). This study also reports a multi-technique investigation into how complexes 1-4 interact with DNA and human serum albumin, HSA. At concentrations ranging from 2 to 50 μM, all the complexes reduced B16F10 murine melanoma cell viability by over 50%. Complex 4 had the highest cytotoxic effect in the series, diminishing B16F10 cell viability to 38% at 2 μM, with an overall order for anticancer activity of 4 > 2 > 3 > 1. Complexes 2-4 showed remarkable activity in inhibiting epimastigote and amastigote forms of T. cruzi. Complex 2 showed better antitrypanosomal activity than the reference drug (IC50 = 1.19 μM and IC50 = 0.25 μM for epimastigote and amastigotes forms, respectivily). Ethidium bromide (EB) displacement assays showed that DNA intercalation progressively increases with the extension of the π-conjugation of the cyclometalating ligand and the presence of substituents in the phenazinic portion (1 > 4-3 > 2), showing that complex 1 is a stronger intercalator than EB itself (Kapp > 107 M-1). Viscosity measurements followed the same trend. Cytotoxicity against cancer cells and antitrypanosomal activity follow the same order, which is different to the tendency of DNA intercalation, suggesting DNA is not the main target of these complexes. Compound 1-4 showed very high affinity with HSA (Kb ∼109 M-1). Circular dichroism results also showed that the complexes alter significantly the secondary structure of the HSA, lowering the α-helix % from 86.2 (pure protein) to less than 5% for compounds 1, 2 and 4 at 2.8 μM. These findings demonstrated the important role of phenazines for the biological activity of triruthenium compounds.
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http://dx.doi.org/10.1039/d0dt01035aDOI Listing
November 2020

Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study.

ChemMedChem 2020 Nov 15;15(21):2019-2028. Epub 2020 Sep 15.

Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal do Mato Grosso do Sul - UFMS, Campo Grande, Mato Grosso do Sul CEP, 79051-470, Brazil.

Chagas disease affects 6-8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC =3.0 μM, SI>65.3), with an IC =3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH -Ph) with IC = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO , 4-CH -Ph) with IC =1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.
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http://dx.doi.org/10.1002/cmdc.202000460DOI Listing
November 2020

Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.

PLoS Negl Trop Dis 2020 03 12;14(3):e0007755. Epub 2020 Mar 12.

Medicinal Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, São Paulo, Brazil.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
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http://dx.doi.org/10.1371/journal.pntd.0007755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067379PMC
March 2020

Organometallic Gold(III) Complex [Au(Hdamp)(L1)] (L1 = -Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease.

ACS Infect Dis 2019 10 26;5(10):1698-1707. Epub 2019 Aug 26.

Department of Clinical Toxicological and Bromatological Analysis School of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo (USP) , Ribeirão Preto , São Paulo 14040-903 , Brazil.

Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against , we evaluated both the and activity of the organometallic gold(III) complex [Au(III)(Hdamp)(L1)]Cl (L1 = -donating thiosemicarbazone), henceforth denoted 4-Cl. Our results demonstrated that 4-Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In assays, 4-Cl in PBS solution loses the protonation and becomes the 4-neutral. 4-Neutral reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage at 2.8 mg/kg/day. All these changes resulted in the survival of 100% of the mice treated with the gold complex during the acute phase. Analyzing the surviving animals of the acute infection, the parasite load after 150 days of infection was equivalent to those treated with the standard dose of Bz without demonstrating the hepatotoxicity of the latter. In addition, we identified a modulation of interferon gamma (IFN-γ) levels that may be targeting the disease's positive outcome. To the best of our knowledge, this is the first gold organometallic study that shows promise in an experimental model against Chagas disease.
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http://dx.doi.org/10.1021/acsinfecdis.8b00284DOI Listing
October 2019

Phenothiazinium Dyes Are Active against In Vitro.

Biomed Res Int 2019 4;2019:8301569. Epub 2019 Jul 4.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av do Café, sn/n, 14040-903 Ribeirão Preto, SP, Brazil.

Chagas disease is a tropical illness caused by the protozoan . The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti- effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in . Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.
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http://dx.doi.org/10.1155/2019/8301569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637691PMC
December 2019

Effect of Fluorination on the Structure and Anti- Activity of Oxorhenium(V) Complexes with ,,-Tridentate Thiosemicarbazones and Benzoylthioureas. Synthesis and Structures of Technetium(V) Analogues.

Inorg Chem 2019 Aug 16;58(15):10129-10138. Epub 2019 Jul 16.

Institute of Chemistry and Biochemistry , Freie Universität Berlin , Fabeckstrasse 34-36 , D-14195 Berlin , Germany.

A series of 16 "3 + 2" mixed-ligand complexes of the general composition [ReO(L1)(L2)] (HL1a-HL1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF substituents; HL2a-HL2d = bidentate ,-diethyl-'-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4-CF substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the C NMR chemical shifts of the N-C═N carbon atoms of the {L1} and the C═O carbon atoms of the {L2} ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu)[TcOCl] and two representatives of the fluorinated ligands (HL1b, 4-F-substituted, and HL1c, 4-CF-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.
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http://dx.doi.org/10.1021/acs.inorgchem.9b01260DOI Listing
August 2019

Heterobimetallic nickel(II) and palladium(II) complexes derived from S-benzyl-N- (ferrocenyl)methylenedithiocarbazate: Trypanocidal activity and interaction with Trypanosoma cruzi Old Yellow Enzyme (TcOYE).

Eur J Med Chem 2019 Oct 5;180:213-223. Epub 2019 Jul 5.

Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Universidade Federal do Triângulo Mineiro, Av. Dr. Randolfo Borges 1400, 38025-440, Uberaba, MG, Brazil. Electronic address:

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type [M(Fedtc)] (M = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, H NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and [Ni(Fedtc)] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. [Pd(Fedtc)] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI = 48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the [Ni(Fedtc)] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.014DOI Listing
October 2019

Dipeptidyl nitrile derivatives have cytostatic effects against Leishmania spp. promastigotes.

Exp Parasitol 2019 May 5;200:84-91. Epub 2019 Apr 5.

Medicinal Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP), Av. Trabalhador São-carlense, 400, São Carlos, SP, 13.566-590, Brazil. Electronic address:

Cysteine proteases are involved in critical cell processes to the protozoa from Leishmania genus, and their inhibition is a therapeutic alternative to treat the disease. In this work, derivatives of dipeptidyl nitriles acting as reversible covalent inhibitors of cysteine proteases were studied as cytostatic agents. The proteolytic activity inside the living and lysed parasite cells was quantified using a selective substrate for cysteine proteases (Z-FR-MCA) from Leishmania amazonensis and L. infantum. The overall proteolytic activity of intact cells and even cell extracts was only marginally affected at high concentrations, with the observation of cytostatic activity and cell cycle arrest of promastigotes. However, the cytotoxic effects were only observed for infected J774 macrophages, which impaired further analysis of the amastigote infection. Therefore, the proteolytic inhibition in intact L. amazonensis and L. infantum promastigotes had no relationship to the cytostatic activity, which emphasizes that these dipeptidyl nitriles act through another mechanism of action.
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http://dx.doi.org/10.1016/j.exppara.2019.04.001DOI Listing
May 2019

In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex.

Biomed Pharmacother 2019 Jan 2;109:157-166. Epub 2018 Nov 2.

Instituto de Química, Universidade Federal de Uberlândia, Campus Santa Mônica, Uberlândia, MG, Brazil. Electronic address:

In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4'-dimethoxy-2-2'-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO)], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO)] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with K values in the range of 10-10 M, with [Cu(4-MH)(dmb)(ClO)] showing the highest K value (1.45 × 10 M). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO)] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.
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http://dx.doi.org/10.1016/j.biopha.2018.10.057DOI Listing
January 2019

Design, synthesis and antitrypanosomatid activities of 3,5-diaryl-isoxazole analogues based on neolignans veraguensin, grandisin and machilin G.

Chem Biol Drug Des 2019 03 25;93(3):313-324. Epub 2018 Nov 25.

LASQUIM - Laboratório de Síntese e Química Medicinal, FACFAN - Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal do Mato Grosso do Sul, UFMS, Campo Grande, MS, Brazil.

Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity.
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http://dx.doi.org/10.1111/cbdd.13417DOI Listing
March 2019

β-amino alcohols and their respective 2-phenyl-N-alkyl aziridines as potential DNA minor groove binders.

Eur J Med Chem 2018 Sep 27;157:657-664. Epub 2018 Jul 27.

Departament of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto - FCFRP-USP, University of São Paulo, Avenida do Café S/n, Ribeirão Preto, SP, 14040-903, Brazil. Electronic address:

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, β-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.055DOI Listing
September 2018

Benefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease.

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.

The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of , leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.
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http://dx.doi.org/10.1128/AAC.00514-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125494PMC
September 2018

Three new platinum complexes containing fluoroquinolones and DMSO: Cytotoxicity and evaluation against drug-resistant tuberculosis.

J Inorg Biochem 2018 06 16;183:77-83. Epub 2018 Mar 16.

Instituto de Química, Universidade Federal de Uberlândia, Campus Santa Mônica, Uberlândia, MG, Brazil. Electronic address:

This work describes the synthesis, characterization and biological evaluation of three platinum complexes of the type [Pt(DMSO)(L)Cl]Cl, in which L represents a fluoroquinolone, namely, ciprofloxacin (cpl), ofloxacin (ofl), or sparfloxacin (spf). The new complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRESIMS) and H, C and Pt NMR (nuclear magnetic resonance). The spectral data suggest that the fluoroquinolones act as bidentate ligands coordinated to Pt(II) through the nitrogen atoms of the piperazine ring. Microbiological assays against wild type Mycobacterium tuberculosis (ATCC 27294) showed that all complexes have been very potent, exhibiting antitubercular potency at concentrations <2 μM, although none of the complexes presented higher potency than established anti-TB drugs. As to the resistant strains, the complex with sparfloxacin, [Pt(DMSO)(spf)Cl]Cl exhibited the best potential against most Mycobacterium tuberculosis clinical isolates. The cytotoxicity of these compounds was also evaluated in three breast cell lines: MCF-10 (a healthy cell), MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both tumor cell lines, [Pt(DMSO)(spf)Cl]Cl was more active and more selective than cisplatin. Flow cytometry analysis revealed that [Pt(DMSO)(spf)Cl]Cl induced late apoptotic cell death in MDA-MB-231 cells.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.03.010DOI Listing
June 2018

Pt, Pd and Au complexes with a thiosemicarbazone derived from diacethylmonooxime: Structural analysis, trypanocidal activity, cytotoxicity and first insight into the antiparasitic mechanism of action.

Eur J Med Chem 2017 Dec 12;141:615-631. Epub 2017 Oct 12.

Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Universidade Federal do Triângulo Mineiro, Av. Dr. Randolfo Borges 1400, 38025-440, Uberaba, MG, Brazil. Electronic address:

New complexes of composition [MX(HL1)] (M = Pt, Pd, X = Cl or I) and [MX(L1)] (M = Au, X = Cl; M = Pt, Pd, X = PPh) have been synthesized using a potentially tridentate thiosemicarbazone (HL1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand HL1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand HL1 to Pt, Pd and Au metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the Au complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the Au complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the [AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them.
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http://dx.doi.org/10.1016/j.ejmech.2017.10.013DOI Listing
December 2017

New uses for old complexes: The very first report on the trypanocidal activity of symmetric trinuclear ruthenium complexes.

J Inorg Biochem 2017 11 31;176:156-158. Epub 2017 Aug 31.

Departamento de Química - Faculdade de Filosofia Ciências e Letras de Ribeirão Preto da Universidade de São Paulo, Av. Bandeirantes, 3900, CEP 14040-901, Monte Alegre, Ribeirão Preto, SP, Brazil. Electronic address:

This work reports on the trypanocidal activity of a series of symmetric triruthenium complexes combined with azanaphthalene ligands of general formula [RuO(CHCOO)(L)]PF (L=(1) quinazoline (qui), (2) 5-nitroisoquinoline (5-nitroiq), (3) 5-bromoisoquinoline (5-briq), (4) isoquinoline (iq), (5) 5-aminoisoquinoline (5-amiq), and (6) 5,6,7,8-tetrahydroisoquinoline (thiq)). All complexes within the series presented in vitro trypanocidal activity against both the trypomastigote and amastigote forms of T. cruzi. The IC values obtained for complexes 1-6 ranged from 1.39 to 165.9μM for the trypomastigote form and from 1.06 to 53.16μM for the amastigote form. These values were lower than the values observed for the metallic core [RuO(CHCOO)(CHOH)] itself and for the free ligands in all cases. Remarkably, complex 6 displayed lower IC values than the reference drug (benznidazole) for the acute (trypomastigote form) and chronic (amastigote form) phases of Chagas disease. These findings, combined with the low toxicity against healthy cells (LLK-MK strain) and a high SI value (Selectivity Index >10) make complex 6 an excellent candidate for in vivo tests.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.08.021DOI Listing
November 2017

A new l-amino acid oxidase from Bothrops jararacussu snake venom: Isolation, partial characterization, and assessment of pro-apoptotic and antiprotozoal activities.

Int J Biol Macromol 2017 Oct 8;103:25-35. Epub 2017 May 8.

Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address:

A new l-amino acid oxidase (LAAO) from Bothrops jararacussu venom (BjussuLAAO-II) was isolated by using a three-step chromatographic procedure based on molecular exclusion, hydrophobicity, and affinity. BjussuLAAO-II is an acidic enzyme with pI=3.9 and molecular mass=60.36kDa that represents 0.3% of the venom proteins and exhibits high enzymatic activity (4884.53U/mg/mim). We determined part of the primary sequence of BjussuLAAO-II by identifying 96 amino acids, from which 34 compose the N-terminal of the enzyme (ADDRNPLEECFRETDYEEFLEIARNGLSDTDNPK). Multiple alignment of the partial BjussuLAAO-II sequence with LAAOs deposited in the NCBI database revealed high similarity (95-97%) with other LAAOs isolated from Bothrops snake venoms. BjussuLAAO-II exerted a strong antiprotozoal effect against Leishmania amazonensis (IC=4.56μg/mL) and Trypanosoma cruzi (IC=4.85μg/mL). This toxin also induced cytotoxicity (IC=1.80μg/mL) and apoptosis in MCF7 cells (a human breast adenocarcinoma cell line) by activating the intrinsic and extrinsic apoptosis pathways, but were not cytotoxic towards MCF10A cells (a non-tumorigenic human breast epithelial cell line). The results reported herein add important knowledge to the field of Toxinology, especially for the development of new therapeutic agents.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.05.025DOI Listing
October 2017

Development and Evaluation of a Nanoemulsion Containing Ursolic Acid: a Promising Trypanocidal Agent : Nanoemulsion with Ursolic Acid Against T. cruzi.

AAPS PharmSciTech 2017 Oct 21;18(7):2551-2560. Epub 2017 Feb 21.

Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Avenida do Café s/n, 14040-903, Ribeirão Preto, São Paulo, Brazil.

Over a hundred years after the discovery of Chagas disease, this ailment continues to affect thousands of people. For more than 40 years, only two drugs have been available to treat it. Ursolic acid is a naturally occurring terpene that has shown a good trypanocidal action. However, the hydrophobicity of this compound presents a challenge for the development of proper delivery systems. Nanostructured systems are a prominent in delivering lipophilic drugs. Thus, a nanoemulsion containing ursolic acid was developed and had its trypanocidal activity and cytotoxicity evaluated. Pseudo-ternary phase diagrams and hydrophilic-lipophilic balance (HLB) system were used in the development. The system was stable throughout 90 days of testing, as evidenced by turbidimetry analysis and measurements of the droplet size (57.3 nm) and polydispersity index (0.24). Fourier transform infrared spectroscopy and mass spectrometry evidenced drug's integrity in the formulation. An in vitro dissolution profile showed 75% of ursolic acid release after 5 min from the nanoemulsion into the alkaline dissolution medium, while only 20% could be released from a physical mixture after 2 h. Trypanocidal activity and cytotoxicity were evaluated on the CL Brener strain and LLC-MK2 (monkey kidney) fibroblast by chlorophenol red-β-D-galactoside (CPRG) method. Biological studies showed that the developed formulation was nontoxic and effective against replicant forms of the parasite. A stable and efficient nanoemulsion could be developed to improve the delivery of a promising drug to treat a threatening illness such as Chagas disease.
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http://dx.doi.org/10.1208/s12249-017-0736-yDOI Listing
October 2017

Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors.

PLoS Negl Trop Dis 2017 02 21;11(2):e0005343. Epub 2017 Feb 21.

Grupo de Estudos em Química Medicinal - NEQUIMED, Instituto de Química de São Carlos - Universidade de São Paulo, São Carlos, São Paulo, Brazil.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.
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http://dx.doi.org/10.1371/journal.pntd.0005343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344518PMC
February 2017

New carbohydrazide derivatives of 1H-pyrazolo[3,4-b]pyridine and trypanocidal activity.

An Acad Bras Cienc 2016 Oct-Dec;88(4):2341-2348. Epub 2016 Dec 1.

Laboratório de Química Medicinal/LQMed, Faculdade de Farmácia, Universidade Federal Fluminense/UFF, Rua Mário Viana, 523, 24241-000 Santa Rosa, Niterói, RJ, Brazil.

This paper reports the in vitro trypanocidal activity evaluation of new carbohydrazide derivatives from 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine, substituted at C-6 position by phenyl, methyl or trifluoromethyl group. These compounds were evaluated in order to identify the antiparasitic profile against trypomastigote and amastigote forms of Trypanosoma cruzi. The 4-carbohydrazide derivatives presented different profiles of activity. In the investigation of the chemical structure influence in the trypanocidal activity, the results indicated there are large lipophilicity and volume differences among these derivatives. The complementarities of their stereoelectronic and physical-chemical aspects seem to be relevant for the biological activity against T. cruzi.
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http://dx.doi.org/10.1590/0001-3765201620160087DOI Listing
February 2018

Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs.

Eur J Med Chem 2016 Sep 3;120:217-26. Epub 2016 May 3.

Departamento de Química, Universidade Federal do Triângulo Mineiro, Av. Dr. Randolfo Borges 1400, 38025-440, Uberaba, MG, Brazil. Electronic address:

Tridentate thiosemicarbazone ligands with an ONS donor set, H2L(R) (R = Me and Et) were prepared by reactions of 1-phenyl-1,3-butanedione with 4-R-3-thiosemicarbazides. H2L(R) reacts with Na[AuCl4]·2H2O in MeOH in a 1:1 M ratio under formation of green gold(III) complexes of composition [AuCl(L(R))]. These compounds represent the first examples of gold(III) complexes with ONS chelate-bonded thiosemicarbazones. The in vitro anti-Trypanosoma cruzi activity against both trypomastigote and amastigote forms (IC50try/ama) of CL Brener strains as well as the cytotoxicity against LLC-MK2 cells of the free ligands and complexes was evaluated. The complex [AuCl(L(Me))] was found to be more active and more selective than its precursor ligand and the standard drug benznidazole with a SItry/ama value higher than 200, being considered as a lead candidate for Chagas disease treatment. Moreover the in vitro activity against the replicative amastigote form (IC50ama) of T. cruzi was additionally investigated revealing that [AuCl(L(Me))] was also more potent than benznidazole still with a similar selectivity index. Finally, docking studies showed that free ligands and complexes interact with the same residues of the parasite protease cruzain but with different intensities, suggesting that this protease could be a possible target for the trypanocidal action of the obtained compounds.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.003DOI Listing
September 2016

Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.

PLoS Negl Trop Dis 2015 14;9(7):e0003916. Epub 2015 Jul 14.

Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.

A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
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http://dx.doi.org/10.1371/journal.pntd.0003916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501791PMC
May 2016

Evaluating the microbicidal, antiparasitic and antitumor effects of CR-LAAO from Calloselasma rhodostoma venom.

Int J Biol Macromol 2015 Sep 7;80:489-97. Epub 2015 Jul 7.

Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address:

CR-LAAO is an L-amino acid oxidase from Calloselasma rhodostoma snake venom that has been broadly studied regarding its structural and biochemical characteristics, however, few studies have investigated its pharmacological effects. The present study aimed at the evaluation of the biotechnological potential of CR-LAAO by determining its bactericidal, antifungal, leishmanicidal and trypanocidal activity, as well as its cytotoxicity on human tumor and non-tumor cell lines. After 24 h of preincubation, CR-LAAO showed bactericidal effects against both Staphylococcus aureus (MIC 0.78 μg/mL) and Escherichia coli (MIC 31.25 μg/mL) strains, inducing dismantle of bacterial cell walls. After 6 h of preincubation with Candida albicans, CR-LAAO was able to inhibit 80% of the yeast growth, and it also showed cytotoxic activity on Leishmania species and Trypanosoma cruzi. Additionally, CR-LAAO showed high cytotoxicity on HepG2 and HL-60 tumor cells (IC50 10.78 and 1.7 μg/mL), with lower effects on human mononuclear cells (PBMC). The cytotoxic effects of CR-LAAO were significantly inhibited in the presence of catalase, which suggests the involvement of hydrogen peroxide in its mechanisms of toxicity. Therefore, CR-LAAO showed promising pharmacological effects, and these results provide important information for the development of therapeutic strategies with directed action, such as more effective antimicrobial agents.
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http://dx.doi.org/10.1016/j.ijbiomac.2015.07.004DOI Listing
September 2015

Novel naphthoquinone derivatives and evaluation of their trypanocidal and leishmanicidal activities.

Org Biomol Chem 2015 Jan 5;13(2):428-37. Epub 2014 Nov 5.

Programa de Pós-Graduação em Farmácia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de Mato Grosso do Sul, 79080-190, Campo Grande, MS, Brazil.

Herein, we report the synthesis of 12 new naphthoquinone derivatives, 6 substituted 1,4-naphthoquinones and 6 heterocycle-fused naphthoquinones, as well as evaluation of their trypanocidal and leishmanicidal activities. Compounds 11a and 13a were active against the amastigote stage of T. cruzi and showed low cytotoxic effects. With respect to leishmanicidal assays, all compounds were inactive against the promastigote stages of L. chagasi and L. braziliensis.
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http://dx.doi.org/10.1039/c4ob01869aDOI Listing
January 2015

In vivo activity of ursolic and oleanolic acids during the acute phase of Trypanosoma cruzi infection.

Exp Parasitol 2013 Aug 3;134(4):455-9. Epub 2013 May 3.

Universidade de Franca - Núcleo de Pesquisa em Ciências Exatas e Tecnológicas da Universidade de Franca, Av. Dr. Armando Salles Oliveira, 201, 14404-600 Franca, SP, Brazil.

Reduction in the parasitemic levels of the Y strain of Trypanosoma cruzi in mice treated with oral or intraperitoneal ursolic (UA) and oleanolic (OA) acids was evaluated during the acute phase of Chagas' disease. Oral administration of UA and OA (50mg/kg/day) provided the most significant reduction in the parasitemic peak, while intraperitoneal administration of UA and OA did not significantly affect the biological activity of the Y strain of T. cruzi. Interleukin levels in mice treated by the intraperitoneal route were compared to untreated chagasic mice. Reduced γ-IFN levels and enhanced IL-10 concentrations potentially explain the exacerbated parasitemia. Our data suggests an immunosuppressive effect for UA and OA, which could interfere with host control of parasitemia. Optimal results were achieved with oral administration. This observation may be explained by the low intestinal absorption of UA and OA, could cause a reduced immune response and promote parasite control. Taken together, these data demonstrate that triterpenes could be interesting compounds to develop therapeutically for the treatment of Chagas' disease.
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http://dx.doi.org/10.1016/j.exppara.2013.04.005DOI Listing
August 2013

Synthesis and biological activity against Trypanosoma cruzi of substituted 1,4-naphthoquinones.

Eur J Med Chem 2013 Feb 1;60:51-6. Epub 2012 Dec 1.

Chemistry Sector (LP4), Center of Exact Sciences and Technology, Federal University of Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil.

The discovery and development of essential drugs for Chagas disease is a major concern worldwide. New substituted 1,4-naphthoquinones were synthesized and tested against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. These products exhibited substantial activity against T. cruzi, especially 2-((8E,11Z)-heptadeca-8,11-dienyl)-3-hydroxynaphthalene-1,4-dione (9) with IC(50) of 7.8 μM.
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http://dx.doi.org/10.1016/j.ejmech.2012.11.034DOI Listing
February 2013