Publications by authors named "Antônio Carlos Doriguetto"

14 Publications

  • Page 1 of 1

Assessment of the biological potential of diaryltriazene-derived triazene compounds.

Sci Rep 2021 01 28;11(1):2541. Epub 2021 Jan 28.

Electrochemistry and Biotechnology Laboratory (EBL), University of CEUMA (UNICEUMA), São Luís, MA, 65.065-470, Brazil.

In the present study, novel, 1,3-diaryltriazene-derived triazene compounds were synthesized and tested. Triazenes are versatile and belong to a group of alkylating agents with interesting physicochemical properties and proven biological activities. This study describes the synthesis, molecular and crystalline structure, biological activity evaluation, and antifungal and antimicrobial potentials of 1,3-bis(X-methoxy-Y-nitrophenyl)triazenes [X = 2 and 5; Y = 4 and 5]. The antimicrobial and antifungal activities of the compounds were tested by evaluating the sensitivity of bacteria (American Type Culture Collection, ATCC) and clinical isolates to their solutions using standardized microbiological assays, cytotoxicity evaluation, and ecotoxicity tests. The antimicrobial potentials of triazenes were determined according to their minimum inhibitory concentrations (MICs); these compounds were active against gram-positive and gram-negative bacteria, with low MIC values. The most surprising result was obtained for T3 having the effective MIC of 9.937 µg/mL and antifungal activity against Candida albicans ATCC 90028, C. parapsilosis ATCC 22019, and C. tropicallis IC. To the best of our knowledge, this study is the first to report promising activities of triazene compounds against yeast and filamentous fungi. The results showed the potential utility of triazenes as agents affecting selected resistant bacterial and fungal strains.
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http://dx.doi.org/10.1038/s41598-021-81823-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844262PMC
January 2021

Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance.

Int J Pharm 2020 Nov 2;589:119840. Epub 2020 Sep 2.

Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 701 Alfenas, Minas Gerais 37130-001, Brazil; Institute of Chemistry, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 701, Alfenas, Minas Gerais 37130-001, Brazil. Electronic address:

Buclizine (BCZ) is a chiral synthetic piperazine derivative which has antihistaminic, anti-muscarinic and antiemetic properties, and has been reintroduced as an appetite stimulant, especially for pediatric patients. Structural information about this drug, as well as other buclizine crystalline forms (solvates, salts and co-crystals) including the BCZ free-base (BCZ-FB), is non-existent. Here, we present for the first time the crystal structure of the monohydrochloride monohydrate salt of BCZ (BCZHCl·HO), and of its anhydrous form, BCZHCl. Interestingly, BCZHCl·HO was obtained by recrystallization from the raw material (BCZHCl) in ethanol:water solution showing that BCZ anhydrous dihydrochloride salt changes easily to a monohydrochloride monohydrate salt modification, which raise concerns about formulation quality control. BCZHCl·HO and BCZHCl crystallize in the orthorhombic space groups (Pna2 and Pca2) belonging to the mm2 point group and are thus classified as non-centrosymmetric achiral structures (NA). Intuitively, we expect these salts to crystallize in a space group with a center of symmetry, since less than 5% of the known racemic compounds crystallize in the NA type. The crystal structures of BCZHCl and BCZ-FB were not determined, but their existence was verified by other techniques (chloride ion analysis, PXRD, HPLC, FT-IR, DSC, TGA) and by comparison of the obtained results with those found for BCZHCl. Additionally, we have also performed an evaluation of the equilibrium solubility (at six different aqueous media) and the dissolution profile of the BCZHCl salt compared to the raw material and BCZ-FB. Different equilibrium solubility values were found comparing the three forms in acidic and neutral pH ranges and all of them were insoluble at pH > 7.0. Moreover, tablets prepared with BCZHCl, BCZHCl or BCZ-FB show significant differences in terms of dissolution profile.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119840DOI Listing
November 2020

Synthesis, crystal structure and leishmanicidal activity of new trimethoprim Ru(III), Cu(II) and Pt(II) metal complexes.

J Inorg Biochem 2020 04 23;205:111002. Epub 2020 Jan 23.

Instituto de Química, Universidade Federal de Alfenas, CEP: 37130-001 Alfenas, MG, Brazil. Electronic address:

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania, which has very limited treatment options and affects poor and underdeveloped populations. The current treatment is plagued by many complications, such as high toxicity, high cost and resistance to parasites; therefore, novel therapeutic agents are urgently needed. Herein, the synthesis, characterization and in vitro leishmanicidal potential of new complexes with the general formula [RuCl(TMP)(dppb)] (1), [PtCl(TMP)(PPh)]PF (2) and [Cu(CHCOO)(TMP)]·DMF (3) (dppb = 1,4-bis(diphenylphosphino)butane, PPH = triphenylphosphine and TMP = trimethoprim) were evaluated. The complexes were characterized by infrared, UV-vis, cyclic voltammetry, molar conductance measurements, elemental analysis and NMR experiments. Also, the geometry of (2) and (3) were determined by single crystal X-ray diffraction. Despite being less potent against promastigote L. amazonensis proliferation than amphotericin B reference drug (IC = 0.09 ± 0.02 μM), complex (2) (IC = 3.6 ± 1.5 μM) was several times less cytotoxic (CC = 17.8 μM, SI = 4.9) in comparison with amphotericin B (CC = 3.3 μM, SI = 36.6) and gentian violet control (CC = 0.8 μM). Additionally, complex (2) inhibited J774 macrophage infection and amastigote number by macrophages (IC = 6.6 and SI = 2.7). Outstandingly, complex (2) was shown to be a promising candidate for a new leishmanicidal therapeutic agent, considering its biological power combined with low toxicity.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111002DOI Listing
April 2020

The foliar application of a mixture of semisynthetic chitosan derivatives induces tolerance to water deficit in maize, improving the antioxidant system and increasing photosynthesis and grain yield.

Sci Rep 2019 06 3;9(1):8164. Epub 2019 Jun 3.

Federal University of Alfenas - UNIFAL-MG, Institute of Natural Sciences- ICN, 700, Gabriel Monteiro Street, P. O. Box 37130-001, Alfenas, MG, Brazil.

Research has shown that chitosan induces plant stress tolerance and protection, but few studies have explored chemical modifications of chitosan and their effects on plants under water stress. Chitosan and its derivatives were applied (isolated or in mixture) to maize hybrids sensitive to water deficit under greenhouse conditions through foliar spraying at the pre-flowering stage. After the application, water deficit was induced for 15 days. Analyses of leaves and biochemical gas exchange in the ear leaf were performed on the first and fifteenth days of the stress period. Production attributes were also analysed at the end of the experiment. In general, the application of the two chitosan derivatives or their mixture potentiated the activities of the antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and guaiacol peroxidase at the beginning of the stress period, in addition to reducing lipid peroxidation (malonaldehyde content) and increasing gas exchange and proline contents at the end of the stress period. The derivatives also increased the content of phenolic compounds and the activity of enzymes involved in their production (phenylalanine ammonia lyase and tyrosine ammonia lyase). Dehydroascorbate reductase and compounds such as total soluble sugars, total amino acids, starch, grain yield and harvest index increased for both the derivatives and chitosan. However, the mixture of derivatives was the treatment that led to the higher increase in grain yield and harvest index compared to the other treatments. The application of semisynthetic molecules derived from chitosan yielded greater leaf gas exchange and a higher incidence of the biochemical conditions that relieve plant stress.
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http://dx.doi.org/10.1038/s41598-019-44649-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547683PMC
June 2019

Solid-State Characterization of Spironolactone 1/3 Hydrate.

J Pharm Sci 2019 07 7;108(7):2458-2464. Epub 2019 Mar 7.

Department of Food and Medicines, Faculty of Pharmaceutical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais 37130-001, Brazil. Electronic address:

Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate.
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http://dx.doi.org/10.1016/j.xphs.2019.03.001DOI Listing
July 2019

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells.

Redox Biol 2019 01 12;20:182-194. Epub 2018 Oct 12.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador, Bahia, Brazil. Electronic address:

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh)]PF (where, PIP-OH = piplartine demethylated derivative; and PPh = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.
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http://dx.doi.org/10.1016/j.redox.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198128PMC
January 2019

Pharmacokinetics and pharmacodynamics of glimepiride polymorphs.

Int J Pharm 2018 Dec 23;553(1-2):272-280. Epub 2018 Oct 23.

Pharmaceutical Sciences Faculty, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.

Glimepiride (GLIM) is used as an oral antihyperglycemic agent for treatment of type 2 diabetes. The drug presents two polymorphic forms (GLIM form I and GLIM form II) described in the literature, and according to in vitro data, GLIM form II is about 3.5 times more soluble and releases 2 times the drug amount than GLIM form I in the physiological pH range. Considering the literature in vitro data and that the diabetes treatment demands glycemic control, avoiding abrupt fluctuations in the blood glucose levels, this work aimed to study the impact of GLIM polymorphism in the in vivo performance of GLIM solid oral dosages. For this, hard gelatin capsules with GLIM form I or II were prepared and orally administered in rats. After that, pharmacokinetic studies were performed by sampling animal blood at different times, and biochemical parameters (pharmacodynamic), such as glucose and insulin, were also evaluated. Our results showed that the in vitro data corroborate with our in vivo assays. GLIM form II provided higher plasma concentration of drug than form I (at baseline up to approximately 200 min after oral administration) and, consequently, increased insulin release and reduced levels of glucose, showing good correlation between pharmacokinetic and pharmacodynamics assays. Thus, this study demonstrated that GLIM polymorphs in oral dosages might alter the drug efficacy, which may expose the patients to risks, such as hypoglycemia.
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http://dx.doi.org/10.1016/j.ijpharm.2018.10.050DOI Listing
December 2018

Pro-apoptotic activity of ruthenium 1-methylimidazole complex on non-small cell lung cancer.

J Inorg Biochem 2018 10 4;187:1-13. Epub 2018 Jul 4.

Instituto de Química, Universidade Federal de Alfenas, CEP 37130-001 Alfenas, MG, Brazil. Electronic address:

Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meim = 1-methylimidazole, dppb = 1,4-Bis(diphenylphosphino)butane, bpy = 2,2'-bipyridine, 4,4'-DMbpy = 4,4'-dimethyl-2,2'-bipyridine, 5,5'-DMbpy = 5,5'-dimethyl-2,2'-bipyridine and phen = 1,10-phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF (5) and [RuCl(1Meim)(dppb)(5,5'-DMbpy)]PF methanol solvate (6) where PF = hexafluorophosphate, showing one 1-methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, H, C{H} and P{H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1-4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.06.008DOI Listing
October 2018

Analysis of polymorphic contamination in meloxicam raw materials and its effects on the physicochemical quality of drug product.

Eur J Pharm Sci 2017 Nov 24;109:347-358. Epub 2017 Aug 24.

Faculty of Pharmaceutical Sciences, Federal University of Alfenas (UNIFAL-MG), 37130-001 Alfenas, MG, Brazil. Electronic address:

This work aims to evaluate the effect of polymorphism on the physicochemical properties of meloxicam, which is an antipyretic and non-steroidal anti-inflammatory drug. Powder X-ray Diffraction, Infrared Spectroscopy with attenuated total reflectance, Thermogravimetric and Differential Scanning Calorimetry techniques were used for the polymorphic characterization. Comparative tests of solubility, intrinsic dissolution and dissolution profiles were performed on meloxicam active pharmaceutical ingredients (APIs) and formulated tablets. A polymorphic contamination (Forms I and III) was found in a studied meloxicam batch, which showed a higher solubility and greater intrinsic dissolution than those containing only the preconized form (Form I). Consequently, the dissolution profiles of the tablets that contained the polymorphic contamination showed higher drug release. Additionally, a thermal behavior study shows that MLX Form I and III are monotropy polymorphs being MLX Form III a metastable phase, which becomes MLX Form I at approximately 200°C in solid state phase transition governed by kinetic variables. The kinetic of conversion of Form III to Form I in saturated solutions was also studied. These results illustrate the importance of the polymorphic characterization of meloxicam APIs and formulated tablets in order to avoid potential quality and efficacy problems of drug products.
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http://dx.doi.org/10.1016/j.ejps.2017.08.029DOI Listing
November 2017

Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate.

Molecules 2016 Mar 9;21(3):328. Epub 2016 Mar 9.

Institute of Chemistry, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, Alfenas-MG 37130-000, Brazil.

Orbifloxacin (ORBI) is a widely used antimicrobial drug of the fluoroquinolone class. In the official pharmaceutical compendia the existence of polymorphism in this active pharmaceutical ingredient (API) is reported. No crystal structure has been reported for this API and as described in the literature, its solubility is very controversial. Considering that different solid forms of the same API may have different physicochemical properties, these different solubilities may have resulted from analyses inadvertently carried out on different polymorphs. The solubility is the most critical property because it can affect the bioavailability and may compromise the quality of a drug product. The crystalline structure of ORBI determined by SCXRD is reported here for the first time. The structural analysis reveals that the ORBI molecule is zwitterionic and hemihydrated. ORBI hemihydrated form was characterized by the following techniques: TG/DTA, FTIR-ATR, and PXRD. A second crystalline ORBI form is also reported: the ORBI anhydrous form was obtained by heating the hemihydrate. These ORBI solid forms were isomorphous, since no significant change in unit cell and space group symmetry were observed. The solid-state phase transformation between these forms is discussed and the equilibrium solubility data were examined in order to check the impact of the differences observed in their crystalline structures.
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http://dx.doi.org/10.3390/molecules21030328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273335PMC
March 2016

Non-centrosymmetric crystals of new N-benzylideneaniline derivatives as potential materials for non-linear optics.

Acta Crystallogr B Struct Sci Cryst Eng Mater 2015 Aug 14;71(Pt 4):416-26. Epub 2015 Jul 14.

Instituto de Química, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, 700, Alfenas, Minas Gerais 37130-000, Brazil.

Three new N-benzylideneaniline derivatives [p-nitrobenzylidene-p-phenylamineaniline (I), 2,4-dinitrobenzylidene-p-phenylamineaniline (II) and p-dinitrobenzylidene-p-diethylamineaniline (III)] containing electron-push-pull groups have been prepared. They present a planar N-benzylideneaniline core and neighbouring functional atoms, which are related through an efficient intramolecular charge transfer (CT). Two of the derivatives crystallize in non-centrosymmetric space groups, a necessary condition for non-linear optical (NLO) responses. The NLO properties were calculated for the molecular conformations determined by single-crystal X-ray diffraction as well as for the four molecules packed into each corresponding unit cell, using a quantum-chemical method at the cam-B3LYP/NLO-V level of theory. As expected from antiparallel face-to-face stacking through centrosymmetry, the main NLO descriptors - namely, the first hyperpolarizability (βtot) and its projection on the dipole moment direction (βvec) - are almost zero for the tetramer of derivative III. Interestingly, the calculated first hyperpolarizability decreases in the non-centrosymmetric unit-cell content of derivative II when compared to its single molecule, which may be related to its molecular pillaring, similar to that observed in derivative III. On the other hand, a desirable magnification of the NLO properties was found for packed units of derivative I, which may be a consequence of its parallel face-to-tail stacking with the CT vectors of all molecules pointing in the same direction. Moreover, the CT vector of compound I makes an angle of θ = 33.6° with its crystal polar axis, resulting in a higher-order parameter (cos(3)θ = 0.6) compared with the other derivatives. This is in line with the higher macroscopic second-order NLO response predicted for derivative I, βtot = 120.4 × 10(-30) e.s.u.
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http://dx.doi.org/10.1107/S2052520615008859DOI Listing
August 2015

Analgesic and anti-inflammatory activities of the 2,8-dihydroxy-1,6-dimethoxyxanthone from Haploclathra paniculata (Mart) Benth (Guttiferae).

J Med Food 2014 Jun 29;17(6):686-93. Epub 2014 Jan 29.

1 Department of Food Sciences of Federal University of Lavras-UFLA , Lavras-MG, Brazil .

In the present study, the pharmacological effects of 2,8-dihydroxy-1,6-dimethoxyxanthone from the bark of Haploclathra paniculata were investigated in mice using in vivo inflammation and nociception models. Acetic acid-induced writhing, paw licking induced by formalin, hot plate, and carrageenan-induced paw edema tests were used to investigate the anti-inflammatory and antinociceptive activities of the xanthone compound. Xanthone, at both doses, inhibited abdominal writhing and the formalin test. At a dose of 20 mg/kg, the time of reaction to the hot plate increased, and significant effects were observed after 30, 60 and 90 min of treatment. At doses of 10 and 20 mg/kg p.o., the 2,8-dihydroxy-1,6-dimethoxyxanthone significantly reduced paw edema at 3 h after the stimulus. The tests also showed no acute toxicity of the xanthone compound in mice. 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability was also studied and confirmed the antioxidant activity of the xanthone. To propose the mechanism of action of anti-inflammatory activity of the xanthone, a molecular docking was performed using the isoenzymes cyclooxygenase 1 and 2 and the results indicate that the molecule is capable of inhibiting both the enzymes. Therefore, it can be concluded that 2,8-dihydroxy-1,6-dimethoxyxanthone from H. paniculata demonstrates analgesic, anti-inflammatory, and antioxidant activities.
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http://dx.doi.org/10.1089/jmf.2013.0122DOI Listing
June 2014

Synthesis and biological evaluation against Leishmania amazonensis of a series of alkyl-substituted benzophenones.

Bioorg Med Chem 2013 Jun 30;21(11):3114-9. Epub 2013 Mar 30.

Laboratório de Fitoquímica e Química Medicinal, Universidade Federal de Alfenas, 37130-000 Alfenas, MG, Brazi.

Nine O-alkyl and O-prenyl derivatives were synthesized from commercial 2,4-dihydroxybenzophenone, 4,e4,4'-dihydroxybenzophenone and were evaluated for their leishmanicidal activity against promastigote forms of Leishmania amazonensis, as well their toxicity in murine macrophages. All derivatives exhibited better biological activity than their hydroxylated benzophenones precursors, and new compound LFQM-123 (3c) was 250-fold more active than its precursor 4,4'-dihydroxybenzophenone (3). Moreover, some of the results were comparable to the standard drug Amphotericin B, suggesting that the increase in lipophilicity could facilitate protozoa membrane permeation. In this study we confirmed that benzophenone derivatives exhibit leishmanicidal properties, with relatively low toxicity, and thus could be exploited as promise prototypes for the design and development of new drug for the treatment of leishmaniasis.
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http://dx.doi.org/10.1016/j.bmc.2013.03.045DOI Listing
June 2013

Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor.

J Enzyme Inhib Med Chem 2013 Aug 2;28(4):661-70. Epub 2012 Apr 2.

Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil.

Cruzain is the major cysteine protease of Trypanosoma cruzi, the infectious agent responsible for Chagas disease, and cruzain inhibitors display considerable antitrypanosomal activity. In the present work we elucidated crystallographic data of fukugetin, a biflavone isolated from Garcinia brasiliensis, and investigated the role of this molecule as cysteine protease inhibitor. The kinetic analyses demonstrated that fukugetin inhibited cruzain and papain by a slow reversible type inhibition with K(I) of 1.1 and 13.4 µM, respectively. However, cruzain inhibition was about 12 times faster than papain inhibition. Lineweaver-Burk plots demonstrated partial competitive inhibition for cruzain and hyperbolic mixed-type inhibition for papain. Furthermore, the docking results showed that the biflavone binds to ring C' in the S2 pocket and to ring C in the S3 pocket through hydrophobic interactions and hydrogen bonds. Finally, fukugetin also presented inhibitory activity on proteases of the T. cruzi extract, with IC₅₀ of 7 µM.
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http://dx.doi.org/10.3109/14756366.2012.668539DOI Listing
August 2013
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