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ABSTRACT: Trypanosoma cruzi glutamate cysteine ligase (TcGCL) is considered a potential drug target to develop novel antichagasic drugs. We have used a variety of computational methods to investigate the interactions between TcGCL with Glutathione (GSH). The three-dimensional structure of TcGCL was constructed by comparative modeling methods using the Saccharomyces cerevisiae glutamate cysteine ligase as template. Molecular dynamics simulations were used to validate the TcGCL model and to analyze the molecular interactions with GSH. Using RMSD clustering, the most prevalent GSH binding modes were identified paying attention to the residues involved in the molecular interactions. The GSH binding modes were used to propose pharmacophore models that can be exploited in further studies to identify novel antichagasic compounds.
Journal of Molecular Modeling 09/2011; 18(5):2055-64. · 1.80 Impact Factor
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ABSTRACT: The title compound, C(13)H(13)NO(4), is one cyclization product of the reaction of ethyl 1-(2-bromo-eth-yl)-4,7-dimeth-oxy-1H-indole-2-carboxyl-ate with sodium azide in refluxing dioxane and was synthesized with the aim of finding new compounds with biological properties. Bond lengths and angles are within the expected values and confirm the bond orders giving in the scheme. The shortest contacts between mol-ecules are set along the a axis, where stacked mol-ecules related by an inversion center form an ABAB array through π-π stacking inter-actions with centroid-centroid distances ranging from 3.922 (2) to 4.396 (2) Å. Weak C-H⋯O hydrogen bonds further stabilize the structure.
Acta Crystallographica Section E Structure Reports Online 01/2011; 67(Pt 2):o318. · 0.35 Impact Factor
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ABSTRACT: The title compound, C26H28O3Si, is an allylic oxidation product of the tert-butyl(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)diphenylsilane with N-bromosuccinimide and 2,2′-azobis-isobutyronitrile. The nine-atom bicyclic system is almost planar, with an r.m.s deviation of 0.0123 (2) Å and a maximum deviation of 0.031 (2) Å for the O atom. In the crystal, the molecules pile up along the b axis but the strongest intermolecular contacts are the π–π stacking interactions between the benzene rings along the c axis [centroid–centroid distance = 3.655 (3) Å].
Acta Crystallographica Section E. 01/2011;
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ABSTRACT: The title compound, C(26)H(28)O(3)Si, is an allylic oxidation product of the tert-but-yl(2,2-dimethyl-2,3-dihydro-benzo-furan-7-yl-oxy)diphenyl-silane with N-bromo-succinimide and 2,2'-azobis-isobutyronitrile. The nine-atom bicyclic system is almost planar, with an r.m.s deviation of 0.0123 (2) Å and a maximum deviation of 0.031 (2) Å for the O atom. In the crystal, the mol-ecules pile up along the b axis but the strongest inter-molecular contacts are the π-π stacking inter-actions between the benzene rings along the c axis [centroid-centroid distance = 3.655 (3) Å].
Acta Crystallographica Section E Structure Reports Online 01/2011; 67(Pt 2):o375. · 0.35 Impact Factor
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ABSTRACT: Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.
Current Medicinal Chemistry 01/2011; 18(1):144-61. · 4.86 Impact Factor
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ABSTRACT: The synthesis of new indazol-4,7-dione derivatives via 1,3-dipolar cycloaddition of diazomethane with 2,3-dimethyl-1,4-benzoquinone (2) and 1,4-naphthoquinone (7) followed by N-alkylation of the pyrazol nitrogen atom of the corresponding quinones (3) and (8) with methyl chloroacetate is described. A series of amides from esters (5) and (10) were also obtained. These compounds were tested in vitro as potential anti-trypanosomal agents. Compounds (4) and (8) were found to have significant activity.
Journal of Heterocyclic Chemistry 03/2009; 39(5):1093 - 1096. · 1.22 Impact Factor
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ABSTRACT: 13C chemical shift assignment of several methyl substituted heterocyclic naphtho- and anthraquinones, including dihydronaphthofuranquinones, azaanthraquinones, benzopyrroloquinolinediones and benzothiophenoquinolinediones, are described. A deshielding effect due to a methyl group was observed over the neighbouring carbonyl carbon, in every case studied. 13C assignments were based on 2D experiments.
Magnetic Resonance in Chemistry 02/2008; 46(2):191-4. · 1.44 Impact Factor
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ABSTRACT: Derivatives of natural quinones with biological activities, such as lapachol, alpha- and beta-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti-T. cruzi activity of the alpha-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones.
Bioorganic & medicinal chemistry 02/2008; 16(2):668-74. · 2.82 Impact Factor
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ABSTRACT: A short and convenient synthesis of benzopyranoquinone 6 and its application to the preparation of epoxynaphthopyanoquinone 1 is described.
Synthetic Communications 08/2006; 31(4)(601–606 (2001)):601-606. · 1.06 Impact Factor
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ABSTRACT: In the search for new potentially anticancer drugs, isoquinolinequinone-containing polycyclic compounds have been designed and synthesized through highly regiocontrolled cycloaddition reactions of methyl 1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate with polarized 1,3-dienes and a thiazole-o-quinodimethane. The new N-heterocyclic quinones were tested on normal human fibroblasts and four distinct human cancer cell lines. Two of the evaluated compounds displayed significant in vitro activity (IC50: 0.44-5.9 microM) comparable to that of the reference drug etoposide.
Bioorganic & Medicinal Chemistry 08/2006; 14(14):5003-11. · 2.92 Impact Factor
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ABSTRACT: The synthesis of dihydronaphthofurandione and dihydrofuroquinolinedione derivatives 4-11 was performed through Diels-Alder reactions of dihydrobenzofurandione 1 with several carbodienes and acrolein N,N-dimethylhydrazone. Then, the use of 5-bromobenzofurandione 2 toward 1,3-pentadiene and the 1-azadiene afforded quinones 6 and 11 with a total regioselectivity. All the prepared quinones were tested for trypanocidal activity in vitro against Trypanosoma epimastigotes, Tulahuen strain. Among the tested compounds, the furoquinolinediones 10 and 11 have shown potent trypanocidal activities but, only the 1,5-regioisomer (11) was found active as a redox cycling agent. Calculation of their stereoelectronic properties by the density-functional theory method provided a new insight for the trypanocidal activity of these heterocyclic quinones.
Bioorganic & Medicinal Chemistry 06/2004; 12(9):2451-8. · 2.92 Impact Factor
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ABSTRACT: Boc-aminoethylindoloquinone 8, a key intermediate for the building of pentacyclic quinoneimines, analogues of kuanoniamine A, was synthesized by alkylation of 4,7-dimethoxyindole 3 with 1,2-dibromoethane followed by transformation into azide, reduction of the latter with trimethylphosphine in the presence of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile and oxydative demethylation of the Boc-amine 6 with silver(II) oxide. Quinone 8 was then treated in situ with the thiazole o-quinodimethane 10 to afford a regioisomeric mixture of the tetracyclic quinones 11. Treatment of the mixture with trifluoroacetic acid and molecular sieves 4-A provided the corresponding quinoneimines 12. Separation of the regioisomers was performed by preparative thin-layer chromatography on silica gel. The structural assignment was made by 2D 1H-13C HMBC correlations performed on the less polar regioisomer 12b. In vitro anti-leishmanial assays showed that the tested compounds possess a good potency towards two Leishmania sp. as well as against a virulent strain of Toxoplasma gondii and without any cytotoxicity against THP-1 cells.
Bioorganic & Medicinal Chemistry 09/2003; 11(16):3407-12. · 2.92 Impact Factor
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ABSTRACT: The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.
Bioorganic & Medicinal Chemistry 06/2003; 11(10):2175-82. · 2.92 Impact Factor
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ABSTRACT: Pyrazinoindoloquinone 6 was synthesized by alkylation of ethyl 4,7-dimethoxyindole-2-carboxylate (1), followed by cyclization of the N-bromoethyl derivative 2b in the presence of ammonia. Oxidative demethylation of 2b and of the oxopyrazinoindole 3 with silver(II) oxide furnished quinones 5b and 6. Reduction of 3 with lithium aluminium hydride in dioxane provided 4, which was oxidized to afford 7. Quinones 5b, 6, and 7 were then treated in situ with the thiazole o-quinodimethane 9 to afford regioisomeric mixtures of the tetracyclic quinones 10 or the pentacyclic derivatives 11 or 12. The structural assignment was made by 2D NMR 1H-13C HMBC correlation performed on the major regioisomer 10a. In vitro antileishmanial assays showed that dimethoxyindole 2a and quinones 12a + 12b possess good inhibitory activity against two Leishmania sp. without any cytotoxicity towards a THP-1 cell line. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
Annalen der Chemie und Pharmacie 11/2002; 2002(23):4005 - 4010. · 3.10 Impact Factor
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ABSTRACT: The synthesis of 3-amino-2-methoxycarbonyl-4,7-dimethoxybenzo[b]thiophene (5) and benzothieno[3,2-d][1,3]oxazin 15 from 3,6-dimethoxy-2-nitrobenzaldehyde (1) is reported. Benzo[b]thiophene-4,7-quinones 9 and 10 were prepared in good yields by oxidative deprotection of the corresponding dimethoxybenzothiophenes 8 and 7. Cycloaddition reaction of quinone 8 with 1-(E)-trimethylsilyloxy-1,3-butadiene followed by acid-induced aromatization provides access to naphtho[2,3-b]thiophene-4,9-quinone 13 and 14. The in vitro activity of the new quinones against Leishmania amazonensis and human-T-cell leukemia virus type 1 (HTLV-1) is reported.
CHEMICAL & PHARMACEUTICAL BULLETIN 10/2002; 50(9):1215-8. · 1.59 Impact Factor
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ABSTRACT: The Diels–Alder reaction between a thiazole o-quinodimethane and 4,6-dichloroquinoline-5,8-dione gave 6-chloro-9-azaanthra[2,3-b]thiazole-5,10-dione as a single regioisomer. Its structure was assigned by 2D 1H–13C HMBC short- and long-range correlations. Measuring the spectra in CF3CO2D indicated that both nitrogen atoms of pyridine and thiazole rings are deuterated. Copyright © 2001 John Wiley & Sons, Ltd.
Magnetic Resonance in Chemistry 12/2001; 40(2):165 - 167. · 1.44 Impact Factor
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ABSTRACT: Derivatives of natural quinones with biological activities, such as lapachol, α- and β-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti-T. cruzi activity of the α-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones. This research was supported by FONDECYT (Research Grants 1020874 and 1061072), Proyecto Anillo ACT 29 CONICYT/PBCT, and DIPUC (Proyecto de Inicio 22 PI/2005).
