Publications by authors named "Clarice Q F Leite"

28 Publications

  • Page 1 of 1

Genetic correlates of clarithromycin susceptibility among isolates of the Mycobacterium abscessus group and the potential clinical applicability of a PCR-based analysis of erm(41).

J Antimicrob Chemother 2018 04;73(4):862-866

Tuberculosis and Mycobacteriosis Laboratory, Bacteriology Center, Instituto Adolfo Lutz, São Paulo, Brazil.

Objectives: To define the genetic basis of clarithromycin resistance among isolates of the Mycobacterium abscessus group (MAG).

Methods: We analysed 133 isolates identified as MAG. Species identification was confirmed by sequencing the rpoB gene. Clarithromycin susceptibility testing was performed according to CLSI recommendations, with an extended 14 day incubation. Known resistance genotypes of erm(41) and rrl were identified by sequencing; the presence of deletions in erm(41) was detected by PCR.

Results: The 133 MAG isolates included 82 M. abscessus, 27 Mycobacterium massiliense and 24 Mycobacterium bolletii. After the 3 day incubation, only five isolates demonstrated clarithromycin resistance (R); after 14 days of extended incubation, an additional 92 exhibited inducible resistance (IR), with the remaining being susceptible (S). The distribution of susceptibility phenotypes varied among the species. Among M. abscessus isolates, 11% were S, 84% IR and 5% R; among M. bolletii isolates, 96% were IR and 4% R; and among M. massiliense isolates 100% were S. Sequencing of rrl identified only a single isolate with the A2058G mutation. Deletions in erm(41) were present in 30 susceptible isolates; among the remaining 103 isolates, 97 were R or IR (sensitivity, 83%; specificity, 100%; positive predictive value, 100%; negative predictive value, 94%). Among the six susceptible isolates without deletions, all carried the erm(41) T28C point mutation.

Conclusions: A significant proportion of MAG isolates demonstrate inducible resistance to clarithromycin that is only detectable with an extended 14 day incubation. Further, the majority of clarithromycin-susceptible MAG isolates have characteristic deletions in erm(41) that can rapidly and reliably be detected by a simple PCR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkx476DOI Listing
April 2018

Novel Zinc(II) Complexes [Zn(atc-Et)₂] and [Zn(atc-Ph)₂]: In Vitro and in Vivo Antiproliferative Studies.

Int J Mol Sci 2016 May 21;17(5). Epub 2016 May 21.

Faculdade de Ciencias Farmaceuticas, UNESP-Univ Estadual Paulista, Campus Araraquara, Araraquara, São Paulo 14800-903, Brazil.

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms17050781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881598PMC
May 2016

Aromatic amine N-oxide organometallic compounds: searching for prospective agents against infectious diseases.

Dalton Trans 2015 Aug;44(32):14453-64

Cátedra de Química Inorgánica, Departamento Estrella Campos, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.

In search of prospective agents against infectious diseases, 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolato-1-oxide M(ii) hexafluorophosphate compounds [M(mpo)(dppf)](PF6), where M = palladium or platinum, were synthesized and fully characterized in the solid state and in solution using experimental and DFT computational techniques. The compounds are isomorphous and the M(ii) transition metal ions are in a nearly planar trapezoidal cis-coordination bound to the pyridine-2-thiolato-1-oxide (mpo) and to the 1,1'-bis(diphenylphosphino)ferrocene molecules, both acting as bidentate ligands. Both compounds showed high cytotoxic activity on Trypanosoma cruzi and Mycobacterium tuberculosis (MTB) and acceptable selectivities towards MTB, but good to excellent selectivity index values as anti-T. cruzi compounds. The inclusion of the ferrocene moiety (dppf ligand) improved the selectivity towards the parasite when compared to the previously reported [M(mpo)2] complexes. Related to the probable mechanism of action of the complexes, molecular docking studies on modelled T. cruzi NADH-fumarate reductase (TcFR) predicted that both be very good inhibitors of the enzyme. The effect of the compounds on the enzyme activity was experimentally confirmed using T. cruzi protein extracts. According to all obtained results, both [M(mpo)(dppf)](PF6) compounds could be considered prospective anti-trypanosomal agents that deserve further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5dt00557dDOI Listing
August 2015

Bioactivity of pyridine-2-thiolato-1-oxide metal complexes: Bi(III), Fe(III) and Ga(III) complexes as potent anti-Mycobacterium tuberculosis prospective agents.

Eur J Med Chem 2014 Nov 27;87:267-73. Epub 2014 Sep 27.

Cátedra de Química Inorgánica, Departamento Estrella Campos, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay. Electronic address:

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M(III)(mpo)3] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga(III)(mpo)3] in CH2Cl2 led to single crystals of the reaction product [GaCl(mpo)2], where the gallium(III) ion is in a square basis pyramidal environment, trans-coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M(III)(mpo)3] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis. The compounds showed excellent activity, both in the standard strain H37Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2014.09.067DOI Listing
November 2014

Hydroxyquinoline derived vanadium(IV and V) and copper(II) complexes as potential anti-tuberculosis and anti-tumor agents.

J Inorg Biochem 2014 Dec 7;141:83-93. Epub 2014 Aug 7.

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. Electronic address:

Several mixed ligand vanadium and copper complexes were synthesized containing 8-hydroxyquinoline (8HQ) and a ligand such as picolinato (pic(-)), dipicolinato (dipic(2-)) or a Schiff base. The complexes were characterized by spectroscopic techniques and by single-crystal X-ray diffraction in the case of [V(V)O(L-pheolnaph-im)(5-Cl-8HQ)] and [V(V)O(OMe)(8HQ)2], which evidenced the distorted octahedral geometry of the complexes. The electronic absorption data showed the presence of strong ligand to metal charge transfer bands, significant solvent effects, and methoxido species in methanol, which was further confirmed by (51)V-NMR spectroscopy. The structures of [Cu(II)(dipic)(8HQ)]Na and [V(IV)O(pic)(8HQ)] were confirmed by EPR spectroscopy, showing only one species in solution. The biological activity of the compounds was assessed through the minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis (Mtb) and the cytotoxic activity against the cisplatin sensitive/resistant ovarian cells A2780/A2780cisR and the non-tumorigenic HEK cells (IC50 values). Almost all tested vanadium complexes were very active against Mtb and the MICs were comparable to, or better than, the MICs of drugs, such as streptomycin. The activity of the complexes against the A2780 cell line was dependent on incubation time presenting IC50 values in the 3-14 μM (at 48 h) range. In these conditions, the complexes were significantly (*P<0.05-**P<0.001) more active than cisplatin (22 μM), in the A2780 cells and even surpassing its activity in the cisplatin-resistant cells A2780cisR (2.4-8 μM vs. 75.4; **P<0.001). In the non-tumorigenic HEK cells poor selectivity toward cancer cells for most of the complexes was observed, as well as for cisplatin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2014.07.019DOI Listing
December 2014

Vanadium Complexes with Hydrazone or Thiosemicarbazone Ligands as Potential Anti-Mycobacterium tuberculosis Agents.

Curr Clin Pharmacol 2015 ;10(1):66-72

School of Pharmaceutical Sciences, Sao Paulo State University, 14801-902, Araraquara, SP, Brazil.

Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis (MTB) and still an important public health problem worldwide. Some factors like the emergence of multidrug resistant (MDR) and extensively drug-resistant (XDR) strains make urgent the research of new active compounds. Searching for new inorganic compounds against TB, three new dioxovanadium(V) complexes were obtained upon reaction of [VO(acac)2] with hydrazone and thiosemicarbazone ligands derived from di-2-pyridyl ketone. Spectroscopic studies and X-ray crystallography revealed asymmetrically oxo bridged binuclear complexes of the type [{VO(L(1,2))}2(μ-O)2], involving the hydrazone ligands, while a mononuclear square pyramidal complex of the type [VO2(L(3))] was formed with the thiosemicarbazone ligand. The compounds were tested against M. tuberculosis and three of them, with MICs values between 2.00 and 3.76 μM were considered promising for TB treatment. Such MIC values are comparable or better than those found for some drugs currently used in TB treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1574884708666131229124748DOI Listing
February 2016

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents.

J Inorg Biochem 2014 Mar 25;132:21-9. Epub 2013 Oct 25.

Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos, SP, Brazil. Electronic address:

Through a systematic variation on the structure of a series of manganese complexes derived from 2-acetylpyridine-N(4)-R-thiosemicarbazones (Hatc-R), structural features have been investigated with the aim of obtaining complexes with potent anti-Mycobacterium tuberculosis activity. The analytical methods used for characterization included FTIR, EPR, UV-visible, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. Density functional theory (DFT) calculations were performed in order to evaluate the contribution of the thiosemicarbazonate ligands on the charge distribution of the complexes by changing the peripheral groups as well as to verify the Mn-donor atoms bond dissociation predisposition. The results obtained are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral complexes of the type [Mn(atc-R)2], paramagnetic in the extension of 5 unpaired electrons, whose EPR spectra are consistent for manganese(II). The electrochemical analyses show two nearly reversible processes, which are influenced by the peripheral substituent groups at the N4 position of the atc-R(1-) ligands. The minimal inhibitory concentration (MIC) of these compounds against M. tuberculosis as well as their in vitro cytotoxicity on VERO and J774A.1 cells (IC50) was determined in order to find their selectivity index (SI) (SI=IC50/MIC). The results evidenced that the compounds described here can be considered as promising anti-M. tuberculosis agents, with SI values comparable or better than some commercial drugs available for the tuberculosis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2013.10.011DOI Listing
March 2014

In vitro and in vivo activities of ruthenium(II) phosphine/diimine/picolinate complexes (SCAR) against Mycobacterium tuberculosis.

PLoS One 2013 28;8(5):e64242. Epub 2013 May 28.

Department of Biological Sciences, College of Pharmacy, Univ Estadual Paulista, Araraquara, São Paulo, Brazil.

Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064242PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665843PMC
January 2014

Increment of antimycobaterial activity on lichexanthone derivatives.

Med Chem 2013 Nov;9(7):904-10

Centro de Ciências Exatas e Tecnologia, Universidade Federal de Mato Grosso do Sul, P. O. Box 549, Campo Grande, MS, Brazil.

A new dihydropyranexanthone derived from the natural xanthone lichexanthone (1) was synthesised and, together with other 18 derivatives including ω-bromo and ω-aminoalkoxylxanthones (containing methyl, ethyl, propyl, tertbutylamino and piperidinyl moieties), were tested against Mycobacterium tuberculosis. Nine ω-aminoalkoxylxanthones showed good antimycobacterial activity, and their in vitro cytotoxicity was determined using VERO cells in order to calculate the selectivity index (SI). One of these nitrogenated xanthone derivatives showed very promising results, with MIC of 2.6 μM and SI of 48. This MIC is comparable to values found in "first and second line" drugs commonly used to treat TB. In order to understand better about this compound, it was evaluated together with two other ones that showed good SI, against resistant clinical strains of M. tuberculosis to verify the existence of cross-resistance. A chemometrical approach was useful to establish a pattern of antitubercular activity among the group of ω-aminoalkoxylxanthones, according to some structural and chemical features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573406411309070003DOI Listing
November 2013

Synthesis, cytotoxicity, antibacterial and antileishmanial activities of imidazolidine and hexahydropyrimidine derivatives.

Med Chem 2013 May;9(3):351-9

Departamento de Quimica, Universidade Federal de Juiz de Fora, Juiz de Fora, Brasil.

This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 μg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573406411309030005DOI Listing
May 2013

Anti-Mycobacterium tuberculosis activity of fungus Phomopsis stipata.

Braz J Microbiol 2012 Jan 1;43(1):224-9. Epub 2012 Jun 1.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista , Araraquara, SP , Brasil ; Faculdades Integradas Pitágoras , Montes Claros, MG , Brasil.

Our purpose was to determine the anti-Mycobacterium tuberculosis activity of the metabolites produced by the endophitic fungus Phomopsis stipata (Lib.) B. Sutton, (Diaporthaceae), cultivated in different media. The antimycobacterial activity was assessed through the Resazurin Microtiter Assay (REMA) and the cytotoxicity test performed on macrophage cell line. The extracts derived from fungi grown on Corn Medium and Potato Dextrose Broth presented the smallest values of Minimum Inhibitory Concentration (MIC) and low cytotoxicity, which implies a high selectivity index. This is the first report on the chemical composition and antitubercular activity of metabolites of P. stipata, as well as the influence of culture medium on these properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/S1517-838220120001000024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769001PMC
January 2012

Ruthenium(II) phosphine/diimine/picolinate complexes: inorganic compounds as agents against tuberculosis.

Eur J Med Chem 2011 Oct 23;46(10):5099-107. Epub 2011 Aug 23.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, CEP 14801-902, Araraquara, SP, Brazil.

This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (Me-bipy), 4,4'-dichloro-2,2'-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF(6) (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF(6) (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF(6) (SCAR03) and [Ru(pic)(dppb)(phen)]PF(6) (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)(2)]PF(6) (SCAR05) and cis-[RuCl(2)(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2011.08.023DOI Listing
October 2011

Synthesis and Anti-Mycobacterium tuberculosis Evaluation of Aza-Stilbene Derivatives.

ScientificWorldJournal 2011 May 26;11:1113-9. Epub 2011 May 26.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil.

Tuberculosis (TB) is a truly global disease, found in every country on earth. One-third of humanity, over 2 billion people, carry the bacillus that causes TB and 2 million people die of the disease each year. Despite that, no new specific drug against Mycobacterium tuberculosis has been developed since the 1960s. There are several candidates for new anti-TB agents, but none proven clinically effective. Stilbenes are compounds found in numerous medicinal plants and food products with some known biological and even antimycobacterial activity. This paper describes the synthesis and the anti-M. tuberculosis activity of eight stilbene analogues. The synthesis and characterization of these compounds are shown, and the results compared with one "first"-line drug used in current therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1100/tsw.2011.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720119PMC
May 2011

Synthesis of 4-aminoquinoline analogues and their platinum(II) complexes as new antileishmanial and antitubercular agents.

Biomed Pharmacother 2011 Jun 4;65(3):204-9. Epub 2011 May 4.

Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora, MG 36036-900, Brazil.

A series of 4-amino-7-chloroquinoline derivatives were synthesized by the reaction of 4,7-dichloro-quinoline with the corresponding diamine and then with propargyl bromide. In addition, platinum(II) complexes were obtained by reacting some of the organic derivatives with K(2)PtCl(4). Several of the synthesized compounds displayed antituberculosis activities. Compound 3 was 47.5 times more active than amphotericin B against Leishmania chagasi (IC(50)=0.04 μg/mL). Compounds 5, 6, 7, 9, 10, 11 and 13 presented promising results against Mycobacterium tuberculosis, with MIC values ranging from 12.5 to 15.6 μg/mL, comparable to the "first and second line" drugs used to treat tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2011.01.003DOI Listing
June 2011

Antimycobacterial and antitumor activities of palladium(II) complexes containing isonicotinamide (isn): X-ray structure of trans-[Pd(N3)2(isn)(2)].

Eur J Med Chem 2010 Nov 6;45(11):4863-8. Epub 2010 Aug 6.

Sao Paulo State Univ, Instituto de Química de Araraquara, Rua Prof. Francisco Degni s/n, C.P. 355, 14800-900 Araraquara, SP, Brazil.

Complexes of the type trans-[PdX(2)(isn)(2)] {X = Cl (1), N(3) (2), SCN (3), NCO (4); isn = isonicotinamide} were synthesized and evaluated for in vitro antimycobacterial and antitumor activities. The coordination mode of the isonicotinamide and the pseudohalide ligands was inferred by IR spectroscopy. Single crystal X-ray diffraction determination on 2 showed that coordination geometry around Pd(II) is nearly square planar, with the ligands in a trans configuration. All the compounds demonstrated better in vitro activity against Mycobacterium tuberculosis than isonicotinamide and pyrazinamide. Among the complexes, compound 2 was found to be the most active with MIC of 35.89 μM. Complexes 1-4 were also screened for their in vitro antitumor activity towards LM3 and LP07 murine cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2010.07.057DOI Listing
November 2010

Design of novel iron compounds as potential therapeutic agents against tuberculosis.

J Inorg Biochem 2010 Nov 17;104(11):1164-70. Epub 2010 Jul 17.

Facultad de Química, Cátedra de Química Inorgánica, Universidad de la República, Gral Flores 2124, C C 1157, 11800 Montevideo, Uruguay.

In the search for new therapeutic tools against tuberculosis two novel iron complexes, [Fe(L-H)(3)], with 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives (L) as ligands, were synthesized, characterized by a combination of techniques, and in vitro evaluated. Results were compared with those previously reported for two analogous iron complexes of other ligands of the same family of quinoxaline derivatives. In addition, the complexes were studied by cyclic voltammetry and EPR spectroscopy. Cyclic voltammograms of the iron compounds showed several cathodic processes which were attributed to the reduction of the metal center (Fe(III)/Fe(II)) and the coordinated ligand. EPR signals were characteristic of magnetically isolated high-spin Fe(III) in a rhombic environment and arise from transitions between m(S) = ± 1/2 (g(eff) ~ 9) or m(S) = ± 3/2 (g(eff) ~ 4.3) states. Mössbauer experiments showed hyperfine parameters that are typical of high-spin Fe(III) ions in a not too distorted environment. The novel complexes showed in vitro growth inhibitory activity on Mycobacterium tuberculosis H(37)Rv (ATCC 27294), together with very low unspecific cytotoxicity on eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M. tuberculosis than the "second-line" therapeutic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2010.07.005DOI Listing
November 2010

Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: anti-Mycobacterium tuberculosis activity and cytotoxicity.

Eur J Med Chem 2010 May 28;45(5):1898-905. Epub 2010 Jan 28.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, 14801-902 Araraquara, SP, Brazil.

The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of "first line" or "second line" drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2010.01.028DOI Listing
May 2010

Pt(II) and Ag(I) complexes with acesulfame: crystal structure and a study of their antitumoral, antimicrobial and antiviral activities.

J Inorg Biochem 2010 May 18;104(5):533-40. Epub 2010 Jan 18.

Instituto de Química, Universidade Estadual Paulista Júlio de Mesquita Filho - UNESP, Rua Prof. Francisco Degni s/n, CEP 14801-970, Araraquara, SP, Brazil.

Two new complexes of platinum(II) and silver(I) with acesulfame were synthesized. Acesulfame is in the anionic form acesulfamate (ace). The structures of both complexes were determined by X-ray crystallography. For K(2)[PtCl(2)(ace)(2)] the platinum atom is coordinated to two Cl(-) and two N-acesulfamate atoms forming a trans-square planar geometry. Each K(+) ion interacts with two oxygen atoms of the S(O)(2) group of each acesulfamate. For the polymeric complex [Ag(ace)](n) the water molecule bridges between two crystallographic equivalent Ag1 atoms which are related each other by a twofold symmetry axis. Two Ag1 atoms, related to each other by a symmetry centre, make bond contact with two equivalent oxygen atoms. These bonds give rise to infinite chains along the unit cell diagonal in the ac plane. The in vitro cytotoxic analyses for the platinum complex using HeLa (human cervix cancer) cells show its low activity when compared to the vehicle-treated cells. The Ag(I) complex submitted to in vitro antimycobacterial tests, using the Microplate Alamar Blue (MABA) method, showed a good activity against Mycobacterium tuberculosis, responsible for tuberculosis, with a minimal inhibitory concentration (MIC) value of 11.6microM. The Ag(I) complex also presented a promising activity against Gram negative (Escherichia coli and Pseudomonas aeruginosa) and Gram positive (Enterococcus faecalis) microorganisms. The complex K(2)[PtCl(2)(ace)(2)] was also evaluated for antiviral properties against dengue virus type 2 (New Guinea C strain) in Vero cells and showed a good inhibition of dengue virus type 2 (New Guinea C strain) replication at 200microM, when compared to vehicle-treated cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2010.01.004DOI Listing
May 2010

Screening of molecules with anti-TB activity from the brazilian cerrado plants.

Rev Port Pneumol 2010 Jan;16SA:S83-8

Faculdade de Ciências Farmacêuticas, UNESP, CEP 14801-902, Araraquara (SP), Brasil. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0873-2159(15)30097-0DOI Listing
January 2010

Ruthenium (II) phosphine/picolinate complexes as antimycobacterial agents.

Eur J Med Chem 2010 Feb 6;45(2):598-601. Epub 2009 Nov 6.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, CEP 14801-902, Araraquara, SP, Brazil.

The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis- [Ru(pic)(dppm)(2)]PF(6) (1), cis- [Ru(pic)(dppe)(2)]PF(6) (2) and [Ru(pic)(2)(PPh(3))(2)] (3) [pic=2-pyridinecarboxylate; dppm=bis(diphenylphosphino)methane; dppe=1,2-bis(diphenylphosphino)ethane; PPh(3)=triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro antimycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26 microg/mL, respectively. The results are comparable to or better than "first line" or "second line" drugs commonly used in the treatment of TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2009.10.049DOI Listing
February 2010

Antitumor and antimycobacterial activities of cyclopalladated complexes: X-ray structure of [Pd(C2,N-dmba)(Br)(tu)] (dmba=N,N-dimethylbenzylamine, tu=thiourea).

Eur J Med Chem 2009 Nov 4;44(11):4611-5. Epub 2009 Jul 4.

Departamento de Química Geral e Inorgânica, Instituto de Química, UNESP, CEP, 14801-970 Araraquara, SP, Brazil.

The reactions between [Pd(C(2),N-dmba)(micro-X)](2) (dmba=N,N-dimethylbenzylamine; X=Cl, Br) and thiourea (tu) in the 1:2 molar ratio at room temperature resulted in the mononuclear compounds [Pd(C(2),N-dmba)(Cl)(tu)] (1) and [Pd(C(2),N-dmba)(Br)(tu)] (2), which were characterized by elemental analyses and infrared (IR), (1)H- and (13)C{(1)H} NMR spectroscopies. The crystal and molecular structures of 2 were determined by single-crystal X-ray diffraction. In vitro cytotoxicity assays of the compounds 1, 2, tu, dmba and cisplatin were carried out using two murine tumor cell lines, namely mammary adenocarcinoma (LM3) and lung adenocarcinoma (LP07). The compounds 1, 2, tu and dmba were also tested against Mycobacterium tuberculosis and their MIC values were determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2009.06.032DOI Listing
November 2009

Synthesis and in vitro anti Mycobacterium tuberculosis activity of a series of phthalimide derivatives.

Bioorg Med Chem 2009 Jun 3;17(11):3795-9. Epub 2009 May 3.

Lapdesf-Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista Júlio de Mesquita Filho, Araraquara, SP, Brazil.

New phthalimide derivatives were easily prepared through condensation of phthalic anhydride and selected amines with variable yields (70-90%). All compounds (3a-l) were evaluated against Mycobacterium tuberculosis H(37)Rv using Alamar Blue susceptibility. The compounds 3c, 3i, and 3l have the minimum inhibitory concentrations (MICs) of 3.9, 7.8, and 5.0 microg/mL, respectively, and could be considered new lead compounds in the treatment of tuberculosis and multi-drug resistant tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2009.04.042DOI Listing
June 2009

Synthesis, characterization, X-ray structure and in vitro antimycobacterial and antitumoral activities of Ru(II) phosphine/diimine complexes containing the "SpymMe2" ligand, SpymMe2=4,6-dimethyl-2-mercaptopyrimidine.

J Inorg Biochem 2008 Sep 29;102(9):1783-9. Epub 2008 May 29.

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos, SP, Brazil.

The reaction of cis-[RuCl(2)(dppb)(N-N)], dppb=1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe(2), 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe(2))(dppb)(N-N)]PF(6), N-N=bipy (1) and Me-bipy (2), bipy=2,2'-bipyridine and Me-bipy=4,4'-dimethyl-2,2'-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl(2)(dppb)(N-N)], N-N=bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe(2). The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC(50) values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25microg/mL, compared to the free ligands (MIC of 25 to >50microg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC(50) values of 0.46+/-0.02 and 0.43+/-0.08microM, respectively, against MDA-MB-231 breast tumor cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2008.05.009DOI Listing
September 2008

Synthesis, characterization and antimycobacterial activity of Ag(I)-aspartame, Ag(I)-saccharin and Ag(I)-cyclamate complexes.

Arch Pharm (Weinheim) 2007 Oct;340(10):538-42

Departamento de Química Geral e Inorgânica, Instituto de Química, Universidade Estadual Paulista, Araraquara, SP, Brazil.

The present work describes the synthesis and antimycobacterial activity of three Ag(I)-complexes with the sweeteners aspartame, saccharin, and cyclamate as ligands, with the aim of finding new candidate substances for fighting tuberculosis and other mycobacterial infections. The minimal inhibitory concentration of these three complexes was investigated in order to determine their in-vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium malmoense, and Mycobacterium kansasii. The MIC values were determined using the Microplate Alamar Blue Assay. The best MIC values found for the complexes were 9.75 microM for Ag(I)-aspartame against M. kansasii and 15.7 microM for Ag(I)-cyclamate against M. tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ardp.200700040DOI Listing
October 2007

Synthesis, X-ray structure and antimycobacterial activity of silver complexes with alpha-hydroxycarboxylic acids.

J Inorg Biochem 2007 Feb 20;101(2):291-6. Epub 2006 Oct 20.

Laboratório de Bioinorgânica e Cristalografia, Departamento de Química, UFSC, CEP 88040-900 Florianópolis, SC, Brazil.

In this paper, synthesis, characterization and antimycobacterial properties of a new water-soluble complex identified as silver-mandelate are described. Elemental and thermal analyses are consistent with the formula [Ag(C(6)H(5)C(OH)COO)](n). The polymeric structure was determined by single X-ray diffraction and the two-dimensional structure is based on the bis(carboxylate-O,O') dimer [Ag-O, 2.237(3), 2.222(3) Angstrom]. The structure is extended along both the b and c axes through two oxygen atoms of a bidentate alpha-hydroxyl-carboxylate residue [Ag-OH(hydroxyl), 2.477(3) Angstrom; Ag-O(carboxylate), 2.502(3) Angstrom; O-Ag-O, 63.94(9) degrees]. A strong d(10)-d(10) interaction was observed between two silver atoms. The Ag - Ag distance is 2.8307(15) Angstrom. The NMR (13)C spectrum in D(2)O shows that coordination of the ligand to Ag(I) occurs through the carboxylate group in solution. Potentiometric titration shows that only species with a molar metal:ligand ratio of 2:2 are formed in aqueous solution. The mandelate complex and the silver-glycolate, silver-malate and silver-hydrogen-tartarate complexes were tested against three types of mycobacteria, Mycobacterium avium, Mycobacterium tuberculosis and Mycobacterium kansasii, and their minimal inhibitory concentration (MIC) values were determined. The results show that the four complexes are potential candidates for antiseptic or disinfectant drugs for discharged secretions of patients affected with tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2006.10.001DOI Listing
February 2007

Potential tuberculostatic agent: micelle-forming pyrazinamide prodrug.

Arch Pharm (Weinheim) 2006 Jun;339(6):283-90

Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.

Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ardp.200500039DOI Listing
June 2006

Screening and characterization of mutations in isoniazid-resistant Mycobacterium tuberculosis isolates obtained in Brazil.

Antimicrob Agents Chemother 2004 Sep;48(9):3373-81

Department of Clincal Analysis, State University of Maringá, Paraná, Brazil.

We investigated mutations in the genes katG, inhA (regulatory and structural regions), and kasA and the oxyR-ahpC intergenic region of 97 isoniazid (INH)-resistant and 60 INH-susceptible Mycobacterium tuberculosis isolates obtained in two states in Brazil: São Paulo and Paraná. PCR-single-strand conformational polymorphism (PCR-SSCP) was evaluated for screening mutations in regions of prevalence, including codons 315 and 463 of katG, the regulatory region and codons 16 and 94 of inhA, kasA, and the oxyR-ahpC intergenic region. DNA sequencing of PCR amplicons was performed for all isolates with altered PCR-SSCP profiles. Mutations in katG were found in 83 (85.6%) of the 97 INH-resistant isolates, including mutations in codon 315 that occurred in 60 (61.9%) of the INH-resistant isolates and 23 previously unreported katG mutations. Mutations in the inhA promoter region occurred in 25 (25.8%) of the INH-resistant isolates; 6.2% of the isolates had inhA structural gene mutations, and 10.3% had mutations in the oxyR-ahpC intergenic region (one, nucleotide -48, previously unreported). Polymorphisms in the kasA gene occurred in both INH-resistant and INH-susceptible isolates. The most frequent polymorphism encoded a G(269)A substitution. Although KatG(315) substitutions are predominant, novel mutations also appear to be responsible for INH resistance in the two states in Brazil. Since ca. 90.7% of the INH-resistant isolates had mutations identified by SSCP electrophoresis, this method may be a useful genotypic screen for INH resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.48.9.3373-3381.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514764PMC
September 2004

Potential tuberculostatic agents. Topliss application on benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide series.

Bioorg Med Chem 2002 Mar;10(3):557-60

Fac. de Ciências Farmacêuticas, USP, Av. Prof. Lineu Prestes, 580, São Paulo-SP 05508-900, Brazil.

Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss' decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0968-0896(01)00313-3DOI Listing
March 2002
-->