SciELO - Scientific Electronic Library Online

 
vol.51 número1LIPID PEROXIDATION RATES OF DPPC LIPOSOMES CONTAINING DIFFERENT AMOUNTS OF OXIDABLE LIPIDS SHOW OPPOSITE DEPENDENCE WITH THE TEMPERATURE índice de autoresíndice de assuntospesquisa de artigos
Home Pagelista alfabética de periódicos  

Serviços Personalizados

Journal

Artigo

Indicadores

Links relacionados

Compartilhar


Journal of the Chilean Chemical Society

versão On-line ISSN 0717-9707

J. Chil. Chem. Soc. v.51 n.1 Concepción mar. 2006

http://dx.doi.org/10.4067/S0717-97072006000100014 

J. Chil. Chem. Soc., 51, Nº 1 (2006)

REDUCTION OF 5-NITROFURAN COMPOUNDS CATALYZED BY A RHODIUM COMPLEX IMMOBILIZED ON POLY(4-VINYLPYRIDINE): A RELATIONSHIP WITH ANTIBACTERIAL ACTIVITY

M. E. FARKAS1, E. RODRÍGUEZ1, C. LONGO2*, M. MONASTERIOS2, M. C. ORTEGA3, A. B. RIVAS3 A. J. PARDEY4, R. LÓPEZ5, S.A. MOYA5*

1Departamento de Química, Universidad Simón Bolívar, Caracas, Venezuela

2Centro de Investigación y Desarrollo de Radiofármacos, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela

3Unidad de Química Medicinal, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela

4Escuela de Química, Facultad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela

5Departamento de Química de los Materiales, Facultad de Química y Biología Universidad de Santiago de Chile, Santiago de Chile, Chile

E-mail: longoc@camelot.rect.ucv.ve, smoya@lauca.usach.cl


ABSTRACT

This paper describes the catalytic activation studies of the reduction of some 2-substituted-5-nitrofuran compounds by [Rh(COD)(2-picoline)2](PF6) (COD = 1,5-cyclooctadiene) anchored on poly(4-vinylpyridine) in contact with 80% aqueous 2-ethoxyethanol at 100 º C under carbon monoxide atmosphere. The effect of varying the nature of the 2-substituents of the furan ring was evaluated. The importance of the present catalysis studies can be emphasized, because the potential activity against bacteria of the 2-substituted-5-nitrofuran compounds could be monitored by determining the facility of catalytic reduction of the nitro group.

Keywords: Nitrofuran; Rhodium complexes; Poly (4-vinylpyridine); Carbon monoxide; Water; Reduction.


 

INTRODUCTION

It is well known the antibacterial activity of 2-substituted-5-nitrofuran compounds1,2). They act against both Gram-positive and Gram-negative bacteria3); also, they are more active against anaerobic bacteria and are less active against aerobic and facultative anaerobic bacteria and totally lose the activity against bacteria that do not have any nitroreductase enzymatic system4). Further, 5-nitrofuran derivatives that are more easily reduced to nitro anion radical show activity against aerobic and anaerobic bacteria5).

It has been reported that known nitrofuran drugs are useful in the treatment of pneumonia caused by Pneumocystis carinii in inmunodepressed patients6), as in the treatment of duodenal ulcer caused by Helicobacter pylori, when combined with Clarytromicine and Omeprazol, completely eradicating the disease in treated patients7-10). Also, they are useful in urinary tract infections caused by enterococcus resistant to Vancomicin11). Some furan derivatives recently synthesized also showed antifungal activity against Candida albicans12) additional to the antibacterial activity.

It has been demonstrated that nitro group reduction is essential to therapeutic effect of nitro heterocyclic compounds. During chemical reduction, nitro group, in a first step, gains one electron to form a nitro anion radical (Ar-NO2•-) which through one additional electron gaining converts to nitroso derivative (Ar-NO) which in turn can be reduced by two electron gaining to hydroxylamine derivative (Ar-NHOH) or by four electron gaining to the amine derivative (Ar-NH2)13) (Scheme I). In a similar way, nitrofurans are enzymatically reduced by microorganisms14) originating nitroso derivatives, hydroxylamine and amine as toxic species towards bacteria. The latter intermediates have been also reported as species formed during catalytic reduction of nitroarenes15,16).

SCHEME I


Polarographic half-wave potential was early studied17) for various nitrofurans and correlated to partition coefficient, steric effect and in vitro antibacterial activity for a structure-activity relationship18). Accordingly, an inverse relationship between reduction potential and antibacterial activity was established. Catalytic water gas shift reaction (WGSR) conditions provide a reduction media for organic substrates as nitro compounds15,16,19-30) according to Eq. [1].

Our previous work allowed us to demonstrate the activity of poly(4-vinylpyridine) anchored rhodium(I) complexes [Rh(COD)(amine)2](PF6) (amine = pyridine, 2-picoline, 3-picoline, 4-picoline, 3,5-lutidine, 2,6-lutidine) toward WGSR31) and nitrobenzene reduction32), the 2-picoline bearing complex being the most active toward the latter reaction. Based on these results, in this paper we present the reduction of a 2-substituted-5-nitrofuran series reduction under CO/H2O conditions promoted by [Rh(COD)(2-picoline)2](PF6) immobilized on poly(4-vinylpyridine).

EXPERIMENTAL

Materials. The 2-picoline (2-pic) from Aldrich was distilled over KOH. The nitro compounds: 2-nitrofuran, 5-nitrofurfuryl alcohol, 5-nitro-2-furanacrolein, 5-nitro-2-furaldehyde semicarbazone (nitrofurazone), 5-nitrofuroic acid and 5-nitro-2-furfurylidene-1-aminohydantoin (nitrofurantoin) were obtained from Aldrich and used as received. Z-2-[[2-(5-nitrofuran-2-yl)-1-(phenylcarboxamide)-1-vinyl]carboxamide] ethyl acetate amide was kindly provided by Prof. María Capobianco (Laboratorio de Química Medicinal, Facultad de Farmacia, Universidad Central de Venezuela). Water was doubly distilled. 2-Ethoxyethanol (Aldrich) was distilled from anhydrous stannous chloride. Poly(4-vinylpyridine) (P(4-VP), 2% cross-linked) was used as provided by Reilly Industries. All gases and gas mixtures N2, He/H2 (91.5%/8.5%, v/v), CO/CH4 (95.8%/4.2%, v/v) and CO/CH4/CO2/H2 (84.8%/5.1%/5.3%/4.8%, v/v) were purchased from BOC Gases and were used as received. The rhodium-immobilized complex was prepared as reported32). This complex will be referred as Rh(2-pic)2/P(4-VP).

Instrumentation: Analyses of Rh concentration in catalysis solutions were performed on a Perkin-Elmer Lambda 10 UV/Visible spectrophotometer and on a GBC Avanta atomic absorption (AA) spectrometer operated in the flame mode. Gas samples analyses from catalysis runs were performed as previously described in detail31,32) on a Hewlett-Packard 5890 Series II programmable (ChemStation) gas chromatograph fitted with a thermal conductivity detector. The column used was Carbosieve-B (80-100 mesh) obtained from Hewlett-Packard using He/H2 mixture at 50mL/min as the carrier gas. Column temperature was programmed at 60-175 oC with a heating rate of 11.5 oC/min. pH measurements were obtained from a pH-meter Denver Acumet Basic provided with combined calomel glass electrode. Analyses of liquid phase were done on a Hewlett-Packard 5890 Series II programmable gas chromatograph fitted with a HP-1 (methyl silicone gum, 50 m x 0.323 mm x 0.17 mm) column and flame ionization detector, and using He as the carrier gas, a Varian Chrompack 3800 programmable gas chromatograph fitted with a CP-Sil-8-CB (phenyldimethylpolysiloxane) (30 m x 0.250 mm) column and a Varian Chrompack, Saturn 2000 mass selective detector.

Catalyst Testing: Catalytic runs were conducted in all-glass reactor vessels consisting of a 100 mL round bottom flask connected to an "O" ring sealed joint to a two-way Rotoflow Teflon stopcock attached to the vacuum line29). In a typical run, the catalyst and 10 mL of 80% aqueous 2-ethoxyethanol were added to the glass reactor vessel, then the suspension was degassed by three freeze-pump-thaw cycles.

The reaction vessel was charged with CO/CH4 mixture at the desired CO partial pressure (0.9 atm), then suspended in a circulating thermostatted (Cole-Palmer, Model 71) glycerol oil bath at 100 ºC for 8 h maintaining the temperature at ±_ 0.5ºC by continuously stirring the oil bath as well as the reaction mixture which was provided with a Teflon-coated magnetic stirring bar.

Once the catalyst got matured, it is to say reached a constant WGSR activity31,33) (showed by a constant value for [H2] and [CO2]), a given amount (1x10-3 mol) of the 5-nitrofuran compound ([5-nitrofuran compound]/[rhodium complex] molar ratio = 10) was added to the reaction vessel. Then, the glass reactor vessel was charged with CO/CH4 at 0.9 atm partial CO pressure and placed in the heated oil bath for 3 h at 100 ºC. At the end of the reaction time gas samples (1.0 mL) were removed from the reactor vessel in a manner similar to that described in detail for the WGSR catalytic test32) and analyzed by GC. The CH4 was used as internal standard to allow calculation of absolute quantities of CO consumed and CO2 produced, during a time interval. In addition, calibration curves were prepared periodically for CO, CH4, H2, and CO2, and on analyzing known mixtures checked their validities.

RESULTS AND DISCUSSION

Previous systematic research in our group32) has shown the catalytic activity of 1 x 10-4 mol of rhodium(I) amino complexes [Rh(COD)(amine)2]PF6 (amine = 4-picoline, 3-picoline, 2-picoline, pyridine, 3,5-lutidine, 2,6-lutidine) immobilized on 0.5 g of P(4-VP) toward the reduction of nitrobenzene to aniline in 10 mL of 80% aqueous 2-ethoxyethanol under 0.9 atm of CO at 100 ºC and [Rh] = 2.0 wt. %. Under these conditions, aniline production (milimole/3 h) depends on the nature of the rhodium coordinated amine in the metal complex catalyst and decreases in the following order: 2-picoline (0.65) > 4-picoline (0.59) > 3-picoline (0.56) > pyridine (0.49) > 3,5-lutidine (0.38) > 2,6-lutidine (0.34). In addition, formation of aniline, the only organic product (detected by analyzing the catalysis liquid phase) and CO2, the only gas product (detected by analyzing the catalysis gas phase) matched stoichiometrically as required by Eq. [1].

Due to the simplicity and speed of the analysis of gaseous samples, our 2-substituted nitrofuran reduction results are reported as based on CO2 production. We had previously reported in detail the consistency of this analytical method30). These results are summarized in table I and they represent the average value of duplicate runs deriving for the same experimental conditions. The calculated catalytic activity defined as TF(CO2)/24 h was reproducible to within less than 10% for a series of experimental runs. As suggested in the literature34), efforts to isolate 5-aminofuran products were unsuccessful. Indeed, the product obtained after separation of the immobilized catalyst rapidly decomposes to unidentified organic products, as followed by tlc. Attempts, to monitoring the in situ formation or decomposition of the corresponding amine furan via FT-IR and

NMR spectroscopy are in progress and the results will be reported elsewhere. For that reason to report results based on CO2 produced, accordingly to Eq. [2], is a useful way to evaluate the extent of this reaction in a manner analogous to that the reported for Rh(2-pic)2/P(4-VP) catalytic system for nitrobenzene reduction, where aniline and CO2 were the only products detected under similar catalytic conditions32). It is important to stress that the amounts of the CO2 formed under the catalytic conditions described in table I are about 12.9 (0.90 mmol, TF(CO2) = 74 (24 h)-1) - 2.7 (0.19 mmol, TF(CO2) = 30 (24 h)-1) times higher than the amount of CO2 formed in the absence of any of the 5-nitrofuran listed in the same table I. In this case formation of CO2 (0.07 mmol, TF(CO2) = 5.7 (24 h)-1) corresponds to the activity of the rhodium complex toward WGSR, as previously studied31). Indeed, molecular hydrogen was detected (0.06 mmol, TF(H2) = 5.5 (24 h)-1) along with CO2, as required by Eq. [3]. Further, at that point it is important to emphasize that the Rh(2-pic)2/P(4-VP) system exhibits no WGSR activity (i.e. molecular hydrogen is not formed) in the presence of any 5-nitrofuran listed in the table I. Accordingly, the observed catalytic formation of CO2 described in table I should come from the reduction of the 5-nitrofuran compounds and not from the WGSR, which cease under the 5-nitrofuran reduction conditions described in Table 1.

Table I. Reduction of substituted nitrofuran with CO/H2O in the presence of rhodium [Rh(COD)
(2-picoline)2]PF6 complex immobilized on P(4-VP) in contact with aqueous 2-ethoxyethanol as catalyst precursora.

a0.5 g of P(4-VP), [Rh] = 2.0 wt. %, substrate/Rh molar ratio = 10; 10 mL of 80% aqueous 2-ethoxiethanol, P(CO) = 0.9 atm at 100 ºC for 3h.

b(1) 5-Nitro-2-furaldehyde semicarbazone (nitrofurazone); (2) 5-Nitro-2-furanacrolein; (3) Nitrofuran; (4) Z-2-[[2-(5-nitrofuran-2-yl)-1-(phenylcarboxamide)-1-vinyl]carboxamide]

ethyl acetate; (5) 5-Nitro-2-furfuryl alcohol; (6) 5-Nitro-2-furfurylidene-1-aminohydantoin (nitrofurantoin); (7) 5-Nitro-2-furoic acid.

cYield in 3 h.

dTF(CO2) = [(mol of CO2)/(mol of Rh) x (rt)] x 24 h, where (rt) = reaction time in hours.

The results described above suggest that formation of CO2 during nitrofuran moiety reduction comes from successive decarboxylation steps which should lead to the 5-aminofuran production (Scheme II). Later the 5-aminofuran decomposes under the catalytic conditions.

The FT-IR spectrum of the fresh catalyst shows two nCN bands at 1612(s) and 1430(m) cm-1 associates to the 2-picoline ligand of immobilized Rh(2-pic)2/P(4-VP)32) complex. These two nCN bands remain unchanged after the use of the fresh catalyst under the conditions described in table I. Furthermore, the FT-IR spectrum of the supernatant solution left after separation of the solid catalyst exhibits no nCN bands associate to the 2-picoline ligand, indicating no leaching of this ligand. Also, AA spectrometry analysis of this supernatant solution reveals the presence of less than 0.01% of rhodium. In addition, the supernatant solution left after separation of the used Rh(2-pic)2/P(4-VP) solid exhibited no activity towards either WGSR or 5-nitrofuran reduction when tested in the absence of solid catalyst. The above results rule out the possibility of any leaching and the substitution of 2-picoline ligand by the 5-nitrofuran compounds listed in table 1. Accordingly, the immobilized Rh(2-pic)2/P(4-VP) species act as a true catalyst.

The amount of catalyst, [Rh], P(CO) pressure, temperature, reaction medium and reaction time described in table I were chosen to resemble previous conditions reported for the nitrobenzene reduction to aniline by Rh(amine)2/P(4-VP) catalysts (amine = 4-picoline, 3-picoline, 2-picoline, pyridine, 3,5-lutidine, 2,6-lutidine)32). Comparing the results we observed that the amount of CO2 produced in Rh(2-pic)/P(4-VP)/nitrobenzene system is 1.95 mmol in 3 h and it is 10.3 (compound 7) to 2.2 (compound 1) time higher than the reduction of the nitrofuran listed in table I by the same catalyst under similar reactions conditions but different substrate/Rh molar ratio. Apparently, the reduction of nitrobenzene is faster than of nitrofuran. Obviously, the steric hindrance introduced by the nitrofuran ring itself and the groups in 2-position of the 5-nitrofuran should be responsible for this kinetics behavior.

Further, it can be observed that the catalytic activity, expressed in terms of CO2 turnover frequency (TF(CO2) = mol CO2 / mol Rh / day) depends on the nature of the substituent in position 2 to the nitrogen atom of nitrofuran ring and decreases in the following order: 5-nitrofuraldehyde-semicarbazone (nitrofurazone) (74) > 5-nitro-2-furacrolein (70) > 2-nitrofuran (50) > ethylglycinate and 3-(5-nitro-2-furanoil)-2-(N-benzamido)propenoic acid amide (39) > 5-nitro-2-furfurylalcohol (30) = 5(nitro-2-furfurylidene-1-aminohydantoin(nitrofurantoin) (30) > 5-nitrofuroic acid (16).

Observing these results some interesting features can be evidenced. Firstly, the reference substrate 2-nitrofuran can be effectively reduced under WGSR conditions with a TF(CO2)/24 h = 50. Secondly, in the 5-nitrofuran series tested in this study, it can be established two groups of substrates, the more easily reduced and the less easily reduced than nitrofuran. Of amazing interest is the manifest difference showed by nitrofurazone (1) and nitrofurantoin (6) on catalytic reduction under our experimental conditions. Both antibacterial drugs have traditionally showed a similar behavior on biological tests for antibacterial activity evaluation towards aerobic bacteria both gram positive and gram negative35). Conversely, the different activity revealed here can probably be related to the antibacterial behavior on anaerobic bacteria. It is to say, we are probably simulating their enzymatic system for nitro reduction. In this order of ideas, nitrofurantoin, widely used as a commercial antibacterial drug, has shown to be harder on CO/H2O reduction (TF(CO2)/24 h = 30) than nitrofurazone (TF(CO2)/24 h = 74), denoting a probable best antibacterial activity of the latter drug toward anaerobic bacteria.

Standard runs employing furan as substrate demonstrated that furan ring is not prone on opening under reaction conditions, observing only WGSR activity (TF(H2)/24 h = 6.2) owing to the catalyst, as expected31). Results of reduction of tested 5-nitrofurans suggest a critical steric parameter determined by the nature of the group in position 2 of the nitrofuran ring.

We observed that final pH of catalytic solutions usually increases from 4.9 to 6.5. In order to evaluate the influence of raised pH on the catalytic activity, runs were performed adding sufficient 10% NaOH solution to achieve pH of 7.0 and 10.0, after a constant WGSR activity was attained and using 5-nitro-2-furanacrolein as substrate. As it can be observed in table II, acidic media is favorable for the reduction of nitro group substituting a furan moiety. Surprisingly, final pH is always around 6 no matter initial pH. This result allows assuming that acidic catalysis promotes nitrofuran moiety reduction.

Reusability test for the Rh/5-nitro-2-furacrolein system (10 mL of 80% aqueous2-ethoxyethanol under 0.9 atm of CO at 100 ºC and [Rh] = 2 wt. %) demonstrates the loss of activity of rhodium complex in an extent of 50% after the first use. As it was shown before leaching of Rh from the polymer immobilized catalyst does not occur. Accordingly, the observed loss in the catalytic activity is probably owed to poisoning of the complex by some decomposition or further reaction product coming from reduced nitro compound. Maybe two ways to overcome this problem is to attempt to carry out these reactions for a shorter reaction time (15 min. 1 h.), perhaps the catalysis is very fast and is constantly degraded by the reaction conditions and the other alternative is devising a system to remove the product continuously in order to test if product decomposition is spoiling the catalyst. These investigations are in progress and they will be reported elsewhere.


a0.5 g of P(4-VP), [Rh] = 2.0 wt. %, substrate/Rh molar ratio = 10; 10 mL of 80% aqueous 2-ethoxyethanol; P(CO) = 0.9 atm at 100 ºC for 3h.

bTF(CO2) = [(mol of CO2)/(mol of Rh) x (rt)] x 24 h, where (rt) = reaction time in hours.

It has been reported that aminofurans can be regarded as N,C-ambidentate nucleophiles which can further react with soft electrophiles at the position 3 of 2-substituted-5-aminofurans rendering difficult the isolation of the reduction product36). In fact, none of the aminofurans could be isolated in this work.

Reaction scheme consideration: The evaluation of the reaction scheme for the 5-nitrofuran compounds reduction by the Rh(2-pic)2/P(4-VP) catalytic in CO shows a few key features: First, CO2 was the only gaseous product detected. Second, the early reported FT-IR32), suggested the presence of immobilized Rh(I) carbonyl compounds as the principal reaction intermediates, which probably are formed in the present system. Third, catalytic schemes for the reduction of nitrobenzene to aniline have been proposed in which nitrobenzene cycloaddition to a metal carbonyl complex is an important first step37,38). Fourth, the CO2 turnover frequencies in the presence of the 5-nitrofuran compounds are greater than the WGSR activity for the same system in the absence of the 5-nitrofuran compounds. Presumably in the former systems a reactive intermediate prior to rate limiting H2 formation is intercepted by catalytic species generated from the 5-nitrofurans additions to rhodium precursor. Given the above, the reaction mechanism depicted in Scheme II is proposed for the reduction of the 5-nitrofurans to the 5-aminefurans catalyzed by Rh(I)-CO species.

In Scheme II, the cycloaddition (1a) of the nitro group to the Rh-CO bond followed by elimination of CO2 leads to the formation of the 5-nitrosofuran-rhodium P-[Rh(h2-ONR')]+ complex (1b) (R' = C4H2(O)R, the other ligands of the rhodium complex are omitted in the text for clarity). Analogous structures for the nitrobenzene system have been isolated and characterized by X-ray crystal structure39,40).

Scheme II


Reversible insertion of one CO molecule to the Rh-O bond (1c) could form the P-[Rh(h2-CO(O)NR')]+ complex. Decarboxylation of the rhodium P-[Rh(h2-CO(O)NR')]+ (1d) may generate a rhodium-nitrene complex P-[Rh=NR']+ and CO2. Subsequent hydrogenation of these rhodium-nitrene species via intermolecular hydride transfer37) by the P-[Rh-(H)2] species (1e) formed under conditions similar to the WGSR21) affords the 5-aminofuran compound and the unsaturated P-[Rh(2-pic)2]+ species. Carbonylation of the unsaturated P-[Rh(2-pic)2]+ species should regenerate the catalytic precursor, P-[Rh(CO)(2-pic)2]+ complex (1f) to get the reduction catalytic cycle closed.

In summary, the poly(4-vinylpyridine) anchored rhodium(I) complex [Rh(COD)(2-picoline)2](PF6) showed to be a catalyst for 2-substituted-5-nitrofurans reduction under WGSR. The nature of 2-substituent deeply influence the extension of the reaction as a consequence of the steric effects. WGSR catalytic conditions reduction can be employed as a way to anticipate antibacterial activity of 2-substituted nitrofurans. Furthermore, even that we were not able to isolate and identify any organic product coming from the decomposition of the 5-aminofuran, the purpose of this study was achieved in the sense that a different behavior of nitrofurantoin and nitrofurazone was evidenced, oppositely to the in vitro results. Probably our catalytic system is simulating the anaerobical bacteria behavior. Accordingly, nitrofurazone should be more active against anaerobial bacteria than nitrofurantoin. In vitro studies in anaerobical bacteria are in progress.

ACKNOWLEDGEMENTS

The authors acknowledge financial support from CDCH-Universidad Central de Venezuela (Grant PI. 06-10-4654-2000). SAM thanks financial support from FONDECYT.Chile (Grant 1050168)

REFERENCES

1. H.E. Paul, M.F. Paul. Exp. Chemother., 2, 310 (1964).         [ Links ]

2. K. Miura, H.K. Reckendorf. Prog. Med. Chem., 5, 320 (1967).         [ Links ]

3. S.M. Towson, P.F.L. Boreham. J.A. Upcrof, Acta Tropica., 56, 173 (1994).         [ Links ]

4. H. Hoff. Antimicrob. Agent Chemother., 33, 404 (1989).         [ Links ]

5. J.R. Pires, C. Saito, S.L. Gomes, A.M. Giesbrecht, T. do Amaral. J. Med. Chem., 44, 3673 (2001).         [ Links ]

6. P. Walzer, C. Kurtis, J. Foy, J. Zhang. Antimicrob. Agent Chemother., 35, 158 (1992).         [ Links ]

7. D.Y. Graham, M.S. Osato, J. Hoffman, A.R. Opekun, S.Y. Anderson, H.M. El- Zimaity. Aliment. Pharmacol. Ther., 14, 211 (2000).         [ Links ]

8. R. Dani, D.M. Queiroz, M.G. Dias, J.M. Franco, L.C. Magalhaes, G.S. Mendes, L.S. Moreira, L.P. de Castro, N.H. Toppa, G.A. Rocha, M.M. Cabral, P.G. Salles. Aliment. Pharmacol. Ther., 13, 1647 (1999).         [ Links ]

9. W.Z. Liu, S.D. Xiao, Y. Shi, S.M. Wu, D.Z. Zhang, W.W. Xu, G.N.J. Tytgat, Aliment. Pharmacol. Ther., 13, 317 (1999).         [ Links ]

10. B.H Ali, Vet. Res. Commun., 23, 343 (1999).         [ Links ]

11. G.G. Zhanel, D.J. Hoban, J.A. Karlowsky, Antimicrob. Agents Chemother., 45, 324 (2001).         [ Links ]

12. J. Charris, M. Monasterios, J. Domínguez, W. Infante, N. de Castro. Heterocyclic Commun., 8, 275 (2002).         [ Links ]

13. G.L. Kedderis, G.T.Miwa, Drug Metab. Rev., 19, 33 (1988).         [ Links ]

14. A. Gringauz. Introduction to Medicinal Chemistry; How Drugs Act and Why. Willey - VCH, New York, 1997, pp. 272-274.         [ Links ]

15. K. Nomura. J. Mol. Catal. A, 95, 203 (1995).         [ Links ]

16. Y. Shvo, D. Czarkie. J. Organomet. Chem., 368, 357 (1989).         [ Links ]

17. T. Sasaki. Pharm. Bull., 2, 104 (1954).         [ Links ]

18. E.B. Akerblom. J. Med. Chem., 17, 605 (1974).         [ Links ]

19. M.M. Mdleleni, R.G. Rinker, P.C. Ford. J. Mol. Catal., 89, 283 (1994).         [ Links ]

20. K. Kaneda, H. Kuwahara, T. Imanaka. J. Mol. Catal., 88, L267 (1994).         [ Links ]

21. K. Nomura, M. Ishino, M. Hazama, J. Mol. Catal., 66, L19 (1991).         [ Links ]

22. K. Nomura, M. Ishino, M. Hazama. J. Mol. Catal., 78, 273 (1993).         [ Links ]

23. K. Nombra. J. Mol. Catal., 73, L1 (1992).         [ Links ]

24. V. Macho, L. Vojeek, M. Schmidtova, M. Harustiak. J. Mol. Catal., 88, 177 (1994).         [ Links ]

25. A. Ben Taleb, G. Jenner. J. Mol. Catal., 91, L149 (1994).         [ Links ]

26. F. Ragaini, M. Pizzotti, S. Cenini, A. Abbotto, G.A. Pagani, F. Demartin. J. Organomet. Chem., 489, 107 (1995).         [ Links ]

27. S.A. Moya, R. Sariego, P. Aguirre, R. Sartori, P. Dixneuf. Bull. Soc. Chim. Belg., 104, 19 (1995).         [ Links ]

28. S. Cenini, F. Ragaini. J. Mol. Catal. A, 105, 145 (1996).         [ Links ]

29. C. Linares, M. Mediavilla, A.J. Pardey, C. Longo, P. Baricelli, S.A. Moya. Bol. Soc. Chil. Quím., 43, 55 (1998).         [ Links ]

30. C. Linares, M. Mediavilla, A.J. Pardey, C. Longo-Pardey, S.A. Moya. Catal. Lett., 50, 183 (1998).         [ Links ]

31. A.J. Pardey, M. Fernández, M. Canestrari, P. Baricelli, E. Lujano, C. Longo, R. Sartori, S.A. Moya. React. Kinet. Catal. Lett., 67, 325 (1999).         [ Links ]

32. A.J. Pardey, M. Fernández, J. Alvarez, C. Urbina, D. Moronta, V. Leon, C. Longo, P. Baricelli, S.A. Moya. J. Mol. Catal. A, 164, 225 (2000).         [ Links ]

33. A.J. Pardey, P.C. Ford. J. Mol. Catal., 5, 247 (1989).         [ Links ]

34. F.F. Ebetino, J.J. Carrol, G. Gerber. J. Med. Pharm. Chem. 5, 524 (1938).         [ Links ]

35. S. Nakamura, M. Shimizu. Chem. Pharm. Bull., 21, 137 (1973).         [ Links ]

36. D.J. Lythgoe, I. McClenaghan, C.A. Ramsden. J. Heterocyclic Chem., 30, 113 (1993).         [ Links ]

37. K. Nomura. J. Mol. Catal. A, 130, 1 (1998).         [ Links ]

38. M.M. Millan, R.G. Rinker, P.C. Ford. J. Mol. Catal. A, 203-204, 125 (2003).         [ Links ]

39. S.J. Skoog, J.P. Campbell, W.L. Gladfelter. Organometallics, 13, 4137 (1994).         [ Links ]

40. S.J. Skoog, W.L. Gladfelter. J. Am. Chem. Soc., 119, 11049 (1997).         [ Links ]

Creative Commons License Todo o conteúdo deste periódico, exceto onde está identificado, está licenciado sob uma Licença Creative Commons