научная статья по теме OXOVANADIUM(IV) COMPLEXES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: SYNTHESIS, SPECTROSCOPY, AND ANTIMICROBIAL ACTIVITY Химия

Текст научной статьи на тему «OXOVANADIUM(IV) COMPLEXES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: SYNTHESIS, SPECTROSCOPY, AND ANTIMICROBIAL ACTIVITY»

KOOPMHHAUHOHHAa XHMHH, 2008, moM 34, № 6, c. 456-460

yffK 541.49

OXOVANADIUM(IV) COMPLEXES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: SYNTHESIS, SPECTROSCOPY, AND ANTIMICROBIAL ACTIVITY

© 2008 N. Muhammad1, S. Ali1, S. Shahzadi2, and A. N. Khan3

1 Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan 2Department of Chemistry, GC University, Faisalabad, Pakistan 3Department of Biochemistry, Capital Hospital, CDA, Islamabad, Pakistan E-mail: drsa54@yahoo.com Received May 21, 2007

Oxovanadium(IV) complexes with four different non-steroidal anti-inflammatory drugs have been synthesized. These complexes were characterized by different analytical techniques such as CHN, IR, UV-Vis spectroscopy, and mass spectrometry. The IR data show the bidentate nature of the ligands and reveal hexacoordinate geometry in the solid state. The complexes were tested for their biological activity against six different bacterial strains and plant pathogens, and all complexes showed good biological activity with few exceptions.

INTRODUCTION

The current strong interest in vanadium compounds arises from the presence of vanadium in several metal-loenzymes [1], their use as metallopharmaceutical agents [2], and their catalytic abilities [3], as well as their importance as structural probes [4]. Vanadium chemistry is dominated by +4 and +5 oxidation states in which the major species are the stable oxovanadium and

the dioxovanadium cations, VO2+, VO3+, and VO+. These units remain intact during reactions, and much of their behaviour is typical of Lewis acids [5], although Lewis base activity is also known [6].

The pharmacological activity of different vanadium compounds is well known [7-9]. Medicinal applications of vanadium compounds have focused on their in vitro and in vivo activity in the treatment of diabetes. Therefore, in recent years, the insulin-mimetic effects of vanadium compounds have been especially investigated [10-12].

We have attempted to develop new oxovanadium(IV) complexes with O-donor atoms, because the oxovana-dium ion is known to be less toxic than the vanadate ion, and to be the main chemical form in tissues and organs. In this paper, we report the synthesis, spectral characterization, and antimicrobial activity of oxovana-dium(IV) carboxylates of non-steroidal antiinflammatory drugs. These complexes were characterized with different spectral techniques like IR, UV-Vis, and mass spectrometry. The reported complexes were also screened for testing their biological activity, and all complexes showed significant activity with few exceptions.

EXPERIMENTAL

In present paper, VOSO4 ■ 3H2O (Aldrich) was used. Ketoprofen, and Ibuprofen were kindly supplied by Werrick Pharmaceuticals (Islamabad, Pakistan). Flurbiprofen was gifted by Upjohn Pakistan (Pvt.) Ltd., Islamabad. Wyeth Laboratories Pakistan Ltd. provided Fentiazac acid.

Instrumentation. Melting points were determined on an electrothermal melting point apparatus model MP-D Mitamura Rikero Kogyo (Japan), and are uncorrected. Infrared spectra were recorded as KBr pellets on a Bio-Rad Elmer 16 FPc FT-IR instrument in the range 4000-400 cm1, and electron impact mass spectra (EIMS) were recorded on a Finnigan MA ± 312 double focusing mass spectrometer connected to a DPD 11/34 (DEC) computer system. UV visible spectra were recorded on a UV-Vis spectrophotometer Shimadzu model TCC-240A. CHN data were recorded with an organic elemental analyzer, model EA 1110, CE Instrument, Italy.

General method for complex synthesis. Vanadyl sulphate trihydrate (1 mmol) was dissolved in 50 ml methanol upon gentle heating, and stirring in a 250-ml round-bottom flask equipped with a water condenser. A drug (2 mmol) was added in portions to the cold solution. The pH of the solution was adjusted by addition of NaHCO3 until a value of 3 was reached. The pH was monitored by a pH-meter. The green colored solution was refluxed for 6 h. After solvent evaporation at room temperature, the green solid product left behind. The resultant green-colored solid was recrystallized from a chloroform-«-hexane (1 : 1) mixture. The general chemical reaction (1) is given below:

VOSO4 ■ 3H2O + 2RCOOH Methano1. VO(H2O)(OOCR)2 + H2SO4 + 2H2O,

(1)

Lx-L4

(CH3)2

where R = CH-CH2

CH3 I 3 CH—

for L1

CH— I

CH3

F

for L3

I-IV

C6H5 S

T

N

CH2—

for L2 ^ Cl

CH3 I 3 CH—

for L4

The antibacterial activity of reported oxovanadi-um(IV) compounds against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella typhi bacterial strains were screened using the agar well-diffusion method [13]. Imipenum was used as standard drug. The wells were dug in the media with the help of a sterile metallic borer with centers at least 24 mm apart. Two to eight hours old bacteria inoculums containing approximately 104-106 colony forming units (CFU)/ml were spread on the surface of a nutrient agar with the help of sterile cotton swabs. The recommended concentration of the test sam -ple (2 mg/ml in DMSO) was introduced into the respec -tive wells. Other wells were supplemented with DMSO, and reference antibacterial drugs serving as negative and positive controls, respectively. The plates were incubated immediately at 37°C for 20 h. The activity was determined by measuring the diameter of zones showing complete inhibition (mm). Growth inhibition was calculated with reference to positive control.

The antifungal activity of synthesized compounds were tested against various pathogens, namely, Tricho-

Inhibition(%) =

RESULTS AND DISCUSSION

It was received four of oxovanadium(IV) carboxy -lates and some physical properties of the these are re -ported in Table 1. These complexes are stable at room temperature, and having good solubility in common organic solvents.

The infrared spectra of synthesized complexes, and ligands were recorded as KBr discs in the range 4000400 cm-1. The most important frequencies of the com -plexes reported in Table 2, are Vasym(COO), vsym(COO), v(V=O), v(O-H), and v(V-O). The values assigned to these bands are in accordance with the values reported

phyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, and Candida glaberata by using tube diffusion test [13]. The Mi-coanazole (75 Mg/ml) and Amphotericin B (75 Mg/ml) were used as standard drugs. Stock solutions of pure compounds (12 Mg/ml) were prepared in sterile DMSO. Sabouraud dextrose agar was prepared by mixing Sab-ouraud (32.5 g), glucose agar (4%), and agar-agar (4 g) in 500 ml of distilled water followed by steamed dissolution, 4 ml of the media being dispensed into screw capped tubes and autoclaved at 121°C for 15 min. The test compound was added (66.6 Mg/ml) was added from the stock solution to nonsolidified Sabouraud agar media (50°C). Tubes were allowed to solidify at room temperature and inoculated with a 4-mm-diameter portion of inoculums derived from a 7 days old respective fungal culture. For nonmycelial growth, an agar surface streak was employed. The tubes were incubated at 27-29°C for 7-10 days, and the growth in the compound containing media was determined by measuring the linear growth (mm) and growth inhibition with respective control. The amount of growth inhibition was calculated as

in the literature [14, 15]. The spectra of the vanadyl complexes show narrow bands of medium intensity in a range of 920-978 cm-1 due to the V=O stretching vibration. The complexation of the oxovanadium(IV) cation with the ligand is confirmed by the disappearance of the OH band occurring at 2618-2869 cm-1, which is characteristic of carboxylic acids.

The peak for v(COO) in the region 1695-1769 cm-1 has been shifted to the lower frequency, which confirm complexation. The lowering of vasym(COO) and rise in vsym(COO) the (Av = (vasym - vsym) show bidentate nature of the ligands in all the complexes which is in the

( Di ameter of fung al col o ny i n co ntrol pl ate ) - ( Di ameter o f fung al c o l o ny in te s t pl ate -Diameter of fungal colony in control plate

Table 1. Elemental analysis data and some physical data of oxovanadium(IV) carboxylates

Compound Mol. wt. Yield, % M.p., °C Color Contents (calcd/found), %

C H N

VO6C26H36 (I) 495 60 >360 Green 63.03/64.06 7.27/7.30

VO6C34H24CI2N2S2 (II) 742 75 65 Green 54.98/54.85 3.23/3.26 3.77/3.82

VO6C30H26F2 (III) 571 63 >360 Green 63.04/63.15 4.55/4.50

VO8C32H28 (IV) 591 67 192 Green 64.97/65.12 4.73/4.80

range 169-220 cm-1. This value is higher for the ligands. A decrease in the stretching vibration for v(V=O) from the normal value (980 cm-1) for all the complexes show an electron transfer from the ligand to the metal [16]. This can be due to the H2O molecule attached to the metal. Its presence is shown by v(O-H) stretching observed above 3450 cm-1 for all the complexes. The v(V=O) stretches are at 969, 978, 920, and 951 cm-1 for compounds I, II, III, and IV, respectively. The IR spectra data of synthesized complexes are collected in Table 2.

For UV-Vis spectra, methanol was used as a solvent and concentration was kept as 10-3 mol/l. The synthesized oxovanadium(IV) complexes have a d1 system, which shows a single band. However, due to low symmetry or John-Teller effect two or three bands can be observed, i.e.:

i) e * -«— b2, 22 E *— B2;

ii) b* — b2, 22 z D __ z D . B1- B2;

iii) a* -— b2, 2Al — 2B2.

It seems more probable, however, that the first two transitions lie under the envelope of band (i) [17]. The band (iii) is not always observed, being often buried beneath a high intensity charge-transfer band (or more accurately, the low energy of that band), and when it is

Table 2. Infrared data (cm of oxovanadium(IV) carboxylates

Com- v(V=O) v(O H) v(COO) Av v(V-O) v(C=O)

pound asym sym

L1 2869 1719 1321 398

I 969 3451 1609 1440 169 450

L2 2671 1717 1406 311

II 978 3456 1648 1429 219 410

L3 2618 1769 1323 376

III 920 3454 1624 1418 206 450

L4 2732 1695

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