Indian J oumal of ChemistryVol. 35A, April 1996, pp. 304-307

Synthesis, characterization and biological activities of u-hydroxo dibridgediron (III) and mononuclear iron(llI) complexes with some five- membered

heterocycles in the presence of pyridine and oxine as coligands

Lallan Mishrat & Mustafa Kamil Said"Box 4315, Hamdan Street, Abu Dhabi, United Arab Emirates

Received 14 July 1994; revised 24 July 1995; accepted 6 September 1995

Biologically relevant heterocycles viz, 4-amino-3-mercapto 5-phenyl-I,2,4 - triazole, (L1) and2-mercapto 5-phenyl-l ,3,4- oxadizole, (L2) are reacted with Fe(II)jFe(III) salts in the presence of pyridineand oxine bases. The resulting complexes have been characterized by elemental analysis, conductance,magnetic moments, IR, UV jvis, ESR and MOssbauerspectra. The complexes have also been evaluated fortheir antibacterial, antifungal and antitumour activities.

Biologically significant triazole and oxadiazolederivatives are well documented in the literature I ,2.

The bioactivities of these compounds together withsimilar heterocycles have already been correlatedwith their complexing ability with the metal ions", Inthis connection, it is also reported that oxine inhibitsmetabolic processes of bacteria and it's antibacterialactivity could be enhanced' by the incorporation ofcopper ions. The substitution of copper ion by ferricion has been found to be more active", Additionally,the metal complexes of triazoles have showninteresting magnetic properties' owing to their strongcoordinating ability. Thus keeping the above facts inview along with our earlier interest in thisarea":", weisolated Fe(II) and Fe(lII) salts with the heterocyclesL) and L2(structure I) in the presence of pyridine andoxine anticipating better antimicrobial activities ofthe resulting complexes.

(Q}l;lSHIMH,

N-N~~SH

(I)

Materials and MethodsMetal salts (FeS04.7H20 and anhydrous FeCI~l)

were of reagent grade. The heterocycles (L) and L2)were prepared and purified according to the methodsreported in the literatures:". Oxine and pyridine werecommercially available.

tChemistry Department, Banaras Hindu University, Varanasi221005 (India)

Preparation of the metal complexesTo an ethanolic solution of L, (lmmol, 192mg}was

added 5 ml of aqueous solution of FeS04. 7H20 (1mmol, 277.68 mg) followed by dropwise addition ofpyridine/exine (I mmol) in 5 ml of ethanol withstirring. The respective mixtures were then madealkaline (PH = 8-9) with 2 ml of saturated aqueoussolution of Na2C03 when a dark brown solidprecipitated out while stirring was continued upto 30min. The solids 1ol.!usobtainedwere filtered off,washedsuccessively with water, hot ethanol and then dried inhot air oven at 50°(', The complexes of FeCIJ with L,and L2 in the presence of oxine were also preparedusing the similar procedure. The purity of thecomplexes were checked by TLC in n-butanol whichshowed single phase of the complex.

Melting points were determined in open capillariesusing an electrothermal melting point apparatus(Gallen Camp) without making any correction.Carbon, hydrogen and nitrogen analyses were carriedout at CDRI, Lucknow, India. The IR(KBr pellets)and UV/vis spectra in solid state (Nujol mull) andsolution (DMSO) were recorded on Jaseo FT-IR5300 and Cary-14 spectrophotometers respectively.The ESR spectra in solid state as well as in solution(DMF) were recorded on Jeol Jes-Fe 3XG ESRspectrometer at RSIC, Delhi University, Delhi,India, while Mossbauer spectra were recorded atKyushu University, Japan, using the experimentaldetails reported earlier 'PIron, sulphur and chlorinewere estimated by standard methods 1I. Roomtemperature magnetic susceptibilities were measuredon a Faraday Cahn electrobalance with Hg[Co(CN)4]as calibrant, and the magnetic moments werecalculated using Pascal's constants!", The molar

MISHRA et at.: STUDIES OF Il-HYDROXO DIBRIDGED & MONONl,JCLEAR Fe(III) COMPLEXES 305

Table I-Analytical and physical data of the complexes

Complex Found (Caled.), % ~cfr(B.M)

C H N Fe S CI

[Fe(L2l Py(OHhh 47.17 3.19 11.88 15.78 9.13 4.05(47.46) (3.34) (12.77) (16.94) (9.75)

[Fe(L2)Q CI H2O] 47.18 2.97 9.18 12.64 7.23 8.11 5.65(47.42) (3.02) (9.76) (12.94) (7.43) (8.25)

[Fe(L2)Q OHh 50.87 2.89 9.63 13.43 7.79 6.35(51.81) (3.04) (10.66) (14.14) (8.12)

[Fe(L,H)Q CI2l 43.78 2.81 14.65 11.85 6.58 14.78 5.79(44.09) (3.02) (15.12) (12.03) (6.91) (15.34)

conductances of the metal complexes were measuredat 10- 3 M concentrations inDMSO using Syntronicdigital conductivity bridge. The analytical data andother physical properties are listed in Table 1.

The IR spectra of the free ligands LdL2 showedpeaks at 1076/lO60 and 769/748 cm -I due to vN-N(ring) and v C = S vibrations respectively. The doubletobserved for v C = N in the spectra of the free ligand L2at 1572 and 15lO em -I may be due to the differentneighbouring substituents (> C = S and phenyl at 3-and 5-position of the ring respectively). In the IRspectra of their complexes, peaks observed at 1494and >- 1574em - 1 indicated that one> C = N group iscoordinated while the other remains uncoordinated.

The free ligands peak observed at "" 748 em -I dueto > C = S disappeared in the IR spectra of theircomplexes while a new peak appeared at "" 644 em - 1.

This suggests that the thiol form of the ligandcoordinates to the metal with the loss ofSH proton.The deprotonation was also supported by thedisappearance of the peak due to v SH in the spectra oftheir complexes. However, in the complex of (LI), apeak observed at 738 em -I indicated thecoordination of v C = S group with the metal ion.

The uninegative coordination of oxine ligand inthese complexes was attributed due to the peakobserved at 1116-1107 em - I which was in consistencewith the literature':'. In the IR spectra of the (LI)

cornp'ex, the free ligand peaks observed at 3300 and3126 em -, were lowered at 3240 and 3080 em - ,respectively showing the coordination ofNH2 groupwith the metal ion which was further supported by thenegative shift of the free ligand peak due to NH2 from1637 to 1574 cm-I.

Th us (L I) acted as a bidentate ligand coordinatingthrough NH2 and> C = S group whereas (L2)acted asa bidentate ligand coordinating through> C =NandC = S groups. The lower region of the IR spectra of thecomplexes was not well resolved and was found to beoverlapped with the peaks observed for the freeligands.

In the (L2) complexes containing pyridine, theskeletal vibration due to pyridine was observed at""1630 cm -, which showed its participation in thecoordination. The lower region of the spectra ufthiscomplex also showed a peak at "" 615 em - , which wasnot observed in the spectra of the free ligand (L2) andsupported the coordination of pyridine.Furthermore, additional peaks observed at "" 891and 868 em -I in the spectra of [Fe(L2) Py(OHhh and[Fe(L2)Q OHh respectively were assigned to(Fe-OH-Fe) in view of the earlier report".

The presence of terminal OH group in the pyridineadduct was assigned by the peak observed at 3410em - I whereas the presence of water molecule in[Fe(L2) Q CL H20] was identified by a broad peakobserved at 3450 em - I. The number of watermolecules was calculated by the analysis of thiscomplex using literature procedure':'.

The magnetic moment data of the complexesreported in Table I indicated high spin octahedralgeometry and lies in the range as reported for otherFe(III) complexes 15 • Lowering in the magnetic valueobserved for the pyridine adduct is indicative ofsignificant interaction between Fe(lII) ions.Furthermore, magnetic data measured at 80 Kshowed no significant change in the magneticmoment values of these complexes. Therefore,variable temperature magnetic studies could not becarried out.

The electronic spectra of metal complexes in solidstate and solution(DMSO) were recorded. Thesolution spectra of [Fe(L2)Py(OHhh could not berecorded due to its poor solubility. In solid, thespectra of the complexes showed bands in the range of520-550 nm, in addition to a shoulder observed at640-660 nm. These bands could be assigned to spinforbidden d-d- transitions. The higher energy ligandfield bands were obscured by the intensecharge-transfer bands observed at 4lO nm. Theseassignments are comparable to the earlier reportmade for Fe(III) complexes". The shoulder observed

306 INDIAN J CHEM, SEe. A, APRIL 1996

Table 2-ESRt and Mossbauer] spectral parameters for thecomplexes

Complex .1 EQ(mm/s)

s(mm/s)

Power(Solution)

g" g1-

[Fe(L2) Py(OHhh 2.22 2.08 0.357 0.721(-) (-)

[Fe(L2)Q.CI.H20) 2.15 2.05 0.351 0.769(2.40) (2.02)

[Fe(L2)Q(OH)h 2.19 1.87 0.357 0.778(gx=2.48;gy= 1.82 andgz= 1.70)

[Fe(L,H)Q.CI21 2.19 2.05 0.355 0.735(2.28) (2.0 I)

[Near liquid nitrogen temperature (-130'C); tAt roomtemperature.

at 650 nm in the solid state spectra disappeared in thesolution spectra and a new band at 554-585 nmappeared. This shift observed in the solution spectraof the cornplexes'" may be due to the rearrangementin the coordination site around the metal ion. It isquite possible that solvent (DMSO) might besubstituting either aquo or chloro group present inthe complexes. However, the substitution of chlorogroup by DMSO was discarded on the ground thatconductances of the complexes measured in the samesolvent did not lie in the range at least for 1:1electrolyte due to setting free of CI- ion in thesolution. But in the complexes containing H20, thesubstitution of H20 group by DMSO is possible asDMSO is a better donor than water. Furthermore,the substitution of oxine by DMSO could not beconsidered since oxine is a stronger coordinatingligand for Fe(III). Therefore, one could infer that insolution it is quite possible that ligand may be actingas monodentate and the vacant coordination site maybe occupied by the solvent molecule(DMSO). Sincethe spectral features of Fe(II) complexes were foundvery similar to those reported for Fe(III)complexes':", the presence of Fe(III) was consideredeven in the complexes where Fe(II} salt was used asstarting material. It may be possible due to aerialoxidation of Fe (II) to Fe(III).

The 57Fe Mossbauer spectra of the complexes [Fe(L2)Q OHh and [Fe (L2)Q CI H20] at roomtemperature consisted of a doublet characterized bythe quadrupole splitting (~ EQ) and isomer shift(o)(Table 2). It showed the high spin pseudo-octahedralgeometry around Fe(III)ions in view of earlierreport", as well as the complete oxidation of Fe+2

to Fe +3 complexes.The ESR parameters of the complexes for both

solid state and solution (DMF) spectra are listed in

Table 2. The spectral parameters observed for thecomplexes are very.similar to those reported for otherFerl lfjcomplexes!? -19.

Thus, on the basis of these spectral studies andphysical properties, the tentative structure II isproposed for the complexes where ligands act asbinucleating agents.

Antifungal and antibacterial activitiesThe poisoned food method of Grover and Moore'?

and Kirby-Bauer-! were used to evaluate theantifungal and antibacterial activity againstAlternaria alternata and Staphylococcus aureus andE Coli. (Norfloxacin (10 ug/disc) was used asstandard» respectively at different concentrationsexcept [Fe(L2) Py(OHhh which was insoluble.

Antitumour activityThe anti tumour activity of Fe(III) complexes

along with free ligands L(, L2 and oxine was evaluatedat Tokyo College of Pharmacy, Japan according totheir standard procedure against P 388 lymphocyticleukemia Test system in the mice. P 388 cells weremaintained in RPMI-1640 medium supplementedwith 5% fetal calf serum and kanamycin (100 ug/rnl),The cells (3 x 103 cell/well) were cultured in corningdisposable 96-well plates containing 100 IIIof growthmedium per well and were incubated at 37°C in ahumidified atmosphere of 5% CO2. Various drugconcentrations (l0 Ill)were added to the cultures after1st day of the transplantation. At 3rd day, 20 IIIMTT

IH ~ °hH

r-'/~Fe~1"o/12

Py H Py

[Fe ( L2">PY(OH)2J2

MISHRA et 01.: STUDIES OF WHYDROXO DIBRIDGED & MONONUCLEAR Fe(lIl) COMPLEXES 307

solution (5 mgjml) per well was added to eachcultured medium. After a further 4 h of incubation,100 ml of lO% SDS-O.OI N HCl solution was added toeach well and the Formazam crystals in each well weredissolved by stirring with a pipette. The opticaldensity measurements were made by using amicroplate reader (Tohso MPR-A4i) with twowavelength system (550 and 700 nm). In all theseexperiments, 3 replicate wells were used to determineeach point.

In antifungal activity, free oxine showed 100%activity in all concentrations whereas free anhydrousFeCh showed poor activity and FeS04.7H20 showedno activity at all. Ligands L\ and L2 showedsignificant activity (60-70%) and the trend was foundto be L, < L2. Complexes containing oxine showedbetter activity as compared to the free metal salts andligands. Hence the presence of oxine in metalcomplexes might be responsible for their betteractivity. Furthermore, none of the complexes showedantibacterial activity against E. coli whereascomplexes showed little activity againstStaphylococcus aureus specially at 250 ug/rnl(30-37°/~), which may again be due to the presence ofoxine itself since oxine is found very sensitive againstthis bacteria. The antitumour activities (lCso) arelisted below:

Oxine> [Fe(L2) Q CL H20] > [Fe(L2)Q(OHhl >[Fe(L2) Py(OHhh > L2 > i.,

Higher activity was shown by free oxine followed bythe Fe(III)-oxadiazole complexes containing oxineand pyridine than free oxadiazole itself'(Ly). Thus freeoxine is undoubtedly a better choice, but antitumouractivity of the complexes could not be activated by thepresence of oxine as has been reported in the case ofantifungal and antibacterial activities. Thusanti tumour activity of oxadiazole ring is consistent

with the report of Saegusa et a/. 22 where the aminoacid of the system is proposed to interact with theoxadiazole ring causing the abnormal growth of thecell.

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