1 : 1 : 1, M(II)-Npa-TCAjHQ mixed-Iigand complexes [M(II)=
= Co(II), Ni(II)), Cu(II) and Zn(II); Npa = N-pyridylanthranilic
acid; TCA = thiophene-2-carboxylic acid and HQ = 8-hydroxyquinoline]
have been prepared and characterized on the basis of elemental analysis, IR and electronic spectral data, conductivity and magnetic measurements. An octahedral environment around the metal ion has been proposed. ALl the complexes are non-electrolytic in nature. The antifungal activity of the free Iigands and their corresponding metal chelates have been determined on some selected fungi

R. C. Sharma

Rajesh Nagar

English

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CROATICA CHEMICA ACTA CCACAA 61 (4) 849-855 (1988)CCA-1832YU ISSN 0011-1643UDC 54.057OriginaL Sdentific PaperSynthesis and Antifungal Properties of Some Transition MetalComplexes Involving PotentiaUy Active Heterocyclic LigandsR. C. Sharma and Rajesh Nagar*Department of Chemistry, Agra University, Agra-282 004 (INDIA)Received June 15, 19871 : 1 : 1, M(II)-Npa-TCAjHQ mixed-Iigand complexes [M(II)== Co(II), Ni(II)), Cu(II) and Zn(II); Npa = N-pyridylanthranilicacid; TCA = thiophene-2-carboxylic acid and HQ = 8-hydroxyqu-inoline] have been prepared and characterized on the basis ofelemental analysis, IR and electronic spectral data, conductivityand magnetic measurements. An octahedral environment aroundthe metal ion has been proposed. ALl the complexes are non--electrolytic in nature. The antifungal activity of the free Iigandsand their corresponding metal chelates have been determined onsome selected fungi.INTRODUCTIONThe importance of mixed-ligand complexes iri. environmental chemistry,!medicinal chernistry." analytical chemistry" and industrial chemistry- hasled to a large number of reports. The information about the role of metalcomplexesin biological systems, their concentration and presence in diffe-rent equilibria is of immense importance. Recently, it has been reportedšthat the activity of metal or ligand is considerably increased in the formof metal chelate as compared to that of the free ligand or metal ion. 8-hydro-xyquinoline and its derivative have long been establisehd as potential mi-crobial agents and drugs.š-" The role of mixed ligand complexes in biologicalprocesses has been recognized." It is well established that ternary complexesplay a decisive role in the activation of enzymes and also in the storage andtransport of active substances through biological membranes.š-!" In supportof the above, the preparation, characterization and antifungal activity ofthe Co(II), Ni(II), Cu(II) and Zn(II) metal complexes in conjunction withN-pyridylanthranilic acid and thiophene-2-carboxylic acid!8-hydroxyquinolinehave been carried out and presented in this communication.MATERIAL S AND METHODSAll the chemicals used were either of AR, BDH or E. Merck grade. Thelight yellow coloured N-pyridylanthranilic acid was synthesized'? by condensingsodium salt of o-chlorobenzoic acid and 2-amino-pyridine. The solid metal chelateswere synthesized by refluxing a mixture of metal acetates (0.01 M in 30 mlethanol) with two different ligands (Npa and TCA/HQ) (0.01 M in 50 ml ethanol)for two hours at pH 4-6 adjusted by 10f0 alcoholic ammonia solution (given in'I'able I). On concentration the reaction mixture, a coloured precipitate was850 R. C. SHARMA AND R. NAGARobtained. The coloured compound was filtered under suction, washed firs t withwater, ethanol and finally with ether and c1ried over P4010 in vacuum. Theisolated complexes were tested for purity by running their TLe.The IR spectra of the complexes and their corresponding Iigands were recordedon a Perkin Elmer-521 spectrophotometer. Magnetic susceptibilrty measurementswere carried out at room temperature using Guoy's balance. The electronic spectrawere recorded in DMF on a Shimadzu Double beam spectrophotometer UV-150-02.Molar conductance of the complexes was measured in their DMF solutions usingthe Toshniwal conductivity bridge. Molecular weight of the complexes was deter-mined by the cryscopic method.RESULTS AND DISCUSSIONThe solid metal chelates do not possess sharp melting points and de-compose on heating between 230 to 270 aC. The elemental analyses and mole-cular weight determination of the metal complexes (Table-I) indicatel: 1 : 1(MLL') type stoichoimetry. The values of mol ar conductance (3.1-4.6 ohm"crn" mol'") in DMF solution were observed, indicating the non-ionic natureof the complexes."Magnetic PropertiesThe magnetic moments of Co(II), Ni(ll), Cu(ll) and Zn(Il) complexescalculated from the corrected magnetic susceptibilities are given in Table loThe observed magnetic moment of Co(II) complexes is within the 4.7-5.2B. M. range, reported-" for high spin octahedral complexes, The observedmagnetic moment value 3.21 and 3.34 B. M. for Ni(Npa) (TCA) . H20 andNi(Npa) (HQ) . H20 is with in the range expected (2.9-3.4 B. 1'11:.) for octahedralcomplexes.P The observed magnetic moment 2.12 and 2.01 B. M. of theCu(Npa) (TCA) . H20 and Cu(Npa) (HQ) . H20 complexes agrees well with thespin only value.t"Electronic SpectraThe electronic spectra of Co(Npa) (TCA) . H20 and Co(NPa) (HQ) . H10complexes show three absorption bands at 7624, 16366, 19950 and 7636,16393, 19000 cm-i, respectively, assignable to 4TIg --?> 4T2g (F) (VI), 4TIg --?> 4A2g (F)(V2) and 4TIg --?> 4TIg (P) (V3) transitions in distorted octahedral geometry aroundthe metal ion. The ligand field parameters are consistent with the octahedralconfiguration of cobalt complexes. The value of 1)2/VI ratio (2.15 for Co(Npa)(TCA) . H20 and 2.14 for Co(Npa)(HQ) . H20) is within the range of theoreticalvalues 2.1-2.2 (Table II). The value of Racah interelectronic repulsion para--meter B (903, 891 cm'") is less than the free ion value (971 cm-I) suggestinga considerable covalent character of the bond. The three bands observedat 9670, 16339, 24630 and 10095, 16670, 24840 cm"! for Ni(Npa) (TeA) . H20 andNi(Npa)(HQ)' H20 complexes may be assigned to 3A2g --?> 3T2g (F) (VI), 3A2g --?> 3Tlg(F) (V2) and 3A2g --?> 3Tlg (P) (V3) transitions, respectively, in an octahedral geo-metry.P The ligand field parameters Dq, B, f3 and LFSE have been calculated.The Racah parameter B (797 cm'" for Ni(Npa)(TCA)' H20 and 748 crn? forNi(NPa) (HQ) . H20) is less than the free ion value (1040 cm-I). The calculatedvalue of V2/Vl ratio is within the r::mge expected for an octahedral geometry.The copper complexes showasingle broad asymmetric absorption bandaround 14000 cm'? due to the distorted octahedral environment around copperTABLEIAnalytical,MolarConductanceandMagneticSuscept'ibilityDataofComplexes ~Analysis:Found/(Calculated)~'o~S...,Cc1l;:l~o•..•~'OC'"~MetalcomplexColourc1lScc1l~~'-'......-I••CtI.~o;:l...,•...•••..•;:l~'H.~'-',.c:;:lCHNSM~'o'Sr:r:lao""C])b.O'-'c1loC,.c:~~~Oc)'aJ~>-3~80::t.<:Y.l~.~~~~::o ~ ZCo(Npa)(TCA)·H20Pink48.683.336.627.6314.063.484.926.45401ul H >-3(48.93)(3.38)(6.71)(7.68)(14.12)(417)H oLight48.323.316.697.6113.953.213.216.05398ZNi(Npa)(TCA)·H20~green(48.96)(3.38)(6.72)(7.69)(14.08)(417)t'J >-3Cu(Npa)(TCA)·H20Black48.273.256.527.4114.923.122.125.15406~(48.39)(3.34)(6.64)(7.60)(15.06)(421)l' nZn(Npa)(TCA)·H20White48.083.256.597.5114.353.51diam.6.20410o ~(48.18)(3.33)(6.61)(7.75)(14.43)(42:~)'o r-Co(Npa)(HQ).H20Reddish57.893.859.5713.494.605.026.30412t'J-XBrown(58.07)(3.94)(9.67)(13.57)(434)t'J ulNi(Npa)(HQ)·H20Green57.853.819.62-13.454.123.346.15408(58.10)(3.94)(9.68)(13.52)(434)Cu(Npa)(HQ).H20Brown57.383.839.54-14.373.252.015.05419(57.46)(3.90)(9.57)(14.48)(438)Zn(Npa)(HQ).H20White57.133.849.41-14.764.42diam.6.25421(57.22)(3.89)(9.53).(14.83)(440)*At25-cof10-3Msolutionindimethylformamide(DMF)00 en •....852 R. C. SHARMA AND R. NAGARTABLE IIElectronic Spectral Data of Co(II), Ni(II) and Cu(II) Complexes at 250C of 10-4 MSolution in Dimethyformamide (DMF)c1l8';;1 ~c1l i:Complex 8 Assignment ~ o,"'l?'O~ 8 ~@ '8 '" ., CI1 •.....•'-'- '" ..z k,~o' i:Q111<.> cl ""- '" >-4~"Co(Npa)(TCA)'H20 7624 4Tlg-74T2g(F) 874 903 .92 2.15 14.9816366 -7 4A2g(F)19950 -7 'Tl. (P)Ni(Npa)(TCA)'H20 9670 3A2g-7 ~T2g(F) 967 797 .76 1.69 33.1516339 -7 3Tlg(F)24630 -7 3Tig(P)Cu(Npa)(TCA)'H20 14200 2Eg -72T26 1420 24.34Co(Npa)(HQ).H20 7636 4Tlg-7 4T2g(F) 875 891 .91 2.14 15.0016393 -7 4A2J(F)19900 -7 4Tig(P)Ni(Npa)(HQ).H20 10095 3A2g-7 3T2g(F) 1009 748 .72 1.65 34.6116670 -7 3Tlg(F)24840 -7 3Tjg(P)Cu(Npa)(HQ)'H20 14050 2Eg -72T2g 1405 24.09ion.!" The spectral studies, along with the colour and magnetic moment efthe complex, point out the distorted octahedral stereochemistry.Infrared SpectraFor the sake of brevity, only shifted or altogether new peaks appearingin the spectra of metal chelates have been discussed. The free ligand (Npa)shows a band around 3300-3080 cm-i which is shifted to the lower frequencyregion in the case of their complex, suggesting coordination through N of-NH group. The IR spectra of free ligand (Npa and TCA) showing band at1680 cm-i which is shifted to the lower frequency region in the metal com-plexes confirm the coordination of the ligand to metal ion through carboxylicacid moiety.!? A strong band at 1500 cm? in the free 8-hydroxyquinoline maybe assigned to C=N bond. In complexes, this band is shifted to a lower Wavenumber, -1390 cm-I, indicating coordination through nitrogen of the ligand.!"Further, the strong bands in the region 1170-1110 cm-i probably indicatethe presence of coordinated 8-hydroxyquinoline in the M(Npa)(HQ)' H20 com-plexes.P Ring breathing modes'" at 840 cm-i in the case of thiophene-2-car-boxylic acid are lowered in the case of metal complexes. This clearly indi-cates the involvement of sulphur of thiophene ring in complexation. Thepresenee of coordinated water molecule in the complex is revealed by stretch-ing modes occurring at 3600-3525 cm"! and bending modes of H-O-Happearing around 1580 cm-lo The appearance of bands at - 485 (M-N)21,- 435 (M-O)2i and 380-360 cm-i (M-S) support the coordination throughN, O and S donor sites of the ligand.854 R. C. SHARMA AND R. NAGARTABLE IIIAntifungal Activity of LigandjMetal ComplexesAspergillus nigerofo inhibi tionPenicilliurricitrinum% inhibitionAspergillus flavusIl/O inhibitionLigand/metalcomplex Concentration(ppm)100 200 500Concentration(ppm)100 200' 500Concentration(ppm)100 200 500TCA 40.5 50.3 90.3 30.8 42.4 87.5 35.3 40.6 85.6HQ 90.0 92.0 100.0 91.0 93.2 100.0 90.8 95.8 100.0Npa 56.8 68.0 70.3 65.5 72.8 75.7 60.2 69.3 74.4Co(Npa)(TCA).H20 81.3 90.5 100.0 85.5 96.6 100.0 82.3 93.5 100.0Ni(Npa)(TCA).H20 74.8 85.4 100.0 79.7 91.2 100.0 77.3 88.7 100.0Cu(Npa)(TCA).H20 69.5 72.3 90.5 73.5 80.7 93.8 72.6 75.5 92.2Zn(Npa)(TCA)' H20 50.3 55.6 62.9 61.5 67.9 70.3 65.7 60.3 65.5Co(Npa)(HQ).H20 99.1 100.0 100.0 99.4 100.0 100.0 99.3 99.0 100.0Ni(Npa)(HQ)' H20 96.3 99.5 100.0 97.3 100.0 100.0 96.8 100.0 100.0Cu(Npa)(HQ)' H20 93.5 98.2 100.0 94.2 99.0 100.0 93.9 99.0 100.0Zn(Npa)(HQ)' H20 91.2 95.6 100.0 92.3 96.4 100.0 91.5 96.0 100.0Culture media = Agar-Agar. Time = 96 hours. Temperature = 37°C.the chelate is transfered to another system with a strong complexing power,such as thiols, thiophenes, porphyrine and the remaining 8-hydroxyquinolinemay combine with cresolase or other metal enzymes. It has been indicated?that 1: 2 chelate of lVI(II)-8-hydroxyquinoline penetrates the cell and dis-sociates. 1: 1 half chelate would then become a toxic entity by combiningand blocking the metal substances on enzymes. Gershon and Parrnegiani"supported the above mechanism and indicated that the antimicrobial activityof lVI(II)-8-hydroquinoline is not due to the release of 8-hydroxyquinolinewithin the cell but to the dissociated 1 : 1 complex such as the one reported.'The comparable activity of the mixed-ligand complexes to that of ligands(Npa, TCA and HQ) and 1: 2, metal-Npa, even though the former possessless lipophilic character, may be due to the dissociation of mixed complexesat the site of action as shown below:2M(Npa) (TCA) -';> M (Npaj++ M (TCAj++ Npa- + TCA-2M(Npa) (HQ)-';> M (Npaj++ M (HQ)++ Npa- + HQ-Both the 1 : 1, cationic complexes thus formed may be acting as activemoieties at the site of action reinforcing the total activity. Thus, in the mixedcomplexes, in addition to 1 : 1, metal-Npa, 1: 1, metal-TCA/HQ may also beacting as an active agent which increases their activity. Binary complexesindividually show a low activity due to their low lipid solubility whichwill not permit considerable amounts of cationic complexes to go to thesite of action.Apart from this, a comparatively faster diffusion of the metal complexas a whole through the cells of fungi may be one of the important factors.It is evident that these complexes are stable and chemically inert having noJ.TRANSITION METAL COMPLEXES 855specific active centres. Such compounds can exert a powerful inhibitoryeffect on an intracellular biological process by concentrating at the susceptiblesite from which it slowly dissolutes. The growth inhibition capacity of thecomplexes follows the order: Co (II) > Ni (II) > Cu(II) > Zn(II).Aeknowledgement. - Authors feel grateful to Dr. K. N. Me h r o t r a, AgraUniversity, Agra and Dr. J. P. Ta n d o n of Rajasthan University, Jaipur for thevaluable suggestions during the investigation, R. N. is also thankful to C. S. I. R.,New Delhi for f'inancial assistance.REFERENCES1. S. A. A b b a s i, Pol. J. Chem. 54 (1980) 1287.2. P. D. Ha ste n, Drug Interaetion (Henry, Kimpton, London), 1976.3. A. T. P eli P e n k o and M. M. Ta n n a i k s, Z. Anal. Chem. 28 (1973) 745.4. R. Bre cio w, Adv. Chem. Ser. 100 (1971) 21.5. R. Par m e g i a n i and H. G e r s h o n, AppL MiC1"obiol. 11 (1963) 62.6. D. R. H. G o uri e Y, Medicinal Chemistry, ed. E. B u r fer, Willey-Inler-, science, New York, 1960.7. A. Al b e r t, Seleetive Toxicity, Chapman and Hall, London, 1979.8. M. T. B e c k, Chemistry of Complex Equilibria, Van Nostrand Reinhold,London, 1970.9. G. L. E i c hho r n, Inorganic Biochemistry, Elsevier, Amsterdam, 1973.10. H. S i e g e 1, Metal Ions in Biological System, Marcel Dekker, New York, 1979.11. R. C. S h a rrna and R. K. Par ash a r, J. Inorg. Bioehem. 29 (1987) 225.12. B. S i n g h, R. N. S i n g h, and R. C. Ag a r w a 1, Ind. J. Chem. 23 (1984) 480.13. A. B. P. Lever, J. Lev i s, and R. S. 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Meutin, Miniatore, 1953.SAŽETAliSinteza i antigljivično djelovanje nekih kompleksa prijelaznih elemenataR. C. Sharma i R. NagarMješoviti kompleksi Ni(II), Cu(II) i Zn(II) s ligandirna: N-piridilantranilnakiselina (Npa), tiofen-2-karboksilna kiselina (TeA) i 8-hidroksikinolin (HA), sastavaM"(Npa)(TCA) odnosno lVP'(Npa)(HA) pripravljeni su i karaktertzirani elementnomanalizom, infracrvenim i elektronskim spektrirna, vodljivošću i magnetskim momen-tima. Predložena je oktaedarska struktura kompleksa.U otopini u dimetilformamidu ti su kompleksi neelektrolitske prirode. Ispitanoje antigljivično djelovanje slobodnih Iiganada i pripravljenih kompleksa na odabra-nim vrstama gljivica.

Synthesis and Antifungal Properties of Some Transition Metal Complexes Involving Potentially Active Heterocyclic Ligands

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