Antimicrobial and Cytotoxic Activity of Transition Metal Chelates With Some Heterocyclic Imines R. C. Sharma and V. K. Varshney Department
of Chemistry, Institute of Basic Science, Agra University, Agra, India
ABSTRACT Cu(II), Ni(II), Co(R), and Zn(I1) chelates with two heterocyclic imines derived from 2-furylglyoxal-2’aminotbiophenol (FGATP) and 2-thiophenylglyoxal-anthranilicacid (TGAA) were synthesized. Elemental analysis, molar conductance, magnetic measurements and IR and electronic spectral data were explored to elucidate their probable structures. Different crystal field parameters were also calculated to ascertain the geometry of the resulting chelates. All the ligands and their metal chelates were screened, in vitro, for their antimicrobial activity against two bacteria: S.aureus and E.coli and two fungi, viz: A.niger and C.albicans. The in vitro cytotoxic activity of all the compounds was also assessed.
INTRODUCTION A broad spectrum of biological activity including antibacterial, antifungal, anticonvulsant, fungicidal, anti-inflammatory, anticancer, and tranquilizing effects is reported to be associated with heterocyclic compounds [l-4]. Moreover, the biological activity of an organic ligand can be increased several fold on being coordinated with a suitable metal ion [5-S]. This idea prompted us to synthesize some Schiff bases containing heterocyclic moiety and their Cu(II), Ni(II), Co(II), and Zn(I1) metal chelates with a view to evaluate their biological properties.
MATERIALS
AND METHOD
All chemicals used were of A.R. grade. 2-Furylglyoxal and 2-thiophenylglyoxal were synthesized by the oxidation of 2-acetylfuran and 2-acetylthiophene respectively according to the reported method 191.
Address reprint requests and correspondence to: Dr. R. C. Sharma, University, Khandari Road, Agra-282 002, India. Journal of Inorganic Biochemistry, 41,299-304 (1991) 0 1991 Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas,
Department
of Chemistry,
Agra 299
NY, NY 10010
0162-0134/91/$3.50
300
R. C. Sharma and V. K. Varshney
T
==‘,,
P r --Cq,H
SCHEME I.
Synthesis of Schiff Bases Schiff bases (FGATP and TGAA) of the following general structure were synthesized by refluxing equimolecular ethanolic solutions of glyoxal (i.c.. 2furylglyoxal and and 2-thiophenylglyoxal) and corresponding amine (viz., 2-aminothiophenol anthranilic acid) for 3 hours. On cooling the solution, they were separated as colored crystals which were filtered, washed with cold ethanol (0°C). and dried in vacuuo over anhydrous CaCl,. Their purity was further checked by the ‘UC method. Where X = 0, R = -SH X = S, R = --C&H FGATP = 2-furylglyoxal-2
‘-aminothiophenol
TGAA = 2-thiophenylglyoxal-anthranilic
acid.
Synthesis of Metal Chelates Cu(II), Ni(II), Co(II), and Zn(II) metal chelates of above prepared Schiff bases were synthesized by refluxing the ethanolic solutions of ligands and the corresponding metal acetate in 2: 1 ratio over a water bath for about 2--3 hr. The chelates thus obtained were filtered and washed with ethanol followed by ether before drying in vacuuo over anhydrous CaCl :.
Physical Measurements Authenticity of the purity of the compound was judged by their CHN analysis. S (as BaSO,) and metal contents were estimated by standard procedures [ 101. IR spectra were recorded on a Perkin-Elmer model 577 spectrophotometer in the range of 4000--200 cm ’ in Csi disc and electronic spectra in pure DMSO on a Shimadzu digital double beam spectrophotometer UV-150-02 model. The molar conductance of all the chelates were measured in dry DMF using a Toshniwal conductivity metL’r at room temperature. Gouy‘s method was employed to carry out magnetic susceptibility measurements at room temperature using CuSO, . .5H,G as the calihrani
RESULTS AND DISCUSSION All the chelates are colored and stable at room temperature. They are insoluble in common organic solvents but soluble in DMF and DMSO. Their low molar conductance values (5.40-9.85 ohm ’ cm2 mole ’ ) are in good agreement with their nonelectrolyte nature. Analytical data (Table 1) of ligands as well as their chelates suggest I :2 (M: t.,) stoichiometry.
TRANSITION METAL CHELATES CYTOTOXIC
ACTIVITY
301
TABLE 1. Physical and Analytical Data of Ligands and Their Metal Chelates
Sample No.
Compound
1
FGATP (HL)
Black
2
CUL,
3
NiL,
4
COL,
Blackish green Light green Black
5
ZnL,
6
TGAA (HL?
7
CUL,
8
NiL,
9
COL,
10
ZnL,
M.P. (“C)/Decomposition Temperature*
Color
98-99 -
Light yellow Orange red Green
187-189 -
Light brown Brown
-
Light yellow
-
-
% Analysis:
Found/(Calculated)
C
H
N
Metal
Mol. Wt.**
62.38 (62.34) 54.93 (55.01) 55.44 (55.52) 55.59 (55.50) 54.76 (54.82) 60.30 (60.23) 53.72 (53.84) 54.40 (54.29) 54.17 (54.27) 53.72 (53.67)
3.85 (3.89) 3.01 (3.06) 3.12 (3.08) 3.11 (3.08) 3.02 (3.05) 3.42 (3.48) 2.73 (2.76) 2.82 (2.78) 2.83 (2.78) 2.69 (2.75)
6.03 (6.06) 5.29 (5.35) 5.30 (5.39) 5.47 (5.40) 5.26 (5.33) 5.52 (5.41) 4.73 (4.83) 4.82 (4.87) 4.84 (4.87) 4.77 (4.82)
-
-
12.34 (12.14) 11.62 (11.32) 11.27 (11.36) 12.56 (12.44) -
504.37 (523.54) 501.97 (518.69) 503.49 (518.93) 505.35 (525.38) -
11.15 (10.96) 10.46 (10.21) 10.39 (10.25) 11.04 (11.25)
563.46 (579.54) 560.92 (574.69) 562.05 (574.93) 561.98 (581.38)
*All the chelates are decomposed at > 250°C. **Molecular weights were determined in DMSO by cryoscopic
method.
IR Spectral Studies
In the IR spectra of ligands, a sharp band at 1610 cm-’ (FGATP) and at 1615 cm-’ (TGAA) due to vC=N is observed which shifts towards a lower frequency region (1585 f 5 cm-‘) in the spectra of respective chelates, suggesting thereby the participation of the azomethine group in chelation [l 11. Coordination of ligand to central metal ion through carbonyl oxygen is evident by a considerable fall in frequency as well as in the intensity of the vC=O band ligand - 1735 and 1720 cm-‘; complex 1680 + 10 cm-’ [12]. A weak band at 2750 cm-’ in the IR spectra of FGATP and a band of medium intensity at 3550 cm- ’ in TGAA, diagnostic of -SH and -COOH group respectively, disappear in the spectra of respective metal chelates indicating thereby the coordination of ligand to metal ion as a consequence of deprotonation of thiol and carboxylic group [ 131. vasand v, vibrations of the COO- group also appear at 1535 and 1325 cm-’ respectively. A Ye_) value (210 cm- ‘) further indicate the coordination through unidentate carboxylate group [14]. Some new bands at 530-540 cm-‘, 440-450 cm-‘, and 340-325 cm-’ support the formation of M-O, M-N, and M-S bonds respectively [ 15, 161 which further confirm that ligands provide monobasic tridentate coordination. Electronic
Spectra
Copper
and Magnetic
Studies
Chelates. A broad band at 14900- 15330 cm- ’ along with two shoul-
ders at 10640 and *B,, +*Eg transitions
16350 cm-’ assignable to *B,,+*B,,, *B,s-+*Alg, and respectively suggest distorted octahedral geometry for both the
302
R. C. Sharma and V. K. Varshney
TABLE 2. Ligand Field Parameters
Sample No. --___-
I
Compound Cu(FCATPJ1 Ni(FGATP), Co(FGATP,, CMTGAA), Ni(TGAA I: CorrGAAi z
2 3 4 5 6
Cu(I1) chelates
and magnetic
IO Dq I_-_ IO546 10800 824s 10690 11173 X389
[ 171, which
of Metal Chelates Racah Parameter B ___-._ _-
Ncphelauxetic Ratio
736 909 ._ O.bh
711 0x1
is further
moment values (1.99.
CLXX
confirmed by the ratio u, ,‘cJ: ( I.2 1 and I. 32) 1.76 B.M).
Nickef(Z1) Chelates. Electronic
spectra of Ni(I1) chelates display three bands at 10800- 11175 cm- ‘, 17900- 17953 cm ‘. and 25640--26240 cm ’ assignable to ‘AAZE:-+‘Tzn. ‘T,,, and ‘Tjp (P) transitions. respectively. The 30% reduction in B value as compared to free Ni(II) ion (1040 cm ‘) indicates its chelation. Louering the ratio Ye /Y, from 1A (theoretical value) to 1.65 and I .61 due to configuration interaction between ‘T,,(P) and T,,(F) excited states is in ronhrmity with the distorted octahedral geometry [IS] of both the chelates which is further supported by their pLert.values (3.16 and 3.14 B.M.).
Cohalt(II)
Chelates. C’o(lIj chelates show three bands at 7380-7980 cm ‘, I.5625 16369 cm ‘* and 20161-22296 cm ! which could be assigned to “T,p(F) respectively. The second transition --L’T2F(F), t42,(F), and ‘Tip(P) transitions, appears as a shoulder. p,,r values are 4.84 and 4.96 B.M., respectively. Thus it is concluded that there is a high spin octahedral geometry involving a high degree of orbital contribution due to three fold degeneracy of ‘T,, r‘ oround state for h&h the chelates [ 191. Zincfll) Chelates. As expected all the Zn(II) chelates are diamagnetic
TABLE 3. Antimicrobial
Activity of Ligands and Their Metal Chelates Bactena
Sample No. -_--..___
I 2
Compound -____._ FGATIYHI. cu. I
j
S.aureus -..----_______ 100 SO
3
Nil.-
75
4 5
Cd’, %nL -, rGA:,VHL’) CIIL
SO ii?
6 7 8 9 10
SiL ,
COLI ZIIL,
in nature. On
75 25 50 SO 25
Fungi A nigcr
C.alhicanh
TRANSITION
METAL CHELATES
CYTOTOXIC
ACTIVITY
303
TABLE 4. Cytotoxic Activity of Ligands and Their Metal Chelates IC,,(Molar) Sample No.
Compound
(CEM-6)
1
FGATP(HL)
2
CUL,
> 7.20 x 1O-6
1.29 x 1O-5
3
NiL,
> 2.62 x 1O-6
4
COL,
> 3.63 x 10-b
5
ZnL,
6
TGAA(HL’)
> 1.15 x 10-j
7
CUL,
> 1.24 x 10m5
8
NiL,
> 1.25 x 1O-5
9
COL 2
> 9.09 x 10-6
ZnL,
>4.46x
10
1.76 x 1O-5
lo-’
the basis of elemental analysis, molar conductance, and IR spectral data, octahedral geometry is proposed for both the Zn(I1) chelates [20,21]. Ligand field parameters of Cu(II), Ni(II), and Co(E) chelates which are in good agreement with the geometry proposed to them are presented in Table 2. Antimicrobial
Activity
All the synthesized ligands and their respective metal chelates were screened in vitro for their antibacterial activity against Staphylococus aures (gram positive) and Escherichia coli (gram negative) (incubation period at 37°C for 24 hr) and for antifungal activity against two common fungi, Aspergillus niger and Candida albicans (incubation period at 26°C for 96 hr) using serial dilution method [22]. Test solution of FGATP and TGAA were prepared in propyleneglycol and those of complexes were prepared in DMSO diluted with culture media to give the required drug concentration in 2.5% DMSO. Comparison of MIC values (Table 3) of FGATP, TGAA, and their metal chelates infers that the antimicrobial activity of ligands has enhanced several fold in the form of their chelates. Cytotoxic
Activity This was assessed in vitro against CEM-6 human leukemia cell lines by using the reported procedure [23] at the National Cancer Institute, under the “anticancer and From the IC,, values (Table 4) it is AIDS antiviral drug discovery programme.” concluded that none of the compound assessed has cytotoxic activity against the cells used. The authors thank Professor P. J. Sadler of London, Professor J. P. Tondon of Jaipur, and Professor K. N. Mehrotra of Agra University for their keen interest and valuable suggestions during this investigation. Thanks are also due to the National Cancer Institute Bethesda, Maryland, for conducting cytotoxic activity research. Financial support to one of the authors (VKV) from C.S.I.R. New Deihi is also gratefully acknowledged.
REFERENCES 1.
R. P. Bhamaria, R. A. Bellode, and C. V. Deliwala, Indian J. Exp. Bioi. 6, 62 (1968).
384
R. C. Sharma and V. K. Varshney
2.
T. Shen, R. L. Clark, and A. A. Pessolano,
S. Afr.
Pat. 527 7503 (1976); Chem.
Abstr. 86, 72662r (1977). 3.
R. S. Verma,
K. C. Gupta, A. Nath. and V. S. Mishra,
Indian J. Microbioi. 4. 63
(1964). 4.
R. B. Pathak, B. Thana, and S. C Babel. J. ,4ntibacteriai,
Antifungal Agents 8, 12
(1980).
7. 8. 9. IO.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
R. C. Sharma and R. K. Parashar, J. Inorg. Biochem. 28, 225 (1987). R. K. Parashar, R. C. Sharma, and G. Mohan, in Biology ojcopper complexes. J. R. J, Sorenson, Ed., Humana, New Jersey. 1987. K. D. Rainsford and M. W. Whitehouse, J. Pharm. Pharmacol. 28. 83 (19763. A. J. Lewis, Agents Actions 8, 244 (1978). F. Kippins and J. Ornfelt, J. Am. Chem. Sot. 68, 2734 (1946). A. I. Vogel, A Test Book of Quantitative Inorganic Ana&sis, Longmans Green and Co. Ltd., London, pp. 496, 526, 528, 532, and 462, 1964. R. J. Olzewski and D. F. Martin, 9. inorg. Nucl. Chem. 26, 1577 (1964). R. L. Dutta and K. De, Indian J. Chem. 27A, 637 (1988). D. D. Ozha and N. N. Kaul, Cut-r. Sci. 43, 344 (1974). G. B. Decon and R. J. Phillips. Coord. Chem. Rev. 33, 227 (1980). K. Nakamoto, Spectroscopy and structure of Metal Cheiate compounds, John Willey & Sons, New York, 1968. K. K. Narang and A. Agarwal, Inorg. Chim. Acta 9, 137 (1974). R. B. Johri and R. C. Sharma, .I. Indian Chem. Sot. LXV(ll), 793 (1989). A. B. P. Lever, Adv. Chem. 62, 435 (1966). A. C. Rande and V. V. Subha Rao, Indian J. Chem. 4, 42 ( 1966). R. Nath and R. P. Bhatnagar, J. Indian Chem. Sot. LXV(I1). 792 (1988). M. Kumar, P. Kumari, and T. Sharma, .I. Indian Chem. SM. LXV(12), 869 (1988). D. F. Spooner and G Sykes, Methods in Microbiol0g.v. Academic Press. London, 1972. vol. 7B. 0. W. Weislow, R. Kiser. D. Fine, J. Bader, R. H. Shoemaker. and hl. R. Boyd. J’ Natl. Cancer Inst. Xl. 577-586 (1989).
Received June 5. 1990; accepted September 1, 1990
of Chemistry, Institute of Basic Science, Agra University, Agra, India
ABSTRACT Cu(II), Ni(II), Co(R), and Zn(I1) chelates with two heterocyclic imines derived from 2-furylglyoxal-2’aminotbiophenol (FGATP) and 2-thiophenylglyoxal-anthranilicacid (TGAA) were synthesized. Elemental analysis, molar conductance, magnetic measurements and IR and electronic spectral data were explored to elucidate their probable structures. Different crystal field parameters were also calculated to ascertain the geometry of the resulting chelates. All the ligands and their metal chelates were screened, in vitro, for their antimicrobial activity against two bacteria: S.aureus and E.coli and two fungi, viz: A.niger and C.albicans. The in vitro cytotoxic activity of all the compounds was also assessed.
INTRODUCTION A broad spectrum of biological activity including antibacterial, antifungal, anticonvulsant, fungicidal, anti-inflammatory, anticancer, and tranquilizing effects is reported to be associated with heterocyclic compounds [l-4]. Moreover, the biological activity of an organic ligand can be increased several fold on being coordinated with a suitable metal ion [5-S]. This idea prompted us to synthesize some Schiff bases containing heterocyclic moiety and their Cu(II), Ni(II), Co(II), and Zn(I1) metal chelates with a view to evaluate their biological properties.
MATERIALS
AND METHOD
All chemicals used were of A.R. grade. 2-Furylglyoxal and 2-thiophenylglyoxal were synthesized by the oxidation of 2-acetylfuran and 2-acetylthiophene respectively according to the reported method 191.
Address reprint requests and correspondence to: Dr. R. C. Sharma, University, Khandari Road, Agra-282 002, India. Journal of Inorganic Biochemistry, 41,299-304 (1991) 0 1991 Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas,
Department
of Chemistry,
Agra 299
NY, NY 10010
0162-0134/91/$3.50
300
R. C. Sharma and V. K. Varshney
T
==‘,,
P r --Cq,H
SCHEME I.
Synthesis of Schiff Bases Schiff bases (FGATP and TGAA) of the following general structure were synthesized by refluxing equimolecular ethanolic solutions of glyoxal (i.c.. 2furylglyoxal and and 2-thiophenylglyoxal) and corresponding amine (viz., 2-aminothiophenol anthranilic acid) for 3 hours. On cooling the solution, they were separated as colored crystals which were filtered, washed with cold ethanol (0°C). and dried in vacuuo over anhydrous CaCl,. Their purity was further checked by the ‘UC method. Where X = 0, R = -SH X = S, R = --C&H FGATP = 2-furylglyoxal-2
‘-aminothiophenol
TGAA = 2-thiophenylglyoxal-anthranilic
acid.
Synthesis of Metal Chelates Cu(II), Ni(II), Co(II), and Zn(II) metal chelates of above prepared Schiff bases were synthesized by refluxing the ethanolic solutions of ligands and the corresponding metal acetate in 2: 1 ratio over a water bath for about 2--3 hr. The chelates thus obtained were filtered and washed with ethanol followed by ether before drying in vacuuo over anhydrous CaCl :.
Physical Measurements Authenticity of the purity of the compound was judged by their CHN analysis. S (as BaSO,) and metal contents were estimated by standard procedures [ 101. IR spectra were recorded on a Perkin-Elmer model 577 spectrophotometer in the range of 4000--200 cm ’ in Csi disc and electronic spectra in pure DMSO on a Shimadzu digital double beam spectrophotometer UV-150-02 model. The molar conductance of all the chelates were measured in dry DMF using a Toshniwal conductivity metL’r at room temperature. Gouy‘s method was employed to carry out magnetic susceptibility measurements at room temperature using CuSO, . .5H,G as the calihrani
RESULTS AND DISCUSSION All the chelates are colored and stable at room temperature. They are insoluble in common organic solvents but soluble in DMF and DMSO. Their low molar conductance values (5.40-9.85 ohm ’ cm2 mole ’ ) are in good agreement with their nonelectrolyte nature. Analytical data (Table 1) of ligands as well as their chelates suggest I :2 (M: t.,) stoichiometry.
TRANSITION METAL CHELATES CYTOTOXIC
ACTIVITY
301
TABLE 1. Physical and Analytical Data of Ligands and Their Metal Chelates
Sample No.
Compound
1
FGATP (HL)
Black
2
CUL,
3
NiL,
4
COL,
Blackish green Light green Black
5
ZnL,
6
TGAA (HL?
7
CUL,
8
NiL,
9
COL,
10
ZnL,
M.P. (“C)/Decomposition Temperature*
Color
98-99 -
Light yellow Orange red Green
187-189 -
Light brown Brown
-
Light yellow
-
-
% Analysis:
Found/(Calculated)
C
H
N
Metal
Mol. Wt.**
62.38 (62.34) 54.93 (55.01) 55.44 (55.52) 55.59 (55.50) 54.76 (54.82) 60.30 (60.23) 53.72 (53.84) 54.40 (54.29) 54.17 (54.27) 53.72 (53.67)
3.85 (3.89) 3.01 (3.06) 3.12 (3.08) 3.11 (3.08) 3.02 (3.05) 3.42 (3.48) 2.73 (2.76) 2.82 (2.78) 2.83 (2.78) 2.69 (2.75)
6.03 (6.06) 5.29 (5.35) 5.30 (5.39) 5.47 (5.40) 5.26 (5.33) 5.52 (5.41) 4.73 (4.83) 4.82 (4.87) 4.84 (4.87) 4.77 (4.82)
-
-
12.34 (12.14) 11.62 (11.32) 11.27 (11.36) 12.56 (12.44) -
504.37 (523.54) 501.97 (518.69) 503.49 (518.93) 505.35 (525.38) -
11.15 (10.96) 10.46 (10.21) 10.39 (10.25) 11.04 (11.25)
563.46 (579.54) 560.92 (574.69) 562.05 (574.93) 561.98 (581.38)
*All the chelates are decomposed at > 250°C. **Molecular weights were determined in DMSO by cryoscopic
method.
IR Spectral Studies
In the IR spectra of ligands, a sharp band at 1610 cm-’ (FGATP) and at 1615 cm-’ (TGAA) due to vC=N is observed which shifts towards a lower frequency region (1585 f 5 cm-‘) in the spectra of respective chelates, suggesting thereby the participation of the azomethine group in chelation [l 11. Coordination of ligand to central metal ion through carbonyl oxygen is evident by a considerable fall in frequency as well as in the intensity of the vC=O band ligand - 1735 and 1720 cm-‘; complex 1680 + 10 cm-’ [12]. A weak band at 2750 cm-’ in the IR spectra of FGATP and a band of medium intensity at 3550 cm- ’ in TGAA, diagnostic of -SH and -COOH group respectively, disappear in the spectra of respective metal chelates indicating thereby the coordination of ligand to metal ion as a consequence of deprotonation of thiol and carboxylic group [ 131. vasand v, vibrations of the COO- group also appear at 1535 and 1325 cm-’ respectively. A Ye_) value (210 cm- ‘) further indicate the coordination through unidentate carboxylate group [14]. Some new bands at 530-540 cm-‘, 440-450 cm-‘, and 340-325 cm-’ support the formation of M-O, M-N, and M-S bonds respectively [ 15, 161 which further confirm that ligands provide monobasic tridentate coordination. Electronic
Spectra
Copper
and Magnetic
Studies
Chelates. A broad band at 14900- 15330 cm- ’ along with two shoul-
ders at 10640 and *B,, +*Eg transitions
16350 cm-’ assignable to *B,,+*B,,, *B,s-+*Alg, and respectively suggest distorted octahedral geometry for both the
302
R. C. Sharma and V. K. Varshney
TABLE 2. Ligand Field Parameters
Sample No. --___-
I
Compound Cu(FCATPJ1 Ni(FGATP), Co(FGATP,, CMTGAA), Ni(TGAA I: CorrGAAi z
2 3 4 5 6
Cu(I1) chelates
and magnetic
IO Dq I_-_ IO546 10800 824s 10690 11173 X389
[ 171, which
of Metal Chelates Racah Parameter B ___-._ _-
Ncphelauxetic Ratio
736 909 ._ O.bh
711 0x1
is further
moment values (1.99.
CLXX
confirmed by the ratio u, ,‘cJ: ( I.2 1 and I. 32) 1.76 B.M).
Nickef(Z1) Chelates. Electronic
spectra of Ni(I1) chelates display three bands at 10800- 11175 cm- ‘, 17900- 17953 cm ‘. and 25640--26240 cm ’ assignable to ‘AAZE:-+‘Tzn. ‘T,,, and ‘Tjp (P) transitions. respectively. The 30% reduction in B value as compared to free Ni(II) ion (1040 cm ‘) indicates its chelation. Louering the ratio Ye /Y, from 1A (theoretical value) to 1.65 and I .61 due to configuration interaction between ‘T,,(P) and T,,(F) excited states is in ronhrmity with the distorted octahedral geometry [IS] of both the chelates which is further supported by their pLert.values (3.16 and 3.14 B.M.).
Cohalt(II)
Chelates. C’o(lIj chelates show three bands at 7380-7980 cm ‘, I.5625 16369 cm ‘* and 20161-22296 cm ! which could be assigned to “T,p(F) respectively. The second transition --L’T2F(F), t42,(F), and ‘Tip(P) transitions, appears as a shoulder. p,,r values are 4.84 and 4.96 B.M., respectively. Thus it is concluded that there is a high spin octahedral geometry involving a high degree of orbital contribution due to three fold degeneracy of ‘T,, r‘ oround state for h&h the chelates [ 191. Zincfll) Chelates. As expected all the Zn(II) chelates are diamagnetic
TABLE 3. Antimicrobial
Activity of Ligands and Their Metal Chelates Bactena
Sample No. -_--..___
I 2
Compound -____._ FGATIYHI. cu. I
j
S.aureus -..----_______ 100 SO
3
Nil.-
75
4 5
Cd’, %nL -, rGA:,VHL’) CIIL
SO ii?
6 7 8 9 10
SiL ,
COLI ZIIL,
in nature. On
75 25 50 SO 25
Fungi A nigcr
C.alhicanh
TRANSITION
METAL CHELATES
CYTOTOXIC
ACTIVITY
303
TABLE 4. Cytotoxic Activity of Ligands and Their Metal Chelates IC,,(Molar) Sample No.
Compound
(CEM-6)
1
FGATP(HL)
2
CUL,
> 7.20 x 1O-6
1.29 x 1O-5
3
NiL,
> 2.62 x 1O-6
4
COL,
> 3.63 x 10-b
5
ZnL,
6
TGAA(HL’)
> 1.15 x 10-j
7
CUL,
> 1.24 x 10m5
8
NiL,
> 1.25 x 1O-5
9
COL 2
> 9.09 x 10-6
ZnL,
>4.46x
10
1.76 x 1O-5
lo-’
the basis of elemental analysis, molar conductance, and IR spectral data, octahedral geometry is proposed for both the Zn(I1) chelates [20,21]. Ligand field parameters of Cu(II), Ni(II), and Co(E) chelates which are in good agreement with the geometry proposed to them are presented in Table 2. Antimicrobial
Activity
All the synthesized ligands and their respective metal chelates were screened in vitro for their antibacterial activity against Staphylococus aures (gram positive) and Escherichia coli (gram negative) (incubation period at 37°C for 24 hr) and for antifungal activity against two common fungi, Aspergillus niger and Candida albicans (incubation period at 26°C for 96 hr) using serial dilution method [22]. Test solution of FGATP and TGAA were prepared in propyleneglycol and those of complexes were prepared in DMSO diluted with culture media to give the required drug concentration in 2.5% DMSO. Comparison of MIC values (Table 3) of FGATP, TGAA, and their metal chelates infers that the antimicrobial activity of ligands has enhanced several fold in the form of their chelates. Cytotoxic
Activity This was assessed in vitro against CEM-6 human leukemia cell lines by using the reported procedure [23] at the National Cancer Institute, under the “anticancer and From the IC,, values (Table 4) it is AIDS antiviral drug discovery programme.” concluded that none of the compound assessed has cytotoxic activity against the cells used. The authors thank Professor P. J. Sadler of London, Professor J. P. Tondon of Jaipur, and Professor K. N. Mehrotra of Agra University for their keen interest and valuable suggestions during this investigation. Thanks are also due to the National Cancer Institute Bethesda, Maryland, for conducting cytotoxic activity research. Financial support to one of the authors (VKV) from C.S.I.R. New Deihi is also gratefully acknowledged.
REFERENCES 1.
R. P. Bhamaria, R. A. Bellode, and C. V. Deliwala, Indian J. Exp. Bioi. 6, 62 (1968).
384
R. C. Sharma and V. K. Varshney
2.
T. Shen, R. L. Clark, and A. A. Pessolano,
S. Afr.
Pat. 527 7503 (1976); Chem.
Abstr. 86, 72662r (1977). 3.
R. S. Verma,
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Received June 5. 1990; accepted September 1, 1990
