Synthesis, Characterization and Antifungal Activity of Metals Complexes having tetrahydro-1,2,4-triazine based Ligands

Anand Mohan Jha1*, K. K. Jha2, L. K. Mishra 3 & Sangeet4

1 Department of Chemistry, K. S. R. College, Sarairanjan, Samastipur-848127, INDIA

2 P. G. Department of Chemistry, Lalit Narayan Mithila University, Darbhanga-846004, INDIA

3 Department of Chemistry, Patna Science College, Patna-800005, INDIA

4 Department of Chemistry, Patna Science College, Patna-800005, INDIA

* Correspondence: E-mail: amjha6182@gmail.com

(Received 15 Sept, 2018; Accepted 04 Oct, 2018; Published 12 Oct, 2018 )

ABSTRACT: In present work we have reported the synthesis of some novel metal complexes containing 4- [1E- (1H- benzimidazol-2-yl) phenylmethylidineimino)- 6- aryl-5-oxo-3-thioxo 2,3,4,5- tetrahydro- 1,2,4- triazine (BpartrH) ligands. Synthetic utility was further supported by synthesizing complexes with metals ML 2 (M= MnII, CoII, NiII, CuII and ZnII). All the synthesized complexes were characterized by IR and UV spectra and further supported by elemental analysis. All the synthesized complexes were also evaluated for their antifungal potential and few of prepared complexes exhibited potent antifungal activity. Synthesized complexes were also utilized for magnetic susceptibility measurements and values are reported in tabular form in present article.

Keywords: Metal Complexes; Benzimidazole; Chemotherapeutic; Antifungal activity; Medicinal activity; Elemental analyses; Magnetic susceptibility; Triazine and Electrical conductance.

INTRODUCTION: Benzimidazole derivatives possess important pharmacophore nuclei and has privileged structure in medicinal chemistry.1 Their bioactivity is as specific angiotensin II receptor type I selective antagonists2 as well as hepatitis- C virus NSSB polymerase inhibitors.3 Furthermore their various pharmacological activity includes antidiabetic,4 antihistaminic,4 antiulcer,5-6 antiviral, 7 antifungal,8 antiparasitic9 and chemotherapeutic10 applications. The wide spectrum of pharmacological and medicinal activity of benzimidazole derivatives and their metal complexes created immense interest to synthesize, characterize and study their microbial properties. In pursuance of our interest to study the coordination complexes of some new benzimidazole derivatives.11-20 We here report the synthesis, characterization and antifungal activity of some bivalent metal complexes of 4- {1E- (1H-benzimidazol-2-yl) phenylmethylideneimino}- 6- aryl- 5- oxo- 3- thioxo- 2,3,4,5- tetrahydro- 1,2,4- triazine(BpartrH).

The ligand 4- {1E- (1H- benzimidazol-2-yl) phenylmethylideneimino}- 6- aryl-5-oxo-3-thioxo- 2,3,4,5-tetrahydro- 1,2,4- triazine (BpartrH) is potent S, N and O donor coordinating molecule and exists in thione- thiol tautomers (Figure 1). It can coordinate as neutral or mono anionic coordinating molecules.

img2

Figure 1: Structure of Ligands (L1H, aryl= Phenyl, L 2H, aryl= p-chlorophenyl).

MATERIAL AND METHODS: Metal salts and solvents used were extra pure reagent of E. Merck or Anal-R Grade chemical of B.D.H. The ligands were prepared by known procedure8. The metal content of complexes were determined by standard procedure. The elemental analyses were performed as reported earlier.8 The results of IR and UV were obtained from I.I.T, Patna and C.D.R.I. Lucknow.

Preparation of ligand: These ligands were prepared in two steps. The first part was preparation of ligand by condensing phenyl pyruvic acid (C6H5CO-COOH) or p- chlorophenyl pyruvic acid (p-Cl-C 6H4-CO-COOH) with thiocarbohydrazide in aqueous ethanol at reflux temperature to give 4-amino-6-aryl-5-oxo-3-thioxo-2,3,4,5- tetrahydro- 1,2,4- triazine(A).

Second step: In second step the product A was refluxed with 2- benzoyl- (1H- benzimidazole) leading to the formation of 4- {1E- (1H- benzimidazol- 2-yl) phenylmethylideneimino}-6- aryl- 5-oxo-3-thioxo-2,3,4,5- tetrahydro- 1,2,4 triazine (HL1= aryl group is C6H5 and HL2 = aryl group is p-chlorobenzene).

HL1 = 4- {1E-(1H-benzimidazol-2-yl)-phenyl-methylideneimino}-6-phenyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4- triazine and HL2 = 4- {1E-(1H-benzimidazol-2-yl)- phenylmethylideneimino}-6-p-chlorophenyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4- triazine (A).

img2

(X=H or Cl)

Scheme 1: Synthesis of 4-amino-6-aryl-5-oxo-3-thioxo-2,3,4,5- tetrahydro- 1,2,4- triazine.

img2

Scheme 2: Synthesis of tetrahydro triazine derivative.

These ligands were crystallized with (1:1) ethanol dioxane medium as cream coloured crystalline precipitate, M.P. of H2L 1 = 227-228 and those of H2L2 = 231-232.

Preparation of complexes [ML2] ( M= CoII, MnII, NiII, CuII, and Zn II HL = HL1 and HL2): About 20 millimole of ligand dissolved in hot 1:1 dioxane-ethanol mixture 30-40ml was treated with ethanol solution of 10 millimole of metal chloride. The mixed solution was heated upto reflux temperature and pH was raised by adding aqueous solution of sodium acetate under stirring for 7-8 hrs. Gradually separation was observed by formation of colored complexes and precipitation was completed by adding equal volume of water. The separated precipitate was digested on steam bath and collected on Buchner funnel and washed with cold methanol. The precipitate were dried over CaCl2 and finally at 50-60C in an air over. The dried products were analyzed and their analytical results are shown in Table 1. The E.P.R spectra of complexes were recorded on Varian EPR (E-112) Spectrophotometer in micro crystalline form at LNT. The Magnetic susceptibility was determined by Gouy's method making Diamagnetic correction using Pascal's constants.

RESULTS AND DISCUSSION: The elemental analysis of complexes formed by both ligands L1H and L2H corresponds to compositions ML2 (M= MnII, CoII, NiII, Cu II and ZnII, LH= L1H or L2 H). The dried complexes are almost insoluble in water but dissolved slightly in ethanol, methanol and acetone but soluble in dimethyl sulfoxide and dimethylformamide (DMF). The DMF solution of complexes exhibited negligible electrical conductance value (6-10 ohm -1mol-1cm2) indicating that complexes are nonelectrolyte.21 Zinc(II) Complexes ZnL 2 (HL= HL1 or HL2) are diamagnetic while MnII, CoII, NiII and Cu II complexes are Paramagnetic (Table 2) and magnetic moment values were found in the range of high spin octahedral complexes. 22

The electronic absorption spectra (qualitative) of CoII complexes shows strong absorption below 390 nm probably charge transfer type and two weak bands at 450-460 and 520-535 nm assignable to4T1g ? 4T2g and 4T1g ? 4A 2g transitions in octahedral field23. Mn(II) Complexes do not show electronic absorption bands of appreciable intensity as Mn(II) complexes show only spin forbidden transition. 24 Ni(II) Complexes NiL2 (HL= HL1 or HL2) show strong absorption below 400 nm one weak band at 580-590 nm in the instrumental range 200-850 nm. The band is assigned to 3A2g- 4T1g(f) transition similar to high spin octahedral Ni(II) complexes.23-24 Cu (II) complexes also show charge transfer strong absorption below 420 nm and a broad asymmetric band between 640-655 nm assignable to 2B1g ? 2B2g, 2Eg transition similar to distorted octahedral copper (II) Complexes. 25

Table 1: Results of Elemental analysis of Ligands and Complexes.

L1H

CuL21

NiL21

MnL21

ZnL21

CoL21

L1H Found

(Calculated)

% Metal

7.13(6.98)

6.31(6.49)

5.63(5.78)

7.02(7.17)

6.59(6.50)

---------

% Carbon

60.43(60.68)

60.81(61.00)

61.31(61.46)

60.41(60.56)

60.72(60.99)

64.78(65.09)

% Hydrogen

3.22(3.29)

3.21(3.31)

3.46(3.34)

3.43(3.29)

3.46(3.31)

3.89(3.77)

% Nitrogen

18.41(18.46)

18.43(18.56)

18.62(18.70)

18.38(18.43)

18.41(18.56)

19.70(19.81)

% Sulphur

7.21(7.03)

6.93(7.07)

7.01(7.12)

7.11(7.02)

6.93(7.07)

7.39(7.54)

L2H

CuL22

NiL22

MnL22

ZnL22

CoL22

L2H Found (Calc)

% Metal

6.21(6.49)

5.92(6.03)

5.16(5.38)

6.61(6.67)

5.91(6.04)

----------

% Carbon

56.21(56.41)

56.48(56.68)

57.01(57.14)

56.27(56.30)

56.43(56.67)

60.21(60.06)

% Hydrogen

3.11(3.06)

3.21(3.08)

3.21(3.10)

3.31(3.05)

3.21(3.08)

3.63(3.48)

% Nitrogen

17.01(17.16)

17.13(17.25)

17.21(17.39)

17.01(17.13)

17.03(17.24)

18.12(18.28)

% Sulphur

6.42(6.54)

6.51(6.57)

6.48(6.62)

6.43(6.52)

6.41(6.57)

6.71(6.96)


Table 2: Analytical result and Physical data of complexes.

Compound

%Analytical result found (Calculated)

Magnetic moment values at 30 1C in BM

Electrical conductance in ohm-1mol -1 cm2

Metal

Carbon

Hydrogen

Nitrogen

Sulphur

L1H

--------

64.78(65.09)

3.89(3.77)

19.70(19.81)

7.39(7.54)

-------

--------

L2H

--------

60.21(60.06)

3.63(3.48)

18.12(18.28)

6.71(6.96)

-------

--------

CuL21

7.13(6.98)

60.43(60.68)

3.22(3.29)

18.41(18.46)

7.21(7.03)

1.89

7

CuL22

6.21(6.49)

56.21(56.41)

3.11(3.06)

17.01(17.16)

6.42(6.54)

1.86

6

MnL21

5.63(5.78)

61.31(61.46)

3.46(3.34)

18.62(18.70)

7.01(7.12)

5.92

8

MnL22

5.16(5.38)

57.01(57.14)

3.21(3.10)

17.21(17.39)

6.48(6.62)

5.94

5

NiL21

6.31(6.49)

60.81(61.00)

3.21(3.31)

18.43(18.56)

6.98(7.07)

3.08

5

NiL22

5.92(6.03)

56.48(56.68)

3.21(3.08)

17.13(17.25)

6.51(6.57)

3.21

7

ZnL21

7.02(7.17)

60.41(60.56)

3.43(3.29)

18.38(18.43)

7.11(7.02)

Diamagnetic

6

ZnL22

6.61(6.67)

56.27(56.30)

3.31(3.05)

17.01(17.13)

6.43(6.52)

Diamagnetic

5

CoL21

6.59(6.50)

60.72(60.99)

3.46(3.31)

18.41(18.56)

6.93(7.07)

5.12

8

CoL22

5.91(6.04)

56.43(56.67)

3.21(3.08)

17.03(17.24)

6.41(6.57)

5.03

7

Table 3: Antifungal activity of ligands and some complexes at 30 1 C.

Fungi

Conc. in ppm

L1H

L2H

CuL21

CuL22

ZnL12

ZnL22

CoL12

CoL22

Ref

A. Flavus

50

100

35

48

37

52

65

82

68

85

48

60

50

65

47

61

50

63

85

96

A. Niger

50

100

36

46

38

54

63

81

66

86

55

68

60

76

58

73

62

80

82

97

R. phaseoli

50

100

30

44

35

49

58

80

62

87

52

69

58

78

56

72

60

75

79

97

F. oxysporum

50

100

42

52

42

55

68

85

70

88

50

62

60

72

48

63

53

68

81

98

The reference used for antifungal activity was Mycostatin.

The IR spectra of ligand HL1 and HL2 both display NH stretching band of benzimidazole26 and triazine ring NH vibrations are observed at 3185 and 3235 cm-1. The ligand exist in thione form in solid state as the free ligands HL1 and HL 2 show (>C=S) stretch as strong band at 965 and 972 respectively.27 The out of plane bending band of (CH), phenyl ring, triazine and imidazole ring were observed at 905, 868, 745, 692.

The (C=0) group stretching vibration of HL1 is observed as strong band at 1721 and for HL2 at 1728 cm -1 and these vibrations are retained in their metal complexes suggesting that oxo group of CO oxygen is not involved in coordination 28. The imidazole ring (NH) vibration and triazine ring (NH) band was assigned to IR band located at 1505-1512 cm-1. The (C=N) of free ligand was observed at 1630 cm-1. The phenyl and triazine ring skeletal vibrations were located at 1605, 1555, 1445, 1365, 1245 and 1120 cm-1 and these vibrations are retained in complexes with slight chain in band position and intensity due to coordination of ligands. The (C=N) vibration of ligands were found to be shifted at lower position by 20-25 in complexes suggesting that (C=N) tertiary nitrogen of benzimidazole is involved in bonding.29 The thione group (C=S) stretch at 965 and 972 cm-1 disappear and new bands for (C-S) group is observed at 720 12 cm-1 suggesting that coordination of (C=S) sulphur has taken place by deprotonation of thiol tautomers of both HL1 and HL2. The aldimine >C=N stretch of HL1 assigned to a medium band at 1605 2 cm -1 which has been found to be shifted to lower frequency and observed at 1990 5 cm-1 due to coordination of aldiminic (C=N) nitrogen.30-33 Thus both the ligand HL1 and HL 2 are suggested to coordinate as tridentate (NNS) ligand.

Antifungal activity of ligang HL1 and HL2 and some of their complexes were screened by radial growth method31.The screening medium of compositions 20g starch, 20g agar agar, 20g glucose dissolved in 1 litre distilled water were made. To this medium 50 and 100 ppm concentration of ligands and Cu(II), Zn(II) and Co(II) complexes were made in DMF.

The medium were poured in petri plate and shown in Table 3. It was found that Cu(II) complexes of both HL1 and HL2 display larger antifungal activity than those of Zn(II) and Co(II) complexes. The chlorobenzyl derivative L2H complexes show much activity compared to benzyl derivative L1H.

CONCLUSION: In summary we have reported here a suitable and facile method for preparation of some novel metal complexes having benzimidazole and triazine based ligands. All the prepared complexes were evaluated for antifungal potential and few of them were found to be potent antifungal agents. All the characterization data and elemental analysis results were in good agreement with illustrated structures of metal complexes. Magnetic susceptibility results were also in support of synthesized metal complexes. Our present study is very useful from synthetic as well as medicinal perspective. Our work may open new doors in antifungal drug discovery research and metal complex synthesis.

ACKNOWLEDGEMENT: Authors acknowledge support from IIT Patna and C.D.R.I. Lucknow for recording IR and UV Spectra. Authors would also like to thank Lalit Narayan Mithila University, Darbhanga, for providing the necessary laboratory facilities.

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