In-vitro Antifungal Evaluation of Some Cu and Ni Complexes

 

Deepankar Sharma, Purnima Nag*

Department of Chemistry, Jaipur National University, Jaipur-302017, Rajasthan, India.

 

ABSTRACT:

The interaction of Copper and Nickel chloride with oximes of 2-Acetylfuran, 2-Acetylthiophene and 2-Acetylpyridine in absence of an external base resulted in formation of the complexes of the type [MCl₂L₂] (A) and [MCl₂L₂].H₂O (A.H₂O) {Here M: Cu or Ni; L: HON=C(CH₃) Ar; where Ar = C₄H₃S, C₄H₃O or C₅H₄N}. The parent ligands were synthesized by green method using water as a solvent. Complexes were characterized by elemental analysis, ¹H-NMR, IR spectral studies and these spectra were compared with that of free ligands. Spectral measurements suggest an octahedral or distorted octahedral geometry for all these complexes. The in-vitro Antifungal activity of all these complexes has proven that they are active against Candida albicans even at lower concentrations.

 

 

 

INTRODUCTION:

There has always been a great interest in oximes and their coordination chemistry¹. Oximes have been accounted for a various reasons which include their unforgettable analytical applications; ability to form a great variety of polynuclear systems^2-4 of notable importance; providing useful bioinorganic models such as depicting the biological significance of donor imidazole group of the amino acid histidine⁵. Furthermore; oximes are efficient catalysts for the hydrolysis of organonitriles⁶, the evaluation of metal ion-assisted organic reactions⁷ and involvement of oximato ligands in the synthesis of metallic clusters^8,9 and coordination polymers¹⁰ with remarkable magnetic properties^11-13.

 

Metal complexes have often proved that they possess better biological significance than free ligand           systems^14-17. It is renowned that Cu(II) complexation plays a significant part in the pharmacological aspects of antimicrobial agents^18-23. Here upon, Cu(II) complexation has been vastly in use for clinical applications in inhibition of enzymes²⁴, antibacterial^25-28, antiviral^29-31 and anticancer studies^32-34.

 

Nickel on the other hand, is well recognized as an active unit of urease; {NiFe} hydrogenases for the reversible transformation of proton and hydrogen^35,36; {NiFe} CO dehydrogenases (CODHs) for the reversible transformation among CO and CO₂^37,38; and S-methyl CoM reductase which is responsible as a catalyst in last step of methane output by methanogenic bacteria.

 

In perpetuation to our earlier work^39,40 and all the aforementioned valuable findings encouraged us to work further in this area. In this research paper, we report syntheses and in-vitro anti-fungal activity of Cu and Ni complexes derived from oximes of 2-Acetylfuran, 2-Acetylthiophene and 2-Acetylpyridine. The ligands showed their neutral character during complexation and the oxime-OH remains free in all the complexes.

 

MATERIALS AND METHODS:

Chemicals, Reagents and Instrumentation:

2-Acetylfuran, 2-Acetylthiophene, 2-Acetylpyridine, Hydroxylamine hydrochloride, Sodium hydroxide, Nickel chloride hexahydrate and Copper chloride dihydrate (from Merck) were used as procured, without any further purification. Oximato ligands were prepared by reported green method³⁹ in absence of any organic solvent. Nickel and Copper were gravimetrically estimated⁴¹ as Ni(dmg)₂ and CuSCN, respectively. Carbon and hydrogen were determined on a Perkin-Elmer 2100 analyzer. Infra-red spectra were recorded on Perkin-Elmer spectrophotometer (10.4.00 Version) in the range 4000-400 cm^-1 using KBr. ¹H-NMR was recorded on a Bruker-Ascend 300 MHz system using DMSO-d₆ with TMS as reference. The in vitro analysis was carried out on Candida albicans swabbed onto Sabouraud’s Dextrose Agar surface as a Muller Hinton Agar medium.

 

Synthesis of oximes HON=C(CH₃)C₄H₃O:

An equimolar mixture of 2-Acetylfuran (3.25g, 29.52 mmol) and hydroxylamine hydrochloride (2.05g, 29.52 mmol) in 10 ml water was stirred around 50°C for half an hour. To this resulting solution, sodium hydroxide (1.18g, 29.52mmol) was added in portions and stirring was continued at room temperature for another 2 hours (Scheme 1). The creamy white color solid powdered product HON=C(CH₃)C₄H₃O was obtained as precipitate; filtered, washed twice with cold water and dried. Similar procedure was carried out to prepare the compounds HON=C(CH₃)C₄H₃S and HON=C(CH₃)C₅H₄N.

 

Scheme 1: Synthesis of Oxime Ligand

 

Synthesis of [CuCl₂{N(OH)=C(CH₃)C₄H₃O}₂]:

An ethanolic solution of Cupric chloride dihydrate (1.7g, 9.99 mmol) and 1-(furan-2-yl)ethanone oxime (2.5g, 19.98 mmol) was refluxed for an hour (Scheme 2). Contents were cooled; filtered under reduced pressure, washed twice with cold EtOH and dried to obtain pink colored complex [CuCl₂{N(OH)=C(CH₃)C₄H₃O}₂] {2a}; observed melting point 166-168 ⁰C (Yield: 68%).

 

Scheme 2: Synthesis of complex 2a i.e. [CuCl₂{N(OH)=C(CH₃)C₄H₃O}₂]

 

Similar procedure was adopted to synthesize the complexes [NiCl₂{N(OH)=C(CH₃)C₄H₃O}₂] {1a}, [CuCl₂{N(OH)=C(CH₃)C₄H₃S}₂] {2b}, [NiCl₂{N(OH)=C(CH₃)C₄H₃S}₂].H₂O {1b}, [NiCl₂{N(OH)=C(CH₃)C₅H₄N}₂].H₂O {1c} and [CuCl₂{N(OH)=C(CH₃)C₅H₄N}₂].H₂O {2c}.

 

RESULTS AND DISCUSSION:

The reaction of Nickel chloride hexahydrate and Cupric chloride dihydrate with oximato ligands HON=C(CH₃)Ar (Ar = Furan, Thiophene or Pyridine) in 1:2 molar ratio resulted in Copper and Nickel complexes of the type [MCl₂{N(OH)=C(CH₃)Ar}₂] (1a, 2a and 2b) and [MCl₂{N(OH)=C(CH₃)Ar}₂].H₂O (1b, 1c and 2c). All these complexes are active against Candida albicans at analyzed concentrations.

 

All these complexes are colored solids with solubility in non-polar solvents like n-hexane, n-heptane, cyclohexane, DMSO. Table 1 lists the respective color, melting points and elemental analysis of all the synthesized complexes.

 

Table 1: Color, Melting point and Elemental analysis of Complexes Synthesized

S. No.	Complexes	Color	Yield (%)	M. P. (°C)	Elemental Analysis % Observed (Calcd.)
					C	H	N	Cl	M
1	[NiCl2{N(OH)=C(CH3)C4H3O}2] (1a)	Light Blue	71	172-174	37.89 (37.94)	3.73 (3.71)	7.19 (7.37)	18.44 (18.67)	15.61 (15.45)
2	[CuCl2{N(OH)=C(CH3)C4H3O}2] (2a)	Pink	68	166-168	37.44 (37.46)	3.63 (3.67)	7.27 (7.28)	18.51 (18.43)	16.50 (16.52)
3	[NiCl2{N(OH)=C(CH3)C4H3S}2].H2O (1b)	Light Blue	74	190-192	33.79 (33.52)	3.57 (3.75)	6.77 (6.51)	16.67 (16.49)	13.16 (13.65)
4	[CuCl2{N(OH)=C(CH3)C4H3S}2] (2b)	Pink	79	184-186	34.85 (34.58)	3.28 (3.39)	6.88 (6.72)	16.94 (17.01)	15.09 (15.24)
5	[NiCl2{N(OH)=C(CH3)C5H4N}2].H2O (1c)	Light Blue	66	206-208	40.09 (40.04)	4.21 (4.32)	13.39 (13.34)	17.01 (16.89)	14.00 (13.98)
6	[CuCl2{N(OH)=C(CH3)C5H4N}2].H2O (2c)	Dark Pink	72	198-200	39.33 (39.59)	4.38 (4.27)	13.48 (13.19)	16.41 (16.69)	14.65 (14.96)

 

IR Spectra: The IR spectra of all the synthesized complexes have been studied in comparison to that of free ligands. The presence of signal due to υ(OH) in the 3290-3120 cm^-1 region in the spectra of all the complexes implies that deprotonation of oxime O-H bond has not occurred and none of the ligands formed a Metal-Oxygen covalent bond (Table 2). The band observed in free oximes in the range 1690-1640 cm^-1 associated with υ(>C=N) of azomethine group has moved to lower region (1620-1560 cm^-1) in the spectra of the complexes; this has been accounted for a coordinate bond formation through Nitrogen to metal atom³⁹. Further, the υ(C-X) (X = O, S or N) of aromatic ring in spectra of the complexes were observed in the region 1470–1370 cm^-1 in IR spectrum. These values are again comparatively lower than that observed for corresponding oximes⁴² in the region 1490-1405 cm^-1. In the spectra of complexes 1b, 1c and 2c; bands in the region 3390-3350 cm^-1 can be attributed to water molecules⁴³.

 

The bands in the region 600-565 cm^-1 and 490-440 cm^-1 range can be assigned to υ(Ni-N) and υ(Cu-N), respectively. Whereas, appearance of the peaks in the region 1060-960 cm^-1 can be attributed to υ(N-O) in the spectra of complexes.

 

¹H-NMR Spectra:

The appearance of O-H signals in the region 11.83-11.14 ppm in the proton spectra of all the complexes showed that there was no deprotonation of O-H bond during formation of complexes. All the synthesized complexes resembled a high field shift in positions of signals in comparison to parent ligand systems^42,44, suggesting the formation of M←L bond. (Table-3).

 

Antifungal Activity: Antifungal activity of all the synthesized complexes reflected that all the complexes are active against Candida albicans (Table 4, Fig. 1).

 

Table 2: IR spectral data (in cm^-1) for Complexes Synthesized

S. No.	Complexes	υ(O-H), υ(H2O)	υ(C=N)	υ(C-X; aromatic ring)	υ(Ni-N) or υ(Cu-N)	υ(N-O)
1	[NiCl2{N(OH)=C(CH3)C4H3O}2]	3280	1585	1370	590	1005
2	[CuCl2{N(OH)=C(CH3)C4H3O}2]	3245	1610	1415	440	960
3	[NiCl2{N(OH)=C(CH3)C4H3S}2].H2O	3290, 3390	1560	1400	600	1000
4	[CuCl2{N(OH)=C(CH3)C4H3S}2]	3180	1620	1390	490	1060
5	[NiCl2{N(OH)=C(CH3)C5H4N}2].H2O	3150, 3355	1600	1445	565	1050
6	[CuCl2{N(OH)=C(CH3)C5H4N}2].H2O	3120, 3370	1595	1470	480	1045

 

Table 3: ¹H-NMR data for Complexes Synthesized recorded in DMSO-d₆ at 300MHz

S. No.	Complexes	Proton Chemical Shift (in δ ppm)
1	[NiCl2{N(OH)=C(CH3)C4H3O}2]	11.18 (s, 1H), 7.70 (s, 1H), 6.74 (d, J = 3.4 Hz, 1H), 6.54 (s, 1H), 2.06 (s, 3H).
2	[CuCl2{N(OH)=C(CH3)C4H3O}2]	11.44 (s, 1H), 7.98 (s, 1H), 7.12 (d, J = 3.4 Hz, 1H), 6.84 (s, 1H), 2.54 (s, 3H).
3	[NiCl2{N(OH)=C(CH3)C4H3S}2].H2O	11.14 (s, 1H), 7.72 (s, 1H), 7.31 (d, J = 3.8 Hz, 1H), 7.08 – 7.00 (m, 1H), 2.14 (s, 3H).
4	[CuCl2{N(OH)=C(CH3)C4H3S}2]	11.49 (s, 1H), 8.01 (s, 1H), 7.73 (d, J = 3.8 Hz, 1H), 7.37 – 7.27 (m, 1H), 2.66 (s, 3H).
5	[NiCl2{N(OH)=C(CH3)C5H4N}2].H2O	11.50 (s, 1H), 8.58 (s, 1H), 7.82 (dd, J = 16.3, 7.7 Hz, 2H), 7.36 (s, 1H), 2.21 (s, 3H)
6	[CuCl2{N(OH)=C(CH3)C5H4N}2].H2O	11.83 (s, 1H), 8.69 (s, 1H), 8.09 (dd, J = 16.3, 7.7 Hz, 2H), 7.60 (s, 1H), 2.78 (s, 3H)

 

Table 4: Antifungal activity of Complexes Synthesized

S. No.	Complexes	Pathogen	Positive Control	Negative Control	At conc. 10 mg/ml	At conc. 5 mg/ml
1	[NiCl2{N(OH)=C(CH3)C4H3O}2]	Candida albicans	18mm	10mm	30mm	25mm
2	[CuCl2{N(OH)=C(CH3)C4H3O}2]				30mm	23mm
3	[NiCl2{N(OH)=C(CH3)C4H3S}2].H2O				30mm	22mm
4	[CuCl2{N(OH)=C(CH3)C4H3S}2]				37mm	30mm
5	[NiCl2{N(OH)=C(CH3)C5H4N}2].H2O				27mm	22mm
6	[CuCl2{N(OH)=C(CH3)C5H4N}2].H2O				17mm	13mm

 

Fig. 1: Antifungal activity of Synthesized Complexes (Y-axis: Activity values expressed in “mm”, as listed in Table 4)

The in vitro analysis was carried out on Candida albicans swabbed onto Sabouraud’s Dextrose Agar surface as a Muller Hinton Agar medium, by means of Kirby-Bauer well diffusion method⁴⁵. The antifungal plates were kept in incubation at 28°C for 48 hours. Two concentrations of the test compounds of the stock solution (10 mg/ml and 5 mg/ml) were prepared and 100μl was used in each well using DMSO as solvent (Fig. 2). Itraconazole was taken into consideration as a positive control (PC) at a concentration of 50 μg/ml and DMSO as negative control (NC).

 

24 Hours grown culture of Candida albicans on MH agar plate

 

Gram positive oval cells Magnification: 1500X

 

Anticandidaal activity of complex  [CuCl₂{N(OH)=C(CH₃)C₄H₃O}₂] at 2 different concentration , where PC is Itraconazone and   NC  is  DMSO

 

Fig. 2: Anticandidal activity of [CuCl₂{N(OH)=C(CH₃)C₄H₃O}₂]

 

CONCLUSION:

The elemental analysis and spectral studies have suggested that the geometries of these complexes are expected to be octahedral or distorted octahedral and they can be generally represented as [MCl₂L₂] and [MCl₂L₂].H₂O (where M = Ni/Cu, L = corresponding oxime). The in-vitro Antifungal activity of all these complexes reflects that they are all active against Candida albicans.

 

ACKNOWLEDGEMENT:

Keeping in view the current pandemic situation; authors would like to acknowledge services of MNIT, Jaipur for spectral characterization and Dr. B. Lal Clinical Laboratory Pvt. Ltd. - CIRD, Jaipur for in-vitro experiments.

 

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Accepted on 10.04.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(1):24-28.