Spectroanalytical, In vitro Anticancer and Antibacterial studies ...

Research Journal of Chemistry and Environment____________________________________Vol. 26 (2) February (2022) Res. J. Chem. Environ.

67

Spectroanalytical, In vitro Anticancer and Antibacterial studies of Novel substituted Heterocyclic Pyridine

derivatives and its metal complexes Chaitanya Kumar B.R., Sudhakar Babu K.* and Krishna Murthy Naik V.

Department of Chemistry, Sri Krishnadevaraya University, Ananthapuramu- 515 003, A.P, INDIA

*[email protected]

Abstract The metal complexes of pyridine derivative ligand 2-

((E)-2-(1-(4-methylpyridin-2-yl)ethylidene)hydrazinyl)

-4-methyl-6-phenylpyridine-3-carbonitrile (MPHPC)

derived from 2-hydrazinyl-4-methyl-6-phenylpyridine-

3-carbonitrile and 1-(4-methylpyridin-2-yl)ethanone

with metals [Co, Ni and Cu] have been synthesized and

characterized with different spectral investigations

viz.UV-Vis, FT-IR, 1H-NMR and ESR. The ligand and

metal complexes were screened for in vitro cytotoxicity

studies against two carcinoma cell lines A549 (Lung

carcinoma cells) and HepG2 (Hepatocellular

carcinoma cell).

The results were found to possess cytotoxic effect. The

ligand and metal complexes were screened for in vitro

antibacterial activities against for pathogenic bacterial

strains such as gram –ve bacteria like Pseudomonas

desmolyticum, Escherichia coli and Klebsiella

aerogenes as well as gram +ve bacteria like

Staphylococcus aureus. The antibacterial studies were

determined by agar well diffusion method using DMSO

as negative control and Ciprofloxacin as positive

control. Cobalt and nickel complexes show a moderate

sensitivity whereas copper complex has significant

activity at higher doses.

Keywords: Tranisition metals, pyridine derivative,

cytotoxicity, MTT assay, antibacterial activity.

Introduction A vast number of heterocyclic compounds having pyridine

rings have been linked to a variety of pharmacological

effects including antimycobacterial29, antiviral16,17,

antileishmanial32, antimicrobial45 and anti-HIV14, Pyridine

derivatives have been produced and employed as

intermediates with the parent molecule 2-chloropyridine-3-

carboxylic acid and they display antifungal and anticancer

properties. Recent synthetic methods to anticancer13,25

medicines have shown that N-alkylated 2-pyridones are key

intermediates in the production of polycyclic molecules of

biological significance.

New pyridine derivatives have been synthesized, resulting in

fascinating heterocyclic scaffolds that can be used to build

various chemical libraries of drug-like compounds for

biological screening. In the recent literature, Terpyridine

derivatives showed promising cytotoxicity activities with

A549, MCF7 and A2780 cell lines30. Importance of some of

the pyridine derivatives (pyridine-2-carboxamidrazone)

importance in terms of antimycobacterial activity of a

number of derivatives has previously been described6,37.

Transition metal complexes offer a wide range of uses

including anticancer8, antibacterial44 and antifungal36

applications in the biological sector. Though organic

compounds have pharmaceutical effects, a prime asset of

metal based drugs over organic drugs is to alter coordination

number, geometry and redox states. Metals can also interfere

with the pharmacological properties of organic-based drugs

by forming coordination bonds with them. As a result, the

transition metal nucleus is present as a key structural

component in a drug array. However, these compounds have

recently received attention due to their antibacterial

capabilities.

French et al18,19 linked their anticancer action to their ability

to function as tridentate ligands and a variety of transition

metal complexes. Cobalt, nickel and copper have been found

to be relatively non-toxic essential trace elements in human

metabolism and cobalt is a major component in vitamin B12

and other co-enzymes7,28,31,41. Most of the copper and nickel

based complexes have been investigated on the assumption

that endogenous metal ions may be less toxic for normal

cells than cancer cells1,35. Copper complexes with

terpyridine and other derivatives have recently been found

to have antibacterial activity against breast cancer cell lines

MCF-7, normal breast cancer cell line MCF-10A and

cervical cancer cell line HeLa9. Cobalt containing complexes

also act as anticancer drugs9.

Several nitrogen-containing heterocyclic systems exhibit a

wide range of therapeutic activities that is why a recent study

on the synthesis of new heterocycles of 2-hydrazinyl-4-

methyl-6-phenylpyridine-3-carbonitrile condensed with 1-

(4-methylpyridin-2-yl)ethanone was undertaken. This can

result in the development of new biologically active

compounds. We designed and synthesized new pyridine

derivatives as well as their transition metal complexes with

Co, Ni and Cu. These compounds were characterized using

various techniques and they were then tested for cytotoxicity

and antibacterial activity.

Material and Methods Materials: Benzoyl acetone, phosphoryl chloride, sodium

ethoxide, triethylamine, hydrazine monohydrochloride,

cyanoacetamide,1-(4-methylpyridin-2-yl)ethanone, nickel


68

(II) chloride, cobalt(II) chloride and copper(II) chloride were

purchased from Sigma Aldrich. All the other chemicals and

solvents were of analytical reagent grade and purchased

from a commercial source.

Physical measurements: The elemental analysis (C, H and

N) was performed on a Perkin Elmer 2400 CHN analyzer.

Melting points were determined in open capillaries using a

G LAB melting apparatus and were reported uncorrected.

UV-visble spectra of DMF solutions were recorded on a UV-

210 ELICO spectrometer in the spectral window of 200-800

nm. Infrared spectra (FT-IR) were recorder using a Bruker

FT/IR vector 22 spectrometer in the form of KBr

pellets. Proton NMR was recorded in solution state with

AVANCE III 500 NMR spectrometer.

Synthesis of ligand: 2-hydrazinyl-4-methyl-6-

phenylpyridine-3-carbonitrile synthesized earlier as reported

by Rahman37 was dissolved in 20 mL methanol. Add 1-(4-

methylpyridin-2-yl)ethanone 1 mL (0.01 mmol) in hot 10

mL methanolic solution with addition of few drops of

concentrated hydrochloric acid. The reaction mixture was

placed in a round bottom flask and allowed to reflux for two

hours. The light brown solid precipitate generated when the

reaction mixture and was cooled to room temperature was

collected by filtration and the solid product was washed with

MeOH and dried under vacuum.

Molecular formulae of ligand is C21H19N5; Yield: 73.82%;

m.p. 170-172oC; IR cm-1: 3380 (NH), 2250(C≡N),

1615(C=N), 1030(aromatic C-H). 1H-NMR: δ 2.34 (s,3H

CH3), 2.43(s,3H,CH3), 2.47(s,3H,CH3), 6.71(s,1H Py-H),

7.33-7.80(m,5H.Ar-H), 8.32(d,1H,Py-H), 8.52(s,1H,Py-H),

9.28(d,1H,Py-H); MS m/z(%): 341.21; The ligand is

synthesized as illustrated in scheme 1 and 2. Mass spectrum

of MPHPC ligand is shown in the figure 1.

C6H5

O

CH3

O

+

CN

CH2CONH2

NaOEt

NH

CH3

CN

OC6H5

POCl3

T.E.A

N

CH3

CN

ClC6H5

NH2-NH2

N

CH3

CN

NHNH2C6H5

1 2 3

452-hydrazinyl-4-methyl-6-phenylpyridine-3-carbonitrile

Scheme 1: Synthesis of 2-hydrazinyl-4-methyl-6-phenylpyridine-3-carbonitrile

N

CH3

CN

NHNH2C6H5 N

CH3

CH3

O

N

CH3

CN

NC6H5

N

CN CH3

CH3

2-hydrazinyl-4-methyl-6-phenylpyridine-3-carbonitrile

H

Conc HCl

1-(4-methylpyridin-2-yl)ethanone

2-((E)-2-(1-(4-methylpyridin-2-yl)ethylidene)hydrazinyl)-4-methyl-6-phenylpyridine-3-

carbonitrile(MPHPC)

Scheme 2: synthesis of 2-((E)-2-(1-(4-methylpyridin-2-yl)ethylidene)hydrazinyl)-4-methyl-6-phenylpyridine-3-

carbonitrile (MPHPC)


69

Figure 1: Mass spectrum of MPHPC ligand

MCl2.XH2O MPHPC M(MPHPC)2Cl2

M= Co, Ni and Cu

NaOH

complexmetal salt ligand

Scheme 3: Synthesis of metal complexes.

General procedures for the synthesis of complexes: A hot

methanolic solution (20 mL) of ligand mixture (3.52g 0.1

mol) was added to a solution of metal chlorides (M= Co, Ni

and Cu) (0.05 mol) in H2O (50 mL) with addition of 2 ml of

1M NaOH solution.

The resulting colourless solution was refluxed for 2 h and

then allowed to gently concentrate by evaporation at room

temperature for a period of time resulting in a solid substance

that was washed with a tiny amount of MeOH and dried in

the air. Synthesis of metal complex was given in scheme 3.

The ESI-Mass spectrum of [Cu (MPHPC)2Cl2] was shown

in figure 2.

Determination of cytotoxicity: Cell lines were grown in the

presence of the following Dulbeccos Modified Eagles

Medium (DMEM) with supplemented foetal bovine serum

and antibiotics for 24 hours at 370C in a humidified

atmosphere of 5% CO2. The cells were planted at a density

of 25 x 103 cells per well in 96 well plates. The cytotoxicity

of varied concentrations of metal complexes (25, 50, 100,

200 and 400 µg/mL) against human cancer cell lines was

examined in MTT assay. MTT is a yellow dye that is reduced

into purple crystals in the presence of activity in the

mitochondrial succinate dehydrogenase enzyme in viable

cells. The IC50 value was determined after a statistical

analysis of the cytotoxicity of metal complexes against

cancer lines in the presence of MTT.

Antibacterial activity: The antibacterial activity of metal

complexes against different pathogenic bacterial strains both

gram –ve bacteria Pseudomonas desmolyticum [NCIM-

2028], Escherichia coli [NCIM-5051] and Klebsiella aerogenes [NCIM-2098] and gram +ve Staphylococcus

aureus [NCIM-5022] strains (Purchased from National

centre for cell science, Pune, India) was analyzed by agar


70

well diffusion method. Different concentration of metal

complexes (100, 200, 300 and 400 µg/mL) were dispersed

in 10% DMSO solution and standard antibiotic ciprofloxacin

was used as a positive control into the wells. The plates were

incubated for 24 hours at 37°C.

Following the incubation period, the zone of inhibition

around the wells was measured in millimetres. The

antibacterial bacterial activity was determined in triplicate

preceded by the bactericidal activity of metal complexes.

Results and Discussion MPHPC, a newly synthesized Schiff base ligand and its

complexes 1– 4 were found to be very stable at room

temperature. In DMF, they were soluble.

Elemental analysis values were in good agreement for

complexes with a ratio of 1:2. All of them were neutral and

non-conducting compounds (Λm = 31.17–37.78

Ω−1cm2mol−1)21. Physico-chemical and analytical data of

ligand and its metal complexes was given in table 1.

Figure 2: ESI-Mass spectrum of [Cu (MPHPC)2 Cl2] Complex

Table 1

Physicochemical and analytical data of ligand and their metal complexes

S. N. Compound Molecular

Weight

Found

(Calculated)

Melting

point

(0C)

Colour

Yield (%)

Elemental analysis

Found (calculated)

Molar

conductivity

C(%) H(%) N(%)

1

MPHPC

341.21

(341.40)

170-172 LightBrown

(73.82)

73.92

(73.87)

5.61

(5.60)

20.52

(20.51)

-

2

[Co(MPHPC)2Cl2]

835.02

(834.59)

Above

290

DarkGreen

(81.81)

60.40

(60.43)

4.58

(4.58)

16.77

(16.78)

36.94

3

[Ni(MPHPC)2Cl2]

834.42

(834.35)

Above

290

Black

(75.70)

60.44

(60.45)

4.58

(4.58)

16.78

(16.78)

31.17

4

[Cu(MPHPC)2Cl2]

839.78

(839.20)

Above

290

DarkBrown

(67.12)

60.06

(60.10)

4.56

(4.56)

16.67

(16.68)

37.78


71

Electronic spectral bands: The Cu complex gives

absorption band at 19,011 cm-1 which is assignable to d-d

charge transitions having the distorted octahedral structure.

In the electronic spectra of Co complex, the two absorption

bands were observed at 16,891 cm-1 and 28,985 cm-1 due to

d-d transitions and charge transitions respectively. These

transitions suggest octahedral geometry for Co complex. Ni

complexes exhibit two bands at 28,571 cm-1 and 35,714 cm-

1 due to π-→π* and charge transitions respectively and are

in confirmatory with the octahedral geometry for the Ni

ion5,11,27,34,38,42.

IR spectral bands: One of the most extensively used

instruments for detecting functional groups in pure

compounds and mixtures, as well as the type of atom binding

in metal complexes is infrared spectroscopy. IR spectral data

of the ligand [MPHPC] and its metal complexes are shown

in table 3. A medium intensity band is around 3380 cm-1 due

to ν (N-H). These observations suggest the non-involvement

of atom N-H in coordination. The IR spectrum of the ligand

displays at 1615 cm-1 which may be assigned due to the ν

(C=N) azomethine. When compared to complex, this band

remains same which indicates that there is no involvement

(C=N) bond in the complex formation. The participation of

nitrogen in coordination with the metal ion is further

supported by the new band appearance of ν (M-N) at 532-

556 cm-1 respectively in the infrared region4,20,23,40.

ESR analysis of copper complexes: The ESR spectrum of

coppercomplex was recorded in DMF at 300 and 77 K

(figure 3) and the spin Halmiltonian parameters of the

complexes are listed in table 4. The observed spectral

parameters reveal that g║ > g┴ is characteristic of an axially

elongated octahedral geometry. The gavg value is less than

2.28 indicating the covalent character of the metal-ligand

bond. Further, it is supported from the fact that the unpaired

electrons lies predominantly in the dx2-y2 orbital. The

observed value of G for copper complex is 2.62 which

characteristic of mono nuclear configuration which also

suggests that the exchange coupling is present and

misalignment is appreciable. The α2 value (0.78) points out

appreciable in-plane covalency.

gavg=[g║+2g┴]

3

G=[g║−2.0023]

[g┴−2.0023]

The calculated value of g║/A║ for the coppercomplex

reveals slightly distorted structure. The orbital reduction

factors such as K║ and K┴ are estimated from the equation.

K║ (0.141) > K┴ (0.262) indicates poor in-plane π

bonding2,10,24,43,46. Orbital reduction parameters (K║ & K┴)

and bonding parameters were calculated by the following

formulae.

K║2 =

(g║−2.0023)

8x𝜆0 X d-d transition

K┴2 =

(g┴−2.0023)

8x λ0 X d-d transition

α2 = −A║/ p + (g|| - 2.0023) +3/7(g┴ − 2.0023) + 0.04

It has an octahedral geometry, according to the physico-

chemical and spectral data shown in figure 4.

Table 2

UV-Visible spectra of metal complexes with MPHPC ligand

S.N. Complex Wavelength

λ max (nm)

Frequency

(cm-1)

Assignment

1

[Co(MPHPC)2Cl2]

345 28,985 CT transition

592 16,891 d-d transition

2

[Ni(MPHPC)2Cl2]

280 35,714 π-→π* transition


3

[Cu(MPHPC)2Cl2]


526 19,011 d-d transition

Table 3

IR data of Ligand (MPHPC) and their metal complexes

MPHPC [Co(MPHPC)2Cl2] [Ni(MPHPC)2Cl2] [Cu(MPHPC)2Cl2] Assignment

3380 3360 3365 3368 N-H

2250 2210 2215 2230 CN

1615 1612 1609 1610 C==N

1030 983 995 973 Aromatic CH

543 532 556 M-N


72

Table 4

ESR spectral data of Copper Complex

Complex

g||

g┴,

gavg

G

A║ x 10-5

A┴ x 10-5

K║

K┴

λ

α

[Cu(MPHPC)2Cl2]

(RT)

2.09 2.05 2.06 1.83 - - - - - -

[Cu(MPHPC)2Cl2]

(LNT)

2.08 2.03 2.02 2.62 0.0273 0.0297 0.141 0.262 606 0.7899

*RT=Room Temperature; LNT= Liquid Nitrogen temperature

250 300 350

-4000

-3000

-2000

-1000

0

1000

2000

Inte

nsi

ty

Field strength(mT)

250 300 350

-2000

-1500

-1000

-500

0

500

1000

Inte

nsity

Field strength (mT)

(a) (b)

Figure 3: ESR spectra of Copper complex recorded at (a) LNT and (b) RT

N

CH3

CN

N

C6H5

N

C

N

CH3

CH3

H

N

H3C

NC

N

C6H5

N

C

N

H3C

H3C

H

M

Cl

Cl

M= Co, Ni and Cu

Figure 4: Proposed structure of metal complexes.

Cytotoxicity: On the basis of in vitro analysis, the

cytotoxicity of synthesized ligands and metal complexes

against A549 and HepG2 cell line cancer cells was assessed.

The ligand and metal complexes were tested against cell

lines with Cis-platin as the positive control. These were

shown in tables 5 and 6. Increasing the concentration of

metal complexes causes a decrease in the cell viability

showing significant cytotoxicity to accumulate internal cells

and higher stress, eventually leading to cell death3,15,22. Even

though the concentrations were increased, the ligand alone

had little effect. The activity increased dramatically as the

quantities of metal complexes increased. Nickel complex

had the most activity for A549 cell lines whereas for HepG2

cell line, cobalt complex had the most. The cytotoxicity of

all the metal complexes is shown in figure 5 and 6.


73

Table 5

Cytotoxicity of Ligand and metal complexes with Lung cancer cell lines A549

A549 cell line

Concentrations (µg/mL)

25 50 100 200 400 IC50

Standard (Cis-Platin) 49.09 - - - - -

MPHPC 97.86 95.43 91.78 87.54 84.26 -

[Co(MPHPC)2Cl2] 95.64 83.32 69.98 56.64 48.78 365

[Ni(MPHPC)2Cl2] 94.72 80.31 65.26 54.32 44.23 286

[Cu(MPHPC)2Cl2] 96.34 85.52 79.96 60.82 49.64 381

0 50 100 150 200 250 300 350 400 450

40

50

60

70

80

90

100

% C

ontr

ol g

row

th

Drug concentration (mg/mL)

MPHPC

[Co(MPHPC)2Cl2]

[Ni(MPHPC)2Cl2]

[Cu(MPHPC)2Cl2]

a) A549 cell line

Figure 5: Graphical representation of metal complexes with cytotoxicity effect on A549 cell lines

Table 6

Cytotoxicity of Ligand and metal complexes with Lung cancer cell lines HepG2

HepG2 cell line

Concentrations (µg/mL)

25 50 100 200 400 IC50

Standard (Cis-Platin) 54.48 - - - - -

MPHPC 96.78 94.23 90.68 86.82 84.36 -

[Co(MPHPC)2Cl2] 96.31 82.52 68.64 54.87 46.32 320

[Ni(MPHPC)2Cl2] 95.82 80.41 70.56 55.32 48.68 361

[Cu(MPHPC)2Cl2] 96.34 85.52 74.21 58.79 47.44 355

0 50 100 150 200 250 300 350 400 450

40

50

60

70

80

90

100

% C

ontr

ol g

row

th

Drug concentration(mg/mL)

MPHPC

[Co(MPHPC)2Cl2]

[Ni(MPHPC)2Cl2]

[Cu(MPHPC)2Cl2]

b) HepG2 cell line

Figure 6: Graphical representation of metal complexes with cytotoxicity effect on HepG2 cell lines


74

Antibacterial activity: The antibacterial activity of the

ligand MPHPC and its metal complexes was investigated.

The zone of inhibition was measured in millimetres and the

values of the substances studied are listed in table 7. It is

clear from the results that the metal complexes have greater

antibacterial action than the free ligand MPHPC. The

increased activity of metal complexes can be explained using

Overton's concept and Chelation theory12,33,26,39.

One possible explanation for the observed increased activity

after chelation is that the positive charge of the metal in the

chelated complex is partially shared with the ligand donor

atoms, resulting in electron delocalization throughout the

chelate ring.

This, in turn, increases the lipophilicity of the metal chelate

and facilitates its permeation through the lipoid layers of

bacterial membranes. Antibacterial activities of the ligand

and their complexes at various concentrations with different

pathogenic strains were given in figure 7. Copper complexes

have significant antibacterial activity when compared to

other metal complexes.

Table 7

Antibacterial activity of Ligand and Metal complexes with different pathogenic strains

Treatment Bacterial Strains

Sample Concentration

(µg/mL)

S. aureus E. coli P. desmolyticum K. aerogenes

Ciprofloxacin 10 14.10 11.45 11.52 12.06

MPHPC 100 0.95 1.06 0.89 0.97

[Co(MPHPC)2Cl2]

100 2.34 2.26 2.14 2.28

200 3.54 3.32 3.36 3.46

300 3.82 3.76 3.62 3.85

400 4.06 3.92 3.96 4.02

[Ni(MPHPC)2Cl2]

100 2.48 2.24 2.28 2.36

200 3.46 3.28 3.30 3.32

300 3.78 3.56 3.65 3.68

400 4.02 3.82 3.94 4.18

[Cu(MPHPC)2Cl2]

100 2.92 2.56 2.64 2.87

200 4.22 3.94 4.14 4.16

300 6.24 5.82 5.88 5.92

400 9.05 8.82 8.86 8.94

Figure 7: Antibacterial activity at various concentrations of the Ligand and their complexes with different

pathogenic strains.


75

Conclusion A new pyridine derivative of the ligand [MPHPC] and their

transition metal complexes (where M = Cu, Co and Ni, have

been synthesized and characterized. Elemental, conductivity

and mass spectrometry analyses revealed the complexes

stoichiometry and composition. The bonding properties of

the above ligand and metal complexes were confirmed by

FT-IR, UV-Vis, 1H NMR and ESR spectral data. Based on

the findings of copper complex, ESR parameters suggest that

the complex has an octahedral geometry. The decrease in

cell viability associated with increasing metal complex

concentrations has resulted in considerable cytotoxicity,

resulting in the accumulation of internal cells and increased

stress, finally leading to apoptosis.

Metal complexes have high cytotoxicity than free ligand.

Nickel complexes had the highest activity for A549 cells

where as for HepG2 cells, all complexes have nearly the

same activity. The antibacterial activity of the ligand

(MPHPC) and its metal complexes in vitro suggests that the

complexes are more effective than the free ligand. When

compared to other metal complexes, copper complex has the

most antibacterial action.

Acknowledgement Authors are thankful to National Centre for Cell Science,

Pune for providing Cancer Cell lines and SAIF centres KUD,

Dharwad and IIT Bombay for providing instrument facility

for ESR, NMR and Mass analysis. The authors are also

thankful to G. John, MAHE, Manipal University for his

cooperation in my research work.

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(Received 28th September 2021, accepted 02nd December

2021)

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