Accepted Manuscript

Synthetic bioactive novel ether based Schiff bases and their copper(II) complexes

Muhammad Shabbir, Zareen Akhter, Hammad Ismail, Bushra Mirza

PII: S0022-2860(17)30746-9
DOI: 10.1016/j.molstruc.2017.05.127
Reference: MOLSTR 23868

To appear in: Journal of Molecular Structure

Received Date: 17 March 2017

Revised Date: 25 May 2017
Accepted Date: 27 May 2017

Please cite this article as: M. Shabbir, Z. Akhter, H. Ismail, B. Mirza, Synthetic bioactive novel ether
based Schiff bases and their copper(II) complexes, Journal of Molecular Structure (2017), doi: 10.1016/
j.molstruc.2017.05.127.

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 ACCEPTED MANUSCRIPT

Cl

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Cl
R N
R N C OH
H Cu
O

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R N
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HC
Cl

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 ACCEPTED MANUSCRIPT

Synthetic bioactive novel ether based Schiff bases and their copper(II)
complexes
Muhammad Shabbira, Zareen Akhtera*, Hammad Ismailb, Bushra Mirzac
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Department of Chemistry, Quaid-i-Azam University, Islamabad-45320. Pakistan.
b

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Department of Biochemistry & Biotechnology, University of Gujrat, 50700 Gujrat, Pakistan.
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Department of Biochemistry, Quaid-i-Azam University, Islamabad-45320. Pakistan.

*Corresponding author

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Telephone +92 051 90642111; fax: +92 051 9064224
E-mail address: zareenakhter@yahoo.com, zareen_a@qau.edu.pk

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Abstract

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Novel ether based Schiff bases (HL1- HL4) were synthesised from 5-chloro-2-hydroxy
benzaldehyde and primary amines (1-amino-4-phenoxybenzene, 4-(4-aminophenyloxy)
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biphenyl, 1-(4-aminophenoxy) naphthalene and 2-(4-aminophenoxy) naphthalene).From these
Schiff bases copper(II) complexes (Cu(L1)2-Cu(L4)2)) were synthesized and characterized by
elemental analysis and spectroscopic (FTIR, NMR) techniques. The synthesized Schiff bases and
copper(II) complexes were further assessed for various biological studies. In brine shrimp assay
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the copper(II) complexes revealed 4-fold higher activity (LD50 3.8µg/ml) as compared with
simple ligands (LD50 12.4µg/ml). Similar findings were observed in potato disc antitumor assay
with higher activities for copper(II) complexes (IC50 range 20.4-24.1µg/ml) than ligands (IC50
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range 40.5-48.3µg/ml). DPPH assay was performed to determine the antioxidant potential of the
compounds. Significant antioxidant activity was shown by the copper(II) complexes whereas
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simple ligands have shown no activity. In DNA protection assay significant protection behavior
was exhibited by simple ligand molecules while copper(II) complexes showed neutral behavior
(neither protective nor damaging).
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Keywords: Schiff bases, Copper(II) complexes, Biological studies

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1. Introduction

Schiff bases-an important class of ligands and their metal complexes had a variety of
applications including biological, clinical, analytical and industrial in addition to their important
roles in catalysis and organic synthesis [1, 2].Schiff bases play an important role in inorganic
chemistry as they easily form stable complexes with most transition metal ions. The development
of the field of bioinorganic chemistry has increased the interest in Schiff base complexes, since it

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has been recognized that many of these complexes may serve as models for biologically
important species. Various transition metal complexes with bi, tri and tetradentate Schiff bases
containing nitrogen and oxygen donor atoms play an important role in biological systems

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because they possess unusual configuration, structural lability and are sensitive to molecular
environment [3, 4]. Schiff base ligands are able to coordinate with different metals thus
stabilizing them in various oxidation states. Due to imine, hydroxyl and various other groups

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Schiff base complexes possess elevated position in biological fields [5, 6]. Ligands derived from
substituted salicylaldimine have played an important part in revealing the preferred coordination
geometries of metal complexes. Particularly copper(II) complexes reveal surprising molecular
diversity not only in coordination geometry but also in more subtle changes in the ligands. Schiff

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bases can form a new class of drugs through mechanisms of immune potentiation and therapeutic
potential. The complex combination of Schiff bases with metallic ions represents a class of
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compounds with the most interesting properties, both from the point of view of chemical and
biological behavior. The literature data quotes the antimicrobial, anti-inflammatory and
antioxidant action of the complex combinations of Schiff bases with different cations [7, 8].It is
well known that some drugs have greater activity when administered as metal complexes than as
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free organic compounds [9].

In continuation of our work on Schiff bases and their copper(II) complexes[10,11 ] present work
deals with the synthesis and characterization of another series of Schiff base ligands (E)-4-
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chloro-((4-phenoxyphenylimino)methyl)phenol (HL1), (E)-4-chloro-2-((4-(4-

biphenyloxy)phenylimino)methyl)phenol (HL2), (E)-4-chloro-2-((4-(naphthalen-1-
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yloxy)phenylimino)methyl)phenol(HL3),(E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)
methyl)phenol(HL4),copper(II) complexes Bis((E)-4-chloro-((4-
phenoxyphenylimino)methyl)phenolate)copper(II) Cu(L1)2, Bis((E)-4-chloro-2-((4-(4-
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biphenyloxy)phenylimino)methyl)phenolate)copper Cu(L2)2, Bis((E)-4-chloro-2-((4-

(naphthalen-1-yloxy)phenylimino)methyl)phenolate)copper(II) Cu(L3)2 and Bis((E)-4-chloro-2-
((4-(2-naphthoxy)phenylimino)methyl)phenolate)copper(II)Cu(L4)2. As the synthesized ligands
and their copper(II) complexes are novel and so far no work has been carried out about their
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pharmacological worth, therefore biological studies (cytotoxic, antitumor and inhibition of

hydroxyl (OH) free radical induced DNA damage assay) were worked up to assess their
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bioactive nature.

2. Experimental

2.1. Materials and methods

Standard distillation procedure and drying methods were used to purify the solvents [12]. 5-
chloro-2-hydroxy benzaldehyde was purchased from fluka and used as such. Melting points of
the compounds were determined, on MPD Mitamura Riken Kogyo (Japan) electrothermal

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apparatus. CHNS 932 (Leco-USA) elemental analyzer was used for elemental analysis. Infrared
measurements (4000-400 cm-1) were recorded on a Thermoscientific (USA) Nicolet 6700
spectrometer. NMR spectra of Schiff bases (1H & 13C) were recorded in solution on Bruker ARX
300 MHz using tetramethylsilane (TMS) as internal reference.
The methodology adopted for biological assays has already been reported in our earlier reports
[10, 11, 13, 14].

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2.2 General procedure for the synthesis of Schiff bases (HL1- HL4) and copper(II) complexes
(Cu(L1)2-Cu(L4)2)

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Schiff bases (HL1-HL4) were prepared by condensation reactions of 5-chloro-2-hydroxy
benzaldehyde and aromatic amines [15]. These Schiff bases were then used to prepare copper
(II) complexes (Cu(L1)2-Cu(L4)2) from copper acetate by the same general synthetic procedure as

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reported earlier by our research group [10,11](schemes 1&2).

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Scheme1: Synthesis of Schiff bases (HL1-HL4)

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Scheme2: Synthesis of Copper (II) complexes (Cu(L1)2-Cu(L4)2)
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2.2.1. (E)-4-chloro-((4-phenoxyphenylimino)methyl)phenol (HL1)

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(E)-4-chloro-((4-phenoxyphenylimino)methyl)phenol (HL1) was synthesized by refluxing

equimolar amounts of 1-amino-4-phenoxybenzene 1.85 g (10 mmol) and 1.58 g (10 mmol) 5-
chloro-2-hydroxy benzaldehyde.
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Yield 89%, M.P.156 °C. FTIR: ( υ /cm-1) 2742 (−OH), 1610 (-CH=N), 1H NMR (300 MHz,
CDCl3, δ ppm): 13.23 (s, 1H, -OH) 8.58 (s, 1H, -CH=N), 7.42-6.98 (12H, m, Ar- H), 13C NMR
(75 MHz ,CDCl3, δ ppm): 160.12 (-C=N), 159.59-118.81 (18C, Ar-C), CHN found (calcd.) for
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C19H14NO2Cl : C: 70.46 (70.48), H: 4.32 (4.33), N: 4.30 (4.27).

2.2.2. (E)-4-chloro-2-((4-(4-biphenyloxy)phenylimino)methyl)phenol(HL2)
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(E)-4-chloro-2-((4-(4-biphenyloxy)phenylimino)methyl)phenol (HL2) was synthesized by

heating equimolar amounts of 4-4(aminophenyloxy)biphenyl 2.61 g (10 mmol) and 1.58 g (10
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mmol) 5-chloro-2-hydroxy benzaldehyde.

Yield 93%, M.P.171 °C. FTIR: ( υ /cm-1) 2708 (−OH), 1608 (-CH=N), 1H NMR (300 MHz,
CDCl3, δ ppm): 13.30, (s, 1H, -OH), 8.59 (s, 1H, -CH=N), 7.62-6.99 (16H, m, Ar- H), 13C NMR
(75 MHz, CDCl3, δ ppm): 160.11 (-C=N), 158.92-117.52 (24C, Ar-C), CHN found (calcd.) for
C19H18NO2Cl : C: 75.07 (75.09), H: 4.52 (4.50), N: 4.51 (3.50).

2.2.3. (E)-4-chloro-2-((4-(naphthalen-1-yloxy)phenylimino)methyl)phenol(HL3)

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(E)-4-chloro-2-((4-(naphthalen-1-yloxy)phenylimino)methyl)phenol (HL3)was prepared by

taking equimolar amounts of 1-(4-aminophenoxy)naphthalene 2.35 g (10mmol) and 1.58 g (10
mmol) 5-chloro-2-hydroxy benzaldehyde.
Yield 83%, M.P.167 °C. FTIR :( υ /cm-1) 2773 (-OH), 1617 (-CH=N), 1H NMR (300 MHz
,CDCl3, δ ppm): 13.32 (s, 1H, -OH), 8.57 (s, 1H, -CH=N), 8.23-6.98 (14H, m, Ar- H), 13C NMR
(75 MHz ,CDCl3, δ ppm): 163.41 (-C=N), 157.54-114.08 (22C, Ar-C), CHN found (calcd.) for
C23H16NO2Cl : C: 73.84 (73.89), H: 4.30 (4.28), N: 3.72 (3.75).

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2.2.4. (E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)methyl)phenol (HL4)

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(E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)methyl)phenol (HL4)was prepared by mixing
equimolar amounts of 2-(4-aminophenoxy)naphthalene 2.35 g (10 mmol) and 1.58 g (10 mmol)
5-chloro-2-hydroxy benzaldehyde.

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Yield 87%, M.P.155 °C. FTIR :( υ /cm-1) 2746 (-OH), 1620 (-CH=N),1H NMR (300 MHz
,CDCl3, δ ppm): 13.28, (s, 1H, -OH), 8.85 (s, 1H, -CH=N), 8.12-6.85 (14H, m, Ar- H), 13C NMR
(75 MHz ,CDCl3, δ ppm): 162.07 (-C=N), 159.35-118.81 (22C, Ar-C), CHN found (calcd.) for
C23H16NO2Cl : C: 73.99 (73.98), H: 4.53 (4.50), N: 3.72 (3.75).

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2.2.5. Bis((E)-4-chloro-((4-phenoxyphenylimino)methyl)phenolate)copper(II) Cu(L1)2
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Bis((E)-4-chloro-((4-phenoxyphenylimino)methyl)phenolate)copper(II) Cu(L1)2 was prepared by
taking 0.182 g (1 mmol) anhydrous copper (II) acetate and 0.65 g (2 mmol) of (E)-4-chloro-((4-
phenoxyphenylimino)methyl)phenol.
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Yield: 61%, melting point.233 °C FTIR (υ/cm-1): 1595 (-C=N), 525 (Cu-O), 410 (Cu-N), CHN
found (calcd) for C38H26N2O4ClCu: C: 67.57 (67.56), H: 3.88 (3.85), N: 4.13 (4.15).
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2.2.6.Bis((E)-4-chloro-2-((4-(4-biphenyloxy)phenylimino)methyl)phenolate)copper(II) Cu(L2)2
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Bis((E)-4-chloro-2-((4-(4-biphenyloxy)phenylimino)methyl)phenolate)copper(II) Cu(L2)2
was synthesized by using 0.182 g (1 mmol) anhydrous copper (II) acetate and 0.80 g (2 mmol) of
(E)-4-chloro-2-((4-(4-biphenyloxy)phenylimino)methyl)phenol.
Yield: 79%. M.P. 219oC FTIR (υ/cm-1): 1595 (-C=N), 538 (Cu-O), 406 (Cu-N), CHN found
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(calcd) for C50H34N2O4ClCu: C: 72.71 (72.73), H: 4.11 (4.12), N: 3.35 (3.39).

2.2.7. Bis((E)-4-chloro-2-((4-(naphthalen-1-yloxy)phenylimino)methyl)phenolate)copper
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(II) Cu(L3)2
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Bis((E)-4-chloro-2-((4-(naphthalen-1-yloxy)phenylimino)methyl)phenolate)copper(II) Cu(L3)2
was synthesized by using 0.182 g (1 mmol) anhydrous copper(II) acetate and 0.75 g (2 mmol) of
(E)-4-chloro-2-((4-(naphthalen-1-yloxy)phenylimino)methyl)phenol.
Yield: 69%. M.P.181 °C FTIR (υ/cm-1): 1588 (-C=N), 545 (Cu-O), 412 (Cu-N), CHN found
(calcd) for C46H30N2O4ClCu: C: 71.39 (71.41), H: 3.86 (3.89), N: 3.65 (3.62).

2.2.8.Bis((E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)methyl)phenolate)copper(II) Cu(L4)2

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Bis((E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)methyl)phenolate)copper(II) Cu(L4)2 was

synthesized by taking 0.182 g (1 mmol) anhydrous copper(II) acetate and 0.75 g (2 mmol) of
(E)-4-chloro-2-((4-(2-naphthoxy)phenylimino)methyl)phenol.
Yield: 75%. M.P. 199 °C FTIR (υ/cm-1): 1612 (-C=N), 532 (Cu-O), 407 (Cu-N), CHN found
(calcd) for C46H30N2O4ClCu: C: 71.40 (71.41), H: 3.86 (3.89), N: 3.63 (3.62).

3 Results and Discussion

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Schiff bases (HL1-HL4) and their copper(II) complexes (Cu(L1)2- Cu(L4)2) have been
successfully synthesised and characterised by FTIR, NMR (1H & 13C) spectroscopy and

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elemental analysis. The synthesized compounds were further tested for various biological assays
(cytotoxic, antitumor and inhibition of hydroxyl (OH) free radical induced DNA damage).

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3.1 FTIR spectroscopy

FTIR spectroscopy has proved to be a particularly useful technique for characterization of the
synthesized compounds indicating the expected functionalities. For the Schiff bases (HL1-HL4),

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the broad bands in 2708-2773 cm-1 are due to –OH vibration (ortho position) associated
intramolecular(OH...N) with the nitrogen atom of the imine moiety . All the ligands exhibited the
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absorption due to azomethine bond (υCH=N) in the region of 1608-1620 cm-1.
In copper(II) complexes(Cu(L1)2- Cu(L4)2) no absorption band was observed at 2708-2773cm-1
due to disappearance of intramolecular hydrogen bonds after coordination of nitrogen atom of
CH=N moiety to the copper metal and appearance of absorptions in the region 522-545 cm-1
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confirmed the coordination of oxygen with copper. The complexes exhibited the absorptions of
azomethine region (406-412 cm−1) at lower frequencies than free ligands, indicating the
coordination through azomethine nitrogen [10, 11] (Table1).The FTIR spectra of Schiff bases
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and their copper(II) complexes are presented in figure S1(a-h).

Table1. FTIR (υ /cm-1) data of ligands (HL1-HL4) and copper(II) complexes(Cu(L1)2- Cu(L4)2)
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Compound -CH=N -OH Cu-O Cu-N

HL1 1610 2742 - -

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HL2 1608 2708 - -

HL3 1617 2773 - -
HL4 1620 2746 - -
Cu(L1)2 1595 - 525 410
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Cu(L2)2 1595 - 538 406

Cu(L3)2 1588 - 545 412
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Cu(L4)2 1612 - 522 407

3.2 NMR Spectroscopy

The structural formulation of ligands has been further inferred from NMR (1H &13C)
spectroscopic studies. The chemical shift values for the Schiff bases (HL1-HL4) are summarized
in Table 2. The 1H NMR spectra showed the characteristic azomethine singlet in the region of
8.85-8.57 ppm. Aromatic protons were present in all the ligands which were verified by the

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appearance of multiplets in the range of 8.23-6.85 ppm. Resonance signals observed around
13.32-13.23 were due to phenolic protons in the ligands.
Table 2. NMR (1H &13C) spectral data of Schiff bases (HL1-HL8) (ppm)
1 13
H NMR C NMR

compound ν(CH=N) ν (OH)

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ν (Ar-H) ν(C=N) ν (Ar-C)
s, 1H s, 1H

HL1 7.62-6.99 (m,12H) 8.58 13.23 160.12 159.59-118.81 (18C)

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HL2 7.62-6.99 (m, 16H) 8.59 13.30 160.11 158.92-117.52 (24C)

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HL3 8.23-6.98 (m, 14H) 8.57 13.32 163.41 157.54-114.08 (22C)
HL4 8.12-6.85 (m, 14H) 8.85 13.28 162.07 159.35-118.81 (22C)

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C NMR spectra of ligands (HL1 – HL4) show all the characteristic signals of azomethine and
aromatic carbon atoms in their respective ranges of chemical shift values. Azomethine carbon
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resonated around 163.41-160.11 ppm. The resonance signals observed around 159.59-114.08
ppm were due to aromatic carbon atoms of ligands.
As copper(II) complexes are paramagnetic in nature therefore their NMR studies are not
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possible.

3.3. Biological studies

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3.3.1. Brine shrimp cytotoxic assay

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Brine shrimps assay was carried out to investigate the biological active nature of the compounds.
LD50 was calculated using Finney software and the results are presented in Table 3. Both ligands
and their copper complexes showed highly significant activity. The ligands HL1, HL2, HL3 and
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HL4 displayed cytotoxic nature with LD50 values 15.7, 19.8, 18.9 and 12.4µg/ml respectively.
Interestingly, copper(II) complexes exhibited higher activity than simple ligands with LD50 values
5.6,8.4,3.8, and 5.7µg/ml for Cu(L1)2, Cu(L2)2, Cu(L3)2 and Cu(L4)2 accordingly (Table 3).
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3.3.2 Potato disc antitumor assay

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To test the antitumor nature of the compounds, potato disc assay was implemented. IC50 was
calculated with Graphpad Prsim 5 and data is presented in Table 3. The results indicated that
ligands and copper complexes displayed significant tumor inhibition. The ligands showed IC50
values 48.3, 40.5, 44.1 and 47.2 µg/ml for HL1, HL2, HL3 and HL4 accordingly. On the other
hand, copper complexes showed higher activity than ligands with IC50 in a close range of 20 to
24 µg/ml. Conclusively, antitumor and cytotoxic activity of these compounds correlate with each
other in positive way suggesting their anticancer nature which needs to be further studied.

3.3.3.DPPH Free radical scavenging assay

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DPPH assay was carried out to determine the antioxidant capacity of the compounds. Assay was
performed in triplicates along with ascorbic acid (IC50 4.8µg/ml) as a positive control. Significant
antioxidant activity was shown by the compound Cu(L2)2 (IC50 21.7µg/ml) while other member
of copper family exhibited moderate antioxidant activity in the range 280 to 300µg/ml. The
simple ligands did not end up with any antioxidant activity which represents that the antioxidant
activity is associated with copper metal not due to the precursor molecules.

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Table 3 Results of brine shrimps cytotoxicity, DPPH and DNA protection assays.

Compound Brine shrimps Potato disc DPPH assay DNA protection assay

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cytotoxicity antitumor
assay(LD50 assay (IC50 (IC50 µg/ml)
µg/ml) µg/ml)

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HL1 15.7 48.3 Nil Protective
HL2 19.8 40.5 Nil Protective

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HL3 18.9 44.1 Nil Protective
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HL4 12.2 47.4 Nil Protective
Cu(L1)2 5.6 24.1 280.6 Neutral
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Cu(L2)2 8.4 20.4 21.7 Neutral

Cu(L3)2 3.8 22.2 289.1 Neutral
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Cu(L4)2 5.7 23.3 299.2 Neutral

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Doxorubicin 0.71 0.45 NA NA

Ascorbic acid NA NA 4.8 NA
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Where “NA” represents not applicable.

3.3.4. DNA damage assay
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The effect of the compounds to protect or damage the commercial DNA was estimated by H2O2
induced DNA damage assay. The degree of DNA protection/damage was estimated from the
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thickness, brightness and intensity of bands appeared on agarose gel. The assay was
implemented on three concentrations (1000, 100 and 10µg/ml) in triplicates. Significant DNA
protection behavior was exhibited by all ligand molecules as shown in Fig.1(a). The Fig.1(b)
represents gel image of copper(II) complexes showing neutral behavior (neither protection nor
damaging). Moreover, pro-oxidant effect was not exhibited by any of the tested compound.

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L P N X 1 2 3

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(a)

L P N X 4 5 6

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(b)
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Fig. 1(a&b). Effect of compounds HL4 and Cu(L4)2 on pBR322 plasmid DNA [L = 1Kb ladder,
P= pBR322 plasmid (non-treated), N= pBR322 plasmid treated with FeSO4 and H2O, X=
pBR322 plasmid + 1000µg/ml of HL4 or Cu(L4)2 (prooxidant control)respectively, 1= Plasmid +
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phosphate buffer + 1000µg/ml HL4, 2 = plasmid + phosphate buffer + 100 µg/ml of HL4 + FeSO4
+ H2O2, 3 = plasmid+ phosphate buffer + 10 µg/ml of HL4 + FeSO4 + H2O2, 4 = plasmid+
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phosphate buffer + 1000 µg/ml of Cu(L4)2 + FeSO4 + H2O2, 5= Plasmid + phosphate buffer + 100
µg/ml of Cu(L4)2 (pro-oxidant control), 6= plasmid + phosphate buffer + 10 µg/ml of Cu(L4)2 +
FeSO4 + H2O2].
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4 Conclusions

Schiff bases (HL1- HL4) and their copper(II) complexes (Cu(L1)2- Cu(L4)2) have been
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successfully synthesized and characterized by elemental analysis, FTIR spectroscopy and ligands
by NMR spectroscopy.The evaluation of the biological studies reveal significant activity in brine
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shrimp cytotoxicity assay and antitumor assay which provide the evidence for a very strong
positive correlation between these two assays. These compounds also have considerable
antioxidant activity along with potential to prevent DNA oxidative damage by free radicals. The
findings of this work sustenance the view that some of these synthesized compounds are
promising sources of potential drugs that may be efficient as preventive agent(s) in some
diseases.

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Acknowledgements
The authors are highly grateful to Chemistry and Biochemistry Departments of Quaid-I-Azam
University Islamabad, Pakistan for providing technical support and laboratory facilities.

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Highlights

• Synthesis of novel ether based Schiff bases and copper (II) complexes.
• Characterization of the compounds by elemental analysis and spectroscopic techniques.
• Biological studies (cytotoxic, antitumor & inhibition of hydroxyl (OH) free radical
induced DNA damage assay) to assess bioactive nature.
•

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Copper(II) complexes reveal greater bioactive nature than Schiff bases.

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