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Original article

02 2021

:15;

103559

doi:

10.1016/j.arabjc.2021.103559

Synthesis, characterization, and anticancer activity of some metal complexes with a new Schiff base ligand

Thamer A. Alorini^{^a,⁎}, Ahmed N. Al-Hakimi^{^a,^b}, S. El-Sayed Saeed^{^a}, Ebtesam Hassan Lutf Alhamzi^{^c}, Abuzar E.A.E. Albadri^{^a}

a Department of Chemistry, College of Sciences, Qassim University, Buraidah 51452, Saudi Arabia

b Department of Chemistry, College of Sciences, Ibb University, Ibb, Yemen

c Department of Biology, College of Science, Sana'a University, Yemen

⁎Corresponding author. thamer.ayo@gmail.com (Thamer A. Alorini)

Received: 2021-9-24, Accepted: 2021-11-8,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

A new Schiff base ligand, 2-((E)-((4-(((E)-benzylidene)amino)phenyl)imino)methyl)-naphthalene-1-ol, was prepared by the reflux condensation of p-phenylenediamine with 2-hydroxy-1-naphthaldehyde and benzaldehyde. Metal complexes were prepared by reacting the ligand with metal salts: VCl₃, CrCl₃·6H₂O, MnCl₂·3H₂O, FeCl₃·6H₂O, CoCl₃·6H₂O, NiCl₂·6H₂O, CuCl₂·2H₂O, and ZnCl₂. The ligand and its metallic complexes were characterized by various techniques such as elemental analysis, AAS, NMR, IR, UV–Vis, TGA, DTA, XRD and TEM. The data confirmed that the ligand coordinated with the metal ions in a bidentate nature, bonding through its azomethine nitrogen atom and phenolic oxygen atom; this gave an octahedral geometry. The XRD patterns of the complexes indicated that they were of various structures: the Mn(II), Co(III), and Cu(II) complexes were triclinic, the ligand and Ni(II) complex were orthorhombic, the V(III) and Zn(II) complexes were hexagonal, the Cu(II) complex was monoclinic, and the Fe(II) complex was cubic. TEM analysis confirmed that the complexes were nanoscale in nature. The antibacterial and antifungal activities of the ligand and its complexes against Salmonella enterica serovar typhi and Candida albicans were investigated by the hole plate diffusion method. It was observed that the Co(II) and Zn(II) complexes had intermediate antibacterial activities, while the V(III) complex had the highest activity against C. albicans fungi. The in vitro anticancer activities of the ligand and its metal complexes were tested towards PC-3, SKOV3, and HeLa tumour cell lines, where they exhibited higher antitumour activities against these selected human cell lines than clinically used drugs such as cisplatin, estramustine, and etoposide.

Keywords

Schiff base complex

Antibacterial activity

Antifungal activity

Anticancer activity

Nanoparticle

Show Related Articles from PubMed

AAS: Atomic Absorption Spectroscopy
NMR: Nuclear Magnetic Resonance
IR: Infrared Spectroscopy
UV–Vis: Ultraviolet–visible Spectroscopy
TGA: Thermogravimetric analysis
DTA: Differential Thermal Analysis
XRD: X-ray powder Diffraction
TEM: Transmission Electron Microscopy
DMSO: Dimethyl sulfoxide
SRB: Sulforhodamine B assay
HL: Ligand

1 Introduction

Schiff bases are important chemical compounds in various fields such as inorganic, analytical, and medicinal chemistry due to their versatility; they can form numerous, diverse, stable complexes when they are coordinated with different transition-metal ions. Thus, in recent years, such metal complexes containing Schiff bases have been studied extensively due to their various applications and chemical activities. Schiff bases are formed via the interaction between the carbonyl group of an aldehyde or beta diketone and an amine moiety, and their active group (—N⚌CH—) contains active electrons, making them ideal candidates for developing new drugs (Al-Hakimi et al., 2020; Maurya et al., 2016). In medicinal chemistry, the development of powerful and effective medicinal drugs has been extensively explored. The derivatives of Schiff bases represent a significant category of compounds that have found multiple applications in therapeutic chemistry because of their wide range of pharmacokinetic properties and their prominence in drug discovery programs (El-Saied et al., 2018). Schiff base derivatives and their complexes have reportedly demonstrated a variety of biological properties, such as anti-inflammatory (Azam et al., 2020; Manimohan et al., 2020), antibacterial (El-saied et al., 2020; Shakdofa et al., 2018), antifungal (Al-Hakimi et al., 2020; Bhaskar et al., 2020), antiviral (Buldurun et al., 2020; Slassi et al., 2020), anticancer (Kavitha and Laxma Reddy, 2016; Mbugua et al., 2020), and antioxidant (Keypour et al., 2020; Radha et al., 2020) activities. Schiff bases also have industrial uses (Betiha et al., 2020; Chauhan et al., 2020) and have been used as highly effective sensors (Hosseinzadeh Sanatkar et al., 2020; Mondal et al., 2020) and catalysts (Bocian et al., 2020; Nagalakshmi et al., 2020), as well as beneficial substances for preserving the environment (Kobisy et al., 2020; Zaman Brohi et al., 2020).

Several published studies have demonstrated the extent to which Schiff bases and their transition-metal complexes exhibit biological activities effective against a range of bacterial and fungal species and tumours. For example, Schiff base complexes have shown antitumor and antioxidative activities, as well as lipid peroxidation inhibition (Yang et al., 2000). This is important as microbial infections have threatened human civilization since ancient times, with large proportions of people dying in various parts of the world due to such diseases. According to a report from the Infectious Diseases Society of America, there are several microbial species that pose serious pathogenic risk; these include Klebsiella pneumonia and Pseudomonas aeruginosa, as well as species belonging to the Staphylococcus, Enterococcus, Enterobacter, and Acinetobacter genuses (Malik et al., 2018). Cancer is another category of deadly diseases, and because they lack proper treatment options they threaten humanity in throughout the developing and developed worlds (Mbugua et al., 2020).

Herein, we report the preparation, characterization, and determination of the crystal structure of a new Schiff base constructed from p-phenylenediamine, 2-hydroxy-1-naphthaldehyde, and benzaldehyde as a ligand. Eight complexes derived from this novel base were also prepared. This study assessed the biological activity of the prepared compounds. Namely, all compounds were tested against PC-3, SKOV3, and HeLa tumour cell lines; meanwhile, their antibacterial activities were assayed against Salmonella enterica serovar typhi (S. enterica ser. typhi) and their antifungal activities were evaluated against Fungus Candida albicans.

2 Materials and methods

2.1

2.1 Materials and measurements

p-Phenylenediamine, 2-hydroxy-1-naphthaldehyde, and benzaldehyde were purchased from Acros all compounds were of high purity of 98%, while metal salts were obtained from Sigma–Aldrich, ethanol, methanol, dichloromethane, dimethyl sulfoxide (DMSO), and petroleum ether were of analytical grade and purchased from Alfa Aesar and used without purification. ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopies were performed using a Bruker spectrometer at 850 MHz and 213 MHz, respectively; CDCl₃ was used as the solvent, TMS was the standard reference, and the probe temperature was 25 °C. The Fourier-transform infrared (FTIR) spectra of the ligand and its metallic complexes in the solid-state were measured using an Agilent spectrometer (Cary 600 FTIR, USA), which was operated in the wavenumber range of 4000–400 cm⁻¹. UV–Vis spectra of DMSO solutions (1 × 10⁻⁴ M) of the ligand and their metal complexes were measured using a Shimadzu spectrophotometer (UV-1650PC, Japan); a 1 cm quartz cell and wavelength range of 250–650 nm were employed. The carbon, hydrogen, and nitrogen contents were determined for the prepared ligand and its metallic complexes using a Eurovector CHN (EA3000, Italy) analyser. The metal elements were determined using AAS (model 200 series AAS spectrometer, Agilent-technologies). TGA and DTA analyses were performed under nitrogen using a Shimadzu simultaneous DTA–TG apparatus (DTG-60AH, Japan); the heating rate was 10 °C/min, the temperature range was 27–525 °C, and Al₂O₃ served as the reference material for the DTA measurements. The XRD patterns of the compounds were collected with a Rigaku XRD diffractometer (Ultima IV, USA). The anode material was Cu Kα (λ = 1.54180 Å) which operated with a current of 30 mA and a voltage of 40 kV. TEM analysis was conducted using a JEOL-100S (Japan) microscope. The molar conductivity (Λ_m) values of the prepared metal complexes dissolved in DMSO (1 × 10⁻³ M) at room temperature were determined using an Oakton Conductivity/DTS meter. The magnetic sensitivities of the prepared solid metal complexes were measured at room temperature with the Magnetic Susceptibility Balance – Auto from Sherwood Scientific (United Kingdom). S. enterica ser. typhi was obtained from the Yemen Standardization, Metrology and Quality Control Organization, while C. albicans was obtained from Althubhani Specialist Medical Laboratory (Sana'a, Yemen).

2.2

2.2 Preparation of ligand (HL) (1)

The ligand, 2-((E)-((4-(((E)-benzylidene)amino)phenyl)imino)methyl)-naphthalene-1-ol, was prepared following a literature method (Al-Hakimi et al., 2020), where 1.72 g (0.01 mol) of 2-hydroxy-1-naphthaldehyde and 1.06 g (0.01 mol) of benzaldehyde were dissolved in 20 mL of absolute ethanol and the mixture was stirred until complete dissolution. This solution was then slowly added dropwise to a spherical flask containing 1.08 g (0.01 mol) of p-phenylenediamine dissolved in 15 mL of ethanol. The mixture was left to stir under reflux for 3 h, during which an orange precipitate was formed. The precipitate was then filtered and washed several times with distilled water followed by absolute ethanol. Yield: (84%). M.p.: 230 °C. Colour: Orange. IR, ν(cm⁻¹): 3350(m), 1620(s), 1605(s), 1540(s), 1310(m). ¹H NMR (850 MHz, CDCl₃) (δ, ppm): 6.65–8.10 (m, 15H, Ar–H), 10.05 (s, 1H, N⚌CH), 10.88 (s, 1H, N⚌CH), 13.20 (s, 1H, ArOH). ¹³C NMR (213 MHz, CDCl₃) (δ, ppm): 149.9, 149.36, 148.77, 140.35, 133.85, 131.64, 129.63, 128.21, 126.85, 124.85, 123.71, 122.36, 118.07, 117.0, 113.26. UV–Vis (DMSO), λ_max (nm): 259, 318. Elemental analysis (%): Calculated: C: 82.27, H: 5.19, N: 7.99; Found: C: 82.03, H: 4.93, N: 7.86.

2.3

2.3 Preparation of metal complexes

The ratio of ligand to metal (L:M) was calculated from the molar ratios of several solutions that contained fixed proportions of the metal salt solution with variable quantities of the ligand solution. Mn(II) and Cu(II) metallic complexes (4 and 8, respectively) were prepared using MnCl₂·3H₂O and CuCl₂·2H₂O, respectively, in L:M molar ratios of 1:1. V(III), Cr(III), Fe(III), Co(III), Ni(II), and Zn(II) metallic complexes (2–9, except 4 and 8, respectively) were prepared using VCl₃, CrCl₃·6H₂O, FeCl₃·6H₂O, CoCl₃·6H₂O, NiCl₂·6H₂O, and ZnCl₂, respectively, in L:M molar ratios of 2:1. All the metal complexes were prepared using the following, general method:

An ethanolic solution of the metal salt was mixed with a suitable amount of an ethanolic solution of the ligand in the molar ratios previously mentioned for 3 h on an electric stirrer under reflux at 70 °C. A precipitate was formed, which was then filtered and washed several times with distilled water and then with absolute ethanol to remove the non-reacting organic materials. The solid was then dried in an oven at 50 °C for 2 h.

2.3.1

2.3.1 V(III) Complex (2)

Dark Green precipitate. Yield: (64%). M.p.: 265 °C. IR, ν(cm⁻¹): 3345(m), 1610(s), 1542(s), 1518(s), 1300(m), 620(m), 520(m), 450(s). UV–Vis (DMSO), λ_max (nm): 233, 322, 486. Elemental analysis (%): Calculated: C: 70.17, H: 4.29, N: 6.82; Found: C: 70.29, H: 4.12, N: 6.57.

2.3.2

2.3.2 Cr(III) complex (3)

Red precipitate. Yield: (73%). M.p.: 260 °C. IR, ν(cm⁻¹): 3342(m), 1608(s), 1580(s), 1495(s), 1305(m), 615(s), 535(w), 405(s). UV–Vis (DMSO), λ_max (nm): 227, 317, 344, 459, 484. Elemental analysis (%): Calculated: C: 70.08, H: 4.31, N: 6.81; Found: C: 69.94, H: 4.19, N: 6.94.

2.3.3

2.3.3 Mn(II) complex (4)

Burgundy precipitate. Yield: (78%). M.p.: 290 °C. IR, ν(cm⁻¹): 3520–3300(br), 3440(m), 1617(s), 1595(s), 1530(s), 1300(s), 620(w), 570(m), 410(s). UV–Vis (DMSO), λ_max (nm): 231, 320, 464, 484, 612. Elemental analysis (%): Calculated: C: 56.27, H: 4.33, N: 5.47; Found: C: 56.70, H: 4.42, N: 5.70.

2.3.4

2.3.4 Fe(III) complex (5)

Dark brown precipitate. Yield: (75%). M.p.: >300 °C. IR, ν(cm⁻¹): 3420–3130(br), 1615(s), 1592(s), 1520(s), 1305(s), 652(m), 567(m), 425(m). UV–Vis (DMSO), λ_max (nm): 261, 318, 379, 463, 487. Elemental analysis (%): Calculated: C: 71.34, H: 4.49, N: 6.93; Found: C: 71.57, H: 4.25, N: 6.67.

2.3.5

2.3.5 Co(III) complex (6)

Brown precipitate. Yield: (81%). M.p.: >300 °C. IR, ν(cm⁻¹): 3330–3030(br), 1615(s), 1594(s), 1515(s), 1305(s), 653(m), 535(s), 412(m). UV–Vis (DMSO), λ_max (nm): 262, 317, 433, 458. Elemental analysis (%): Calculated: C: 71.07, H: 4.47, N: 6.91; Found: C: 70.82, H: 4.38, N: 6.98.

2.3.6

2.3.6 Ni(II) complex (7)

Green precipitate. Yield: (74%). M.p.: >300 °C. IR, ν(cm⁻¹): 3430–3120(br), 3320(m), 1617(s), 1600(s), 1536(s), 1250(m), 619(s), 520(m), 418(m). UV–Vis (DMSO), λ_max (nm): 264, 316, 363, 455. Elemental analysis (%): Calculated: C: 71.00, H: 4.59, N: 6.90; Found: C: 70.52, H: 4.51, N: 6.77.

2.3.7

2.3.7 Cu(II) complex (8)

Dark burgundy precipitate. Yield: (75%). M.p.: 270 °C. IR, ν(cm⁻¹): 3520–3230(br), 3443(m), 1612(s), 1544(s), 1511(s), 1298(s), 634(s), 520(s), 416(m). UV–Vis (DMSO), λ_max (nm): 258, 332, 460, 490. Elemental analysis (%): Calculated: C: 55.34, H: 4.26, N: 5.38; Found: C: 55.17, H: 4.06, N: 5.31.

2.3.8

2.3.8 Zn(II) complex (9)

Orange precipitate. Yield: (79%). M.p.: 283 °C. IR, ν(cm⁻¹): 3410(m), 1615(s), 1594(s), 1515(s), 1305(s), 688(m), 534(s), 430(m). UV–Vis (DMSO), λ_max (nm): 260, 330. Elemental analysis (%): Calculated: C: 68.87, H: 4.33, N: 6.70; Found: C: 68.64, H: 4.27, N: 6.89.

2.4

2.4 Cell culture

The American Type Culture Collection (ATCC) provided the following human cell lines: prostate adenocarcinoma (PC-3), ovarian adenocarcinoma (SKOV3), and cervical cancer (HeLa). Under humid, 5% (v/v) CO₂ conditions, cells were incubated in RPMI-1640 (100 g/mL) enriched with penicillin (100 units/L) and heat-inactivated foetal bovine serum (10% v/v) at 37 °C (Ghfar et al., 2021).

2.5

2.5 Cytotoxicity assay

Using the sulforhodamine B (SRB) assay, the cytotoxicities of the prepared chemical compounds were assessed against human tumour cells (PC-3, SKOV3, and HeLa). Before being treated with the chemical compounds, 80% of the confluent proliferating cells were trypsinised and cultivated in a 96-well tissue culture plate for 24 h. Untreated cells (control) were also added to cells that were exposed to the six concentrations of each compound (0.01, 0.1, 1, 10, 100, and 1000 µg/mL). The cells were exposed to the doses for 72 h before being fixed with TCA (10% w/v) for 1 h at 4 °C. After repeated washes, the cells were stained for 10 min in the dark with a 0.4% (w/v) SRB solution. Glacial acetic acid, 1% (v/v), was used to remove any remaining discoloration. The SRB-stained cells were dissolved in Tris-HCl after drying for 12 h, and their colour intensities were quantified using a microplate reader at 540 nm. Using SigmaPlot 12.00 software, the correlation between the viability percentage of each tumour cell line and the chemical concentrations was analysed to determine the IC₅₀ values (i.e., drug dose that reduces survival to 50%) (Alam et al., 2021).

2.6

2.6 In vitro antibacterial and antifungal activity

The ligand and its metallic complexes were diluted with DMSO to concentrations of 100 parts per thousand (ppt). All antimicrobial and antifungal activities tests were conducted in the Department of Botany, Laboratory of Microbiology at Sana'a University (Yemen). The antibacterial and antifungal activity assays of the ligand and its metallic complexes were carried out by the hole plate diffusion method (Magwa et al., 2006). Petri dishes were pre-inoculated with the appropriate bacteria and fungi in the following manner:

One hundred µL of the bacteria and fungi suspension was spread over plates containing Mueller–Hinton agar using a sterile cotton swab (Gachkar et al., 2007; Hanbali et al., 2005). Three wide holes (with diameters of 5 mm) were then made in the agar using a cork borer. Different amounts of the compounds (30 µL, 20 µL, and 10 µL) were introduced into each of the holes in appropriately labelled petri dishes using a sterile micropipette. Gentamicin and clotrimazole (10 µg/ mL) were used as positive controls for bacteria and fungi, respectively (El Malti et al., 2007). The bacteria dishes were then incubated at 37 °C for 24 h, while the yeast, mould, and fungi plates were incubated at 28 °C for 24 h, 3 d, and 24 h, respectively. After incubation, the zones of inhibition were measured and recorded. The zone of inhibition was taken to be the diameter of the zone that visibly shows an absence of growth, including the 5 mm well. Additionally, when no inhibition occurred, the value of 0 mm was assigned to the test sample (Magwa et al., 2006).

3 Results and discussion

3.1

3.1 Chemistry

Our approach began with the preparation of the ligand (Scheme 1), which was achieved by reacting one equivalent of 2-hydroxy-1-naphthaldehyde with one equivalent of benzaldehyde in absolute ethanol, and then slowly adding the completely dissolved mixture dropwise to one equivalent of p-phenylenediamine in 15 mL of ethanol. The metallic complexes were constructed in L:M ratios of 1:1 (Scheme 2) or 2:1 (Scheme 3) by reacting ethanolic solutions of the ligand and various metal chloride salts. All obtained complexes were characterized by FT-IR spectroscopy, UV–Vis electronic absorption, elemental analysis, thermal analysis, X-ray powder diffraction, and TEM, as well as molar conductivity and magnetic susceptibility studies.

Preparation of the metallic complexes in ligand-to-metal(L. M) ratios of 1:1.

Preparation of the metallic complexes in L. M ratios of 2:1.

3.1.1

3.1.1 ¹H NMR spectra

The ¹H NMR spectrum of the ligand in CDCl₃ (Fig. 1) showed signals consistent with the expected values. Importantly, the spectrum lacked the signal of the amino group (—NH₂) characteristic of the starting material. The spectrum showed one peak as a singlet at 13.20 ppm, which was assigned to the hydroxyl (—OH) moiety (Ren et al., 2020), along with two peaks at 10.88 ppm and 10.05 ppm, which were assigned to the —N⚌CH— groups; the difference in the shifts of these two protons is due to the polarity of the 2-hydroxy-1-naphthaldehyde moiety, which is in closer proximity to the group whose proton appears at 10.88 ppm (Al-Hakimi et al., 2020). Another signal appeared as a multiplet within the range of 6.65–8.10 ppm, which is attributed to aromatic protons (Al-Hakimi, 2020; Al-Hakimi et al., 2020).

3.1.2

3.1.2 ¹³C NMR spectra

The ¹³C NMR spectrum of the ligand (Fig. 2) showed peaks appearing at 149.9, 149.36 and 148.77 ppm. These peaks can be attributed to the C—OH, HC⚌N, and HC⚌N groups, respectively. The peaks within the 113.26–140.35 ppm range were assigned to the aromatic carbons (Al-Hakimi, 2020; Al-Hakimi et al., 2020).

3.1.3

3.1.3 Elemental analysis and physical properties

Elemental analysis and physical data (Table 1) supported the proposed structures of the ligand and its metal complexes, with the V(III), Cr(III), Fe(III), Co(III), Ni(II), and Zn(II) complexes showing L:M molar ratios of 2:1 and the Mn(II) and Cu(II) complexes showing L:M molar ratios of 1:1. Furthermore, the molar conductivity values of the complexes indicate that the chloride anions are located within their inner-spheres.

Table 1 Elemental analysis and physical properties of the ligand and its metal complexes.

Comp. No.	Compound (m.w)	Colour	Yield (%)	M.p. (°C)	Ω⁻¹ mol⁻¹ cm²	μ_eff (μB)	Found (Calc.) (%)
Comp. No.	Compound (m.w)	Colour	Yield (%)	M.p. (°C)	Ω⁻¹ mol⁻¹ cm²	μ_eff (μB)	C	H	N	M
1	[HL][C₂₄H₁₈N₂O] (350.41)	Orange	84	230	–	–	82.03 (82.27)	4.93 (5.19)	7.86 (7.99)	–
2	[(HL)(L)V(Cl)₂] (821.66)	Dark Green	64	265	3.8	2.85	70.29 (70.17)	4.12 (4.29)	6.57 (6.82)	6.05 (6.20)
3	[(HL)(L)Cr(Cl)₂] (822.72)	Red	73	260	7.4	3.9	69.94 (70.08)	4.19 (4.31)	6.94 (6.81)	6.47 (6.32)
4	[(HL)Mn(Cl)₂(H₂O)₂] (512.29)	Burgundy	78	290	21.1	5.96	56.70 (56.27)	4.42 (4.33)	5.70 (5.47)	10.78 (10.72)
5	[(L)₂Fe(Cl)(H₂O)] (808.12)	Dark Brown	75	>300	26.9	5.94	71.57 (71.34)	4.25 (4.49)	6.67 (6.93)	6.72 (6.91)
6	[(L)₂Co(Cl)(H₂O)] (811.21)	Brown	81	>300	25.6	4.8	70.82 (71.07)	4.38 (4.47)	6.98 (6.91)	7.14 (7.26)
7	[(HL)(L)Ni(Cl)(H₂O)] (811.98)	Green	74	>300	8.4	2.85	70.52 (71.00)	4.51 (4.59)	6.77 (6.90)	7.03 (7.23)
8	[(HL)Cu(Cl)₂(H₂O)₂] (520.89)	Dark Burgundy	75	270	27.3	1.7	55.17 (55.34)	4.06 (4.26)	5.31 (5.38)	12.06 (12.20)
9	[(HL)₂Zn(Cl)₂] (837.12)	Orange	79	283	6.0	Dia.	68.64 (68.87)	4.27 (4.33)	6.89 (6.70)	7.51 (7.81)

3.1.4

3.1.4 Molar conductivity

To verify the ionic formulas of the prepared metal complexes in solution, the molar conductivities of DMSO solutions of the complexes (1 × 10⁻³ M) were determined (Table 1). A range of 6.0–27.3 Ω⁻¹ mol⁻¹ cm⁻² was obtained; such low values indicate that the complexes are non-electrolytic in nature (Alhakimi et al., 2021; El-tabl et al., 2008). This confirms that the anions are coordinated with the metal ions in all complexes. To further ensure this absence of an electrolytic nature, a AgNO₃ solution was added to the metal complex solutions; as expected, there was no formation of a white precipitate or any turbidity, which confirmed that the chlorine ions are not located outside the coordination sphere as accompanying ions. This supports the proposed shapes of the complexes.

3.1.5

3.1.5 Magnetic susceptibility

The room-temperature magnetic moments of the complexes (2–9) are shown in Table 1. The V(III) and Ni(II) complexes (2 and 7, respectively) show magnetic moments of 2.85 μB, indicating they possess two unpaired electrons in their outer valence shells as well as octahedral geometries (Güngör and Gürkan, 2019). However, the Cr(III) complex (3) showed a magnetic moment of 3.9 μB, confirming the presence of three unpaired electrons in its outer valence shell, resulting in an octahedral geometry around the Cr(III) ion (El-Tabl, 2002; El-tabl et al., 2008). The magnetic moment values for the Mn(II), Fe(III), and Co(III) complexes (4, 5, and 6, respectively) are 5.96, 5.94 and 4.8 μB, respectively, indicating high-spin Mn(II), Fe(III), and Co(III) ions, as well as five, five, and four unpaired electrons in their respective outer valence shells; they also showed octahedral geometries (Murukan and Mohanan, 2006). Cu(II) complex 8 had a magnetic moment of 1.70 μB, which corresponds to one unpaired electron and an octahedral geometry (Singh et al., 2017). Finally, the Zn(II) complex (9) showed a diamagnetic value.

3.1.6

3.1.6 FT-IR spectra

The important absorption bands of the ligand and its metal complexes are presented in Table 2. The IR spectrum of the ligand (Fig. 3) shows a sharp, weak band centred at 3350 cm⁻¹, which is attributed to the hydroxyl group (ν(O—H)) (AL-FAKEH et al., 2020). The spectrum also shows strong bands at 1620 and 1605 cm⁻¹, which are assigned to the two azomethine groups (ν(C⚌N)) (Aly et al., 2012; El-tabl et al., 2008). In addition, medium and strong bands appeared at 1540 and 1310 cm⁻¹, corresponding to ν(C⚌C) and ν(C—O), respectively (El-tabl et al., 2008). By comparing the IR spectrum of the ligand with the spectra of the metal complexes, the method of metal–ligand coordination can be elucidated. The ν(O—H) vibrations of complexes 2, 3, 4, 7, 8, and 9 were observed as strong bands at 3345, 3342, 3440, 3320, 3443, and 3410 cm⁻¹, respectively (El-tabl et al., 2008). Except for complexes 2, 3, and 9, these complexes also show broad band in the 3520–3030 cm⁻¹ range, which is assigned to coordinated water molecules (El-Tabl et al., 2008; Mosa’d Jamil et al., 2018). Medium and strong bands are noted at complexes 2–9 in the 1620–1608 cm⁻¹ and 1595–1542 cm⁻¹ ranges and are due to the ν(C⚌N) vibrations involving the benzene group and the C⚌N unit coordinating with a metal ion, respectively (Al-Hakimi et al., 2020; El-tabl et al., 2008). However, in compounds, 1–9 the medium and strong bands that appear in the 1536–1495 cm⁻¹ and 1305–1250 cm⁻¹ ranges are due to ν(C⚌C) and ν(C—O) vibrations, respectively (El-tabl et al., 2008; El-Tabl et al., 2008). Additionally, complexes 2–9 shows medium bands in the ranges of 688–615, 570–520, and 450–405 cm⁻¹, which are due to ν(M—N), ν(M—O), and ν(M—Cl) vibrations, respectively (El-tabl et al., 2008). These results combined with the elemental analysis indicate that the Schiff base coordinated to the metal ions via the hydroxyl oxygen of its naphthaldehyde moiety and the N atom of one of its azomethine groups.

Table 2 FTIR spectral data of the ligand and its metal complexes.

Comp.No.	ν(OH)	ν(H₂O)	ν(C⚌N)	ν(C⚌C)	ν(C-O)	ν(M—O)	ν(M—N)	ν(M—Cl)
1	3350	–	1620,1605	1540	1310	–	–	–
2	3345	–	1610,1542	1518	1300	620	520	450
3	3342	–	1608,1580	1495	1305	615	535	405
4	3440	3520–3300(br)	1617,1595	1530	1300	620	570	410
5	–	3420–3130(br)	1615,1592	1520	1305	652	567	425
6	–	3300–3030(br)	1615,1594	1515	1305	653	535	412
7	3320	3430–3120(br)	1617,1600	1536	1250	619	520	418
8	3443	3520–3230(br)	1612,1544	1511	1298	634	520	416
9	3410	–	1615,1594	1515	1305	688	534	430

3.1.7

3.1.7 UV–Visible spectra

The electronic spectral data of the ligand (HL) and its metal complexes in DMSO are presented in Table 3. The ligand UV–Vis spectrum (Fig. 4) showed absorbance bands at 318 nm and 259 nm, which may correspond to the n $\to π^{*}$ and $π \to π^{*}$ transitions, respectively, within the aromatic rings in the ligand. On the other hand, these transitions in the complexes appeared as bands that were shifted compared to those of the ligand; specifically, the bands corresponding to the n $\to π^{*}$ and $π \to π^{*}$ transitions appeared in the ranges of 310–332 nm and 227–264 nm, respectively (Al-Hakimi et al., 2020). This indicates bonding between the ligand and the metallic elements. Furthermore, the V(III) complex showed a band at 486 nm representing a ³T_1g (F) $\to$ ³T_2g (P) transition, further indicating an octahedral geometry for the V(III) ion (Dorn et al., 2020). The Cr (III) complex shows three bands at 484, 459, and 344 nm corresponding to the transitions ⁴A_2g (F) $\to$ ⁴T_1g (P), ⁴A_2g (F) $\to$ ⁴T_2g (F), and ⁴A_2g (F) $\to$ ⁴T_1g (F), respectively; this supports the previously identified octahedral geometry of the Cr(III) ion (Tarafder et al., 2000). The Mn(II) complex showed three bands at 612, 484, and 464 nm that were assigned to ⁴T_1g $\to$ ⁶A_1g, ⁴T_2g (G) $\to$ ⁶A_1g, and ⁴T_1g (D) $\to$ ⁶A_1g transitions, respectively, suggesting an octahedral geometry around the Mn(II) ion (Mahmoud et al., 2020). The Fe(III) complex showed bands at 487, 463, and 379 nm corresponding to ⁴T_1g (D) $\to$ ⁶A_1g, ⁴T_2g (G) $\to$ ⁶A_1g, and ⁴T_2g (G) $\to$ ⁶A_1g transitions, respectively, which are indicative of an octahedral geometry (Mahmoud et al., 2020). The Co(III) complex showed two bands at 458 and 433 nm that were assigned to ⁴T_1g (F) $\to$ ⁴T_2g (F) and ⁴T_1g (F) $\to$ ⁴A_2g transitions, suggesting an octahedral geometry for the complex (Mahmoud et al., 2020). The Ni(II) complex showed bands at 455 and 363 nm, which are attributable to ³A_2g (F) $\to$ ³T_g (F) and ³A_2g (F) $\to$ ³T_1g (P) transitions, respectively, indicating an octahedral Ni(II) complex (El-tabl et al., 2008). The Cu(II) complex exhibited bands centred at 490 and 460 nm that were assigned to ligand → metal charge transfer, ²B₁ $\to$ ²B₂, and ²B₁ $\to$ ²E transitions, respectively, indicating a distorted octahedral structure (El-tabl et al., 2008). Finally, the Zn(II) complex showed bands at 330 and 260 nm, indicating the presence of intra-ligand transitions and LMCT (Al-Hakimi et al., 2020; El-Tabl et al., 2008).

Table 3 UV–Vis spectral data of the ligand and its metal complexes.

Comp. No.	compounds	λ_max (nm)	λ_max (cm⁻¹)	Assignment
1	[HL][C₂₄H₁₈N₂O]	318	31,445	n $\to π^{*}$
		259	38,610	$π \to π^{*}$
2	[(HL)(L)V(Cl)₂]	486	20,576	³T_1g (F) $\to$ ³T_2g (P)
		322	31,055	n $\to π^{*}$
		233	42,918	$π \to π^{*}$
3	[(HL)(L)Cr(Cl)₂]	484	20,661	⁴A_2g (F) $\to$ ⁴T_1g (P)
		459	21,786	⁴A_2g (F) $\to$ ⁴T_2g (F)
		344	29,070	⁴A_2g (F) $\to$ ⁴T_1g (F)
		317	31,546	n $\to π^{*}$
		227	44,052	$π \to π^{*}$
4	[(HL)Mn(Cl)₂(H₂O)₂]	612	16,339	⁴T_1g $\to$ ⁶A_1g
		484	20,661	⁴T_2g (G) $\to$ ⁶A_1g
		464	12,551	⁴T_1g (D) $\to$ ⁶A_1g
		320	31,250	n $\to π^{*}$
		231	43,290	$π \to π^{*}$
5	[(L)₂Fe(Cl)(H₂O)]	487	20,533	⁴T_1g (D) $\to$ ⁶A_1g
		463	21,598	⁴T_2g (G) $\to$ ⁶A_1g
		379	26,385	⁴T_2g (G) $\to$ ⁶A_1g
		318	31,447	n $\to π^{*}$
		261	38,314	$π \to π^{*}$
6	[(L)₂Co(Cl)(H₂O)]	458	21,834	⁴T_1g (F) $\to$ ⁴T_2g (F)
		433	23,094	⁴T_1g (F) $\to$ ⁴A_2g
		317	31,546	n $\to π^{*}$
		262	38,168	$π \to π^{*}$
7	[(HL)(L)Ni(Cl)(H₂O)]	455	21,978	³A_2g (F) $\to$ ³T_g (F)
		363	27,548	³A_2g (F) $\to$ ³T_1g (P)
		316	31,646	n $\to π^{*}$
		264	37,879	$π \to π^{*}$
8	[(HL)Cu(Cl)₂(H₂O)₂]	490	20,408	²B₁ $\to$ ²B₂
		460	21,739	²B₁ $\to$ ²E
		332	30,120	n $\to π^{*}$
		258	38,760	$π \to π^{*}$
9	[(HL)₂Zn(Cl)₂]	330	30,303	n $\to π^{*}$
		260	38,462	$π \to π^{*}$

3.1.8

3.1.8 Thermal analyses (DTA and TGA)

TGA and DTA curves in the range of 27–525 °C were collected for the complexes, which confirmed that they were thermally stable up to 100 °C. The thermal data for the complexes are summarized in Table 4 (El-Saied et al., 2018a; Shakdofa et al., 2021 ).

Table 4 Thermal data of the metal complexes.

Comp. No.	Temp. range (^oC)	DTA (peak)		TGA (Wt. loss %)		Assignment
Comp. No.	Temp. range (^oC)	Endo.	Exo.	Calc.	Found	Assignment
2	201–320	304		8.63	8.11	Loss of two chloride atoms
	321–415	393	–	42.65	42.27	Loss of one ligand (HL)
	416–466	–	428	30.48	31.63	Decomposition with the formation of V₂O₃
3	189–286	–	215	8.62	8.26	Loss of two chloride atoms
	287–416	–	299	42.60	41.93	Loss of one ligand (HL)
	417–493	747	–	30.31	31.72	Decomposition with the formation of Cr₂O₃
4	133–265	–	160	7.03	6.81	Loss of two molecules of coordination water
	266–344	–	–	13.84	14.27	Loss of two chloride atoms
	345–496	–	381	65.28	64.30	Decomposition with the formation of MnO
5	160–264	–	256	2.23	2.13	Loss of molecule of coordination water
	265–378	374	–	4.39	4.22	Loss of chloride atom
	379–498	458	–	73.62	74.20	Decomposition with the formation of Fe₂O₃
6	159–253	–	–	2.22	2.47	Loss of molecule of coordination water
	254–358	–	332	4.37	4.80	Loss of chloride atom
	459–494	468	–	72.96	72.31	Decomposition with the formation of Co₂O₃
7	179–243	–	–	2.22	2.52	Loss of molecule of coordination water
	244–361	–	341	4.37	4.88	Loss of chloride atom
	362–514	438	–	84.21	83.76	Decomposition with the formation of NiO
8	115–235	–	–	6.92	6.47	Loss of two molecules of coordination water
	236–304	–	262	13.61	14.83	Loss of two chloride atoms
	305–489	341	–	64.20	65.12	Decomposition with the formation of CuO
9	224–316	–	–	8.47	8.62	Loss of two chloride atoms
	317–465	–	382	81.82	82.13	Decomposition with the formation of ZnO

3.1.9

3.1.9 XRD analysis

The XRD patterns were recorded for the ligand and its complexes. The crystal structure details for all compounds are listed in Table 5. It was noted that the V(III) and Zn(II) complexes have hexagonal crystal systems. Meanwhile, the ligand and Ni(II) complex have orthorhombic crystal systems, while that of the Cr(III) complex is monoclinic, that of the Fe(III) complex is cubic, and those of the Mn(II), Co(III), and Cu(II) complexes are triclinic. Peak broadening in the XRD patterns signifies that the particles are on a nanometre scale (El-Shafiy et al., 2017). This is supported by the parameters of the crystal structures ranging from 12 nm to 217 nm (Saeed et al., 2014). The XRD patterns of the Co(III), Cu(II), and Zn(II) complexes are shown in Figs. 5, 6, and 7 , respectively.

Table 5 The unit cell parameters and crystal data of the ligand and its metal complexes.

Parameters	compounds
Parameters	HL	V(III)	Cr(III)	Mn(II)	Fe(III)	Co(III)	Ni(II)	Cu(II)	Zn(II)
a (Å)	13.179	9.878	24.02	9.692	13.62	8.148	10.082	10.66	12.550
b (Å)	11.045	9.878	8.541	10.072	13.62	9.337	20.16	12.46	12.550
c (Å)	19.731	10.20	14.44	10.300	13.62	11.259	18.92	13.93	7.13
Alfa (°)	90.0	90.0	90.0	80.57	90.0	70.13	90.0	117.8	90.0
Beta(°)	90.0	90.0	93.96	68.40	90.0	77.67	90.0	100.1	90.0
gamma(°)	90.0	120.0	90.0	76.21	90.0	86.09	90.0	94.9	120.0
Volume of unit cell(Å³)	2872	862	2956	904.8	2524	787	3844	1582	973
Crystal size (nm)	217	12	55	43	19	43	31	20	24
Crystal type	Orthorhombic	Hexagonal	monoclinic	Triclinic	Cubic	Triclinic	Orthorhombic	Triclinic	Hexagonal
Space group	Pbcm	P-6	C12 / m1	P-1	Pa-3	P-1	P mmm	P-1	P-6

3.1.10

3.1.10 TEM morphological study

TEM was used to further examine the particle sizes and crystallinities of the samples. TEM bright-field images of the ligand and its metal complexes (Figs. 8 and 9) show that the samples comprise small and varying nanoparticles sizes. It can be clearly seen that the metal complex powders show both spherical and rod-shaped nanoparticles, while the ligand powder particles take on rod shapes and are micro-sized. Furthermore, the particles were estimated size of the ligand and metal complexes with a grain size of about 5.0–206.0 nm. These results agree with the XRD data in Table 5.

High-resolution TEM images of the (A) ligand, (B)V(III) complex, (C) Mn(II) complex, and (D) Fe(III) complex.

High-resolution TEM images of the (E) Co(III), (F) Ni(II), (G) Cu(II), and (H) Zn(II) complexes.

3.2

3.2 Biology

3.2.1

3.2.1 In vitro anticancer activities

The in vitro cytotoxic activities of the ligand and its metal complexes towards PC-3, SKOV3 and HeLa tumour cell lines were determined using SBR assays with six different concentrations of each compound (0.01, 0.1, 1, 10, 100, and 1000 µg/mL). By comparing the results with those of a previous study (Matela, 2020), the tested compounds in the present work exhibited highly cytotoxic activity against the selected human cell lines (Fig. 10). The data in Table 6 show that the Cu(II) complex had the highest activity among the tested compounds against PC-3, SKOV3, and HeLa cells with IC₅₀ values of 0.161, 0.063, and 0.087 µg/mL, respectively. Meanwhile, the Ni(II) complex exhibited the lowest toxicity towards the PC-3, SKOV3 and HeLa cells among the tested compounds, giving IC₅₀ values of 1.8287, 1.2502, and 3.8453 µg/mL, respectively. On the other hand, the range of IC₅₀ values of the ligand and the V(III), Cr(III), Mn(II), Fe(III), Co(III), and Zn(II) complexes for the PC-3, SKOV3, and HeLa cells were 0.1786–1.0607, 0.0615–0.8128, and 0.0719–1.534 µg/mL, respectively. It is worth noting that the prepared compounds (1–9) exhibited higher activities than clinically used drugs such as cisplatin (IC₅₀ ∼ 2.4 µg/mL) (Ray et al., 2007), estramustine (IC₅₀ ∼ 0.35–1.3 µg/mL) (Nicholson et al., 2002), and etoposide (IC₅₀ ∼ 17.4 µg/mL) (Aras and Yerlikaya, 2016). Fig. 11 shows the cytotoxic dose–response curves for compounds 1–9 towards selected human cell lines where cells were exposed to the compounds at different concentrations for 72 h.

Screening of anticancer activity of the ligand and its metal complexes against selected human cell lines.

Table 6 The IC₅₀ values (µg/mL) of the tested ligand and its metal complexes against different human cell lines.

No.	Compound	IC₅₀ (µg/mL)
No.	Compound	PC-3	SKOV3	HeLa
1	[HL][C₂₄H₁₈N₂O]	1.0123 ± 0.05	0.2163 ± 0.005	0.5877 ± 0.14
2	[(HL)(L)V(Cl)₂]	0.7262 ± 0.14	0.1997 ± 0.03	0.0719 ± 0.02
3	[(HL)(L)Cr(Cl)₂]	0.7027 ± 0.25	0.0678 ± 0.03	0.7606 ± 0.05
4	[(HL)Mn(Cl)₂(H₂O)₂]	0.1786 ± 0.02	0.2189 ± 0.05	0.9254 ± 0.05
5	[(L)₂Fe(Cl)(H₂O)]	0.3188 ± 0.02	0.8128 ± 0.20	1.5340 ± 0.30
6	[(L)₂Co(Cl)(H₂O)]	1.0607 ± 0.16	0.0615 ± 0.02	0.3921 ± 0.03
7	[(HL)(L)Ni(Cl)(H₂O)]	1.8287 ± 0.10	1.2502 ± 0.20	3.8453 ± 0.32
8	[(HL)Cu(Cl)₂(H₂O)₂]	0.1612 ± 0.005	0.0630 ± 0.003	0.0872 ± 0.01
9	[(HL)₂Zn(Cl)₂]	0.4436 ± 0.07	0.1646 ± 0.04	1.3064 ± 0.46

The dose–response curves of the cytotoxicities of compounds 1–9 towards PC-3, SKOV3, and HeLa human cell lines. Cells were exposed to different concentrations of the compounds for 72 h. Cell viability was determined by sulforhodamine B (SRB) staining.

3.2.2

3.2.2 Antimicrobial activity

The data in Table 7 show the antibacterial and antifungal activities of ligand and its metal complexes in different volumes against the growth of S. enterica ser. typhi, (Fig. 12) and C. albicans (Fig. 13). It was observed that the Co(III) and Zn(II) complexes had intermediate antibacterial activities against S. enterica ser. typhi when used in volumes of 30, 20, and 10 µL (Fig. 14). On other hand, in the same volumes, the V(III), Cr(III), Mn(II), Fe(III), Ni(II), and Cu(II) complexes and the ligand do not exhibit antibacterial activities against S. enterica ser. typhi. However, the V(III) complex had the highest activity against C. albicans when used in volumes of 30, 20, and 10 µL (Fig. 14). The Fe(III) and Cr(III) complexes also had high antifungal activities against C. albicans in volumes of 30 µL and 20 µL (Fig. 14). The Co(III) and Cu(II) complexes in volumes of 30, 20, and 10 µL had intermediate antifungal activities against C. albicans, while the Mn(II), Ni(II), and Zn(II) complexes and the ligand showed weak antifungal activities against C. albicans when used in the same volumes.

Table 7 Antibacterial and antifungal activities of different levels of the ligand and its metal complexes against the growth of Salmonella enterica serovar Typhi (S. enterica ser. Typhi) and Candida albicans.

No.	Compound	Salmonella typhi			Candida albicans
No.	Compound	30 µL	20 µL	10 µL	30 µL	20 µL	10 µL
–	DMSO	0	0	0	0	0	0
1	[HL][C₂₄H₁₈N₂O]	0	0	0	4	3	2
2	[(HL)(L)V(Cl)₂]	0	0	0	13	12	9
3	[(HL)(L)Cr(Cl)₂]	0	0	0	11	10	8
4	[(HL)Mn(Cl)₂(H₂O)₂]	0	0	0	5	3	0
5	[(L)₂Fe(Cl)(H₂O)]	0	0	0	12	11	9
6	[(L)₂Co(Cl)(H₂O)]	9	8	7	10	9	7
7	[(HL)(L)Ni(Cl)(H₂O)]	0	0	0	4	3	0
8	[(HL)Cu(Cl)₂(H₂O)₂]	0	0	0	9	8	6
9	[(HL)₂Zn(Cl)₂]	7	6	5	5	4	2
–	Gentamycin	–	–	2	–	–	–
–	Clotrimazole	–	–	–	–	–	3

Note: Zone of inhibition in mm.

Antibacterial activities of the ligand and its metal complexes.

Antifungal activities of the ligand and its metal complexes.

Inhibition zone of the (A) Co(III) complex against S. enterica ser. Typhi growth, and those of the (B) V(III), (C) Fe(III), and (D) Cr(III) complexes against C. albicans growth.

4 Conclusion

In this work, we have synthesized a new Schiff base and employed it as a ligand in various metal complexes. Spectral, elemental, and thermal analyses, as well as conductivity measurements, confirmed that the ligand adopted bidentate behaviour and bonded with the metals through its azomethine nitrogen atom and its phenolic oxygen atom, thus exhibiting octahedral geometries. XRD analysis of the complexes indicated that they were of various structures: triclinic, orthorhombic, hexagonal, monoclinic, and cubic. TEM analysis confirmed that the metal complex powders contain both spherical and rod-shaped nanoparticles, while the ligand powder shows rod-shaped, micro-size particles. The antibacterial and antifungal activities of the ligand and its complexes against S. enterica ser. typhi and C. albicans were investigated by the hole plate diffusion method. It was observed that the Co(III) and Zn(II) complexes had intermediate antibacterial activities, while the V(III) complex demonstrated the highest activity against C. albicans fungi among the tested complexes. Furthermore, the in vitro antitumor results showed that the Cu(II) complex had the highest activity among the tested compounds against PC-3, SKOV3, and HeLa cells. Remarkably, the ligand and all its metal complexes showed higher antitumour activities against these selected human cell lines than clinically used drugs such as cisplatin, estramustine, and etoposide.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

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Introduction

Materials and methods

Materials and measurements
Preparation of ligand (HL) (1)
Preparation of metal complexes
Cell culture
Cytotoxicity assay
In vitro antibacterial and antifungal activity

Results and discussion

Chemistry
Biology

Conclusion

Funding

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