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Novel Cd(II) complex bearing naproxen and imidazole ligands: Synthesis,

single-crystal X-ray, structural elucidation, Quantum chemical

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investigation, molecular docking, antioxidant and antimicrobial screening

Abdulbasit Anoze Aliyu1, 2, Joshua Ayoola Obaleye1*, Abdullahi Ola Rajee1, Rawlings
A. Timothy3, Favour A. Nelson3, Monu Joy4

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1Department of Chemistry, Faculty of Physical Sciences, University of Ilorin, Ilorin, Nigeria.

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2Department of Chemistry, Faculty of Natural Sciences, Kogi State (Prince Abubakar Audu)
University, Anyigba, Kogi, Nigeria

3 Computational and Bio-Simulation Research Group, University of Calabar, Calabar, Nigeria.

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4Department of Chemistry & Biochemistry, The University of Texas at Dallas, Richardson, TX 75080,
USA
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*Corresponding author email: jobaleye@yahoo.com

Abstract
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A novel mixed ligand Cd(II) complex [Cd(nap)2(imd)3] bearing naproxen and imidazole ligands have
been synthesized. Characterization of the mono-nuclear complex was carried out via: 1H & 13C-NMR,
FTIR, UV-vis and MS and the structure validated with SC-XRD studies. The complex forms a
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monoclinic crystal structure with space group P21 and a = 13.581(8) Å, b = 8.290(5) Å, c = 16.693(10)
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Å, a = γ = 90°, b = 109.352(18)°,V = 1773.1(18) Å . FTIR data confirmed the binding of the
naproxenato ligand via the deprotonated oxygen atom to the cadmium (II) ion. The coordination
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sphere around the Cd(II) center is a 7-coordinate system with a distorted pentagonal bipyramidal
geometry having a CdN3O4 chromophore with bidentate ligation of the carboxylate ligand naproxen.
Docking with the ADP-ribosyl transferase binding component protein (PDB: 6v1s) gave a binding
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affinity of -9.8 kcal/mol for the complex [Cd(nap)2(imd)3], establishing eight hydrogen bonds, with
the shortest bond length observed in serine. It exhibited greater binding affinity (-9.5 kcal/mol) and
established a higher number of hydrogen bonds compared to azithromycin. Tyrosine A:100 exhibited
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the shortest bond length among the six hydrogen bond interactions detected during docking with
prostaglandin reductase 2 (PDB: 2zb7), resulting in a binding affinity of -8.6 kcal/mol. In comparison,
ibuprofen demonstrated lower binding affinity (-7.6 kcal/mol) and formed fewer hydrogen bonds.

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 Overall, molecular docking results strongly suggest that [Cd(nap)2(imd)3] exhibits high binding
affinities with both ADP-ribosyltransferase binding component and prostaglandin reductase 2,

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indicating its potential as a candidate for treating bacterial infections and inflammation. The complex
exhibited higher radical scavenging activity than the unbound ligands but was less than the ascorbic
acid standard in the in-vitro antioxidant experiment. The complex showed promising inhibitory action

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against some bacterial and fungal strains. The current results may be due to the combined impact of
the ligands and the metal ion during complex formation.

Keywords: NSAID; Naproxen; Imidazole; Antioxidant; Antimicrobial; DFT; Molecular docking

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1.0 Introduction

Metal complexes have garnered a noticeable attention in the expansive field of coordination

chemistry, offering diverse applications ranging from ion exchange, hydrogen storage, and catalysis
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to biological and medicinal functions [1-6]. The intricate synergy between ligands and metal ions

within these complexes performs a major function in ascertaining their properties and broadening
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their applications. Thus, the coordination behavior of a metal ion goes a long way in influencing the

biological activity of the resulting complex [7-10]. Carboxylic acid-derived ligands, a prominent

category in coordination chemistry, have garnered substantial interest owing to their diverse modes
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of coordination as well as robust association with heteroatomic ligands containing nitrogen atoms via

hydrogen bonding [11-13]. This versatility enables the design of intriguing structures with properties
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fine-tuned for various practical applications. Although there has been significant advancement in

creating coordinating complexes. However, a comprehension of the self-harmony process,

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particularly controlling experimental conditions viz: ratio of metal to ligand, reaction temperature,

pH, and choice solvent resulting to the obtained structures, have proven to be persistently tasking

[14,15]. Ligands such as imidazole and pyridine, frequently investigated as co-ligands with
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carboxylic acids, add another layer of complexity and versatility to these systems [16-18].

The non-steroidal anti-inflammatory drugs (NSAIDs) constitute a pharmacological class widely

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employed in relieving pain, reduction of inflammation, and attenuation of fever. Operating by

inhibiting cyclooxygenase enzymes, NSAIDs, including naproxen (Fig.1a), with IUPAC name (S)-2-

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 (6-methoxynaphthalen-2-yl) propanoic acid, exert their effects by blocking prostaglandin production

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responsible for pain and inflammation [19,20]. The therapeutic applications of NSAIDs span various

conditions, from osteoarthritis and rheumatoid arthritis to headaches, migraines, and dysmenorrhea

[21,22]. Notably, the interaction between NSAIDs or metal-NSAID complexes and DNA has been of

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profound significance due to their potential anticancer, antioxidant, and anti-inflammatory activities

[16,17, 23-25]. The primary clinical application of NSAIDs lies in their efficacy as anti-

inflammatory agents, particularly in musculoskeletal diseases [21].

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The combination of NSAIDs with transition metal ions has been a notable area of interest,

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exploring their potential therapeutic applications. Aspirin, Naproxen, and Ibuprofen among NSAIDs

eminently acts as coordination ligands in binding to metal ions to form stable complexes. Naproxen,

known for its painkilling and anti-inflammatory and properties, is widely employed as a
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prominent ligand in several metal complexes [26-29]. Additionally, imidazole (Fig.1b), a versatile
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ligand known for its coordination ability and biological relevance [30-33], complements naproxen in

forming mixed ligand complexes. The exploration of mixed ligand complexes has become an

intriguing avenue for researchers, with the potential to offer enhanced stability and tailored

reactivity.
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Cadmium, a transition metal, presents an intriguing platform for the design of mixed ligand
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complexes, sharing some similarities with zinc in terms of coordination preferences due to their

similar electronic configurations. The diverse coordination geometries of cadmium prompt

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investigations into their potential applications in various biological contexts [23,34-38]. While recent

studies have explored the cytotoxic effects of cadmium-containing compounds on cancer cells,

antimicrobial, antiviral, and antioxidant investigations have revealed their potential applications in
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combating microbial and viral infections, as well as mitigating oxidative stress [39-41]. However, a

comprehensive understanding of the crystal structure, quantum chemical properties, and molecular
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interactions of cadmium complexes with mixed ligands is essential for elucidating their potential

biological activities.

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 This manuscript presents a comprehensive investigation into the cadmium complex formed by the

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mixed ligands naproxen and imidazole. Naproxen, a member of the phenylalkanoic acid class,

emerges as a pivotal ligand, contributing to the expanding knowledge of mixed ligand metal

complexes with potential applications in medicinal chemistry. The integrated use of crystallography,

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quantum chemistry, and molecular docking provides a multifaceted perspective on the cadmium

complex, paving the way for further exploration of its pharmacological properties. Our interest in

this study is driven by the scarcity of structural features for cadmium complexes formed with

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naproxen and imidazole ligands, as this is the first of such complex to be reported, and the potential

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benefits derived from exploring such mixed ligand systems. Through this investigation, we aim to

elucidate the structural and electronic features that underlie the bioactivity of the cadmium complex,

thereby contributing to the growing understanding of mixed ligand metal complexes and their
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applications in medicinal chemistry.
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Fig.1: Chemical structure of naproxen and imidazole with atom numbering

2.0 Experimentation
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2.1 Reagents and Materials

All reagents are of reagent grade and were used as obtained without any further purification.
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Analytical grade naproxen, imidazole, DDPH (1,1-diphenyl-2-picrylhydrazyl), methanol, DMF, and

DMSO are products of Sigma-Aldrich, USA. NaOH and Cd(OAc)2.2H2O are products of Merck

chemicals. Isolates of Aspergillus niger, Candida albicans, Staphylococcus aureus, Bacillus

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anthracis, Salmonella typhi, and Escherichia coli were used for the antimicrobial screening.

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 2.2 Synthesis of the complex

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The complex has been successfully synthesized via the direct reaction of naproxen (nap) with

imidazole (IMD) in a CH3OH/H2O solvent system (Scheme 1). A 10 mL methanolic solution of nap

(0.4 mmol, 92.1 mg) and NaOH (0.4 mmol, 16 mg) was subjected to continuous stirring for 1 hour at

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room temperature. Following this, (0.2 mmol, 53.3 mg) solution of Cd(OAc)2.2H2O dissolved using 5

mL of methanol-water (3:2) was added. Subsequently, 5 mL of a methanolic solution containing 0.4

mmol (27.2 mg) of imidazole was slowly incorporated into the reaction mixture. The entire mixture

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was subjected to continuous stirring for an additional duration of 5 hours at ambient temperature.

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After a gradual process of solvent evaporation for five days, colorless crystals were obtained, which

were deemed appropriate for study using SC-XRD. The crystals were harvested from the mother

liquor, subjected to air drying, and, after that, preserved for subsequent examination. Scheme 1
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displays the synthesis pathway for the complex.
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[Cd(nap)2(imd)3]: Colourless crystals, Yield: 76 %, M.W = 775.13, m.p = 175 ᣞC, FTIR (cm-1):
3406, 3126, 3054, 2939, 2846, 2615, 2425, 2323, 2275, 2190, 2054, 2010, 1912, 1771, 1676, 1554,
1492, 1399, 1259, 1212, 1162, 1115, 1063, 1023, 925, 890, 853, 813, 751, 689, 650, 575, 528, 471.
Elemental Analysis (C37H38CdN6O6): Calc. (%): C, 57.33; H, 4.94; N, 10.84, found (%): C, 57.38; H,
4.88; N, 11.02. UV-Vis: λmax (nm): 265, 273, 321, 335, TOF-MS: 777.20 [M+2]+, 1H-NMR (400
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MHz, DMSO- d6) (δ/ppm): 12.03 (s, NH(1)-imd), 7.73 (s, H2-imd), 7.66 - 7.71 (m, 1H, Ar-H), 7.68 (dd,
1H, Ar-H), 7.47 (d, 1H, Ar-H), 7.24 (d, H4-imd), 7.10 (d, 1H, Ar-H), 7.08 (d, 1H, Ar-H), 7.01 (s, H5-
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imd), 3.86 (s, 3H, OCH3), 3.63 (q, 1H, -CHCH3), 1.77 (s, 3H, CH3), 1.40 (dd, J = 6.8, 5.6 Hz, 3H). 13C-
NMR (100-125 MHz, DMSO- d6) (δ/ppm): 176.64 (C(14) & C(15)) (-COO), 157.08 (C(2) & C(26))
(C-OMe), 140.28 (C(29), C(32) & C(35)) (Cimd(2)), 133.19 C(10) (2-napthalene), 129.38 (C(5)) (2-
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napthalene), 128.92 (C(9)) (2-napthalene), 127.80 (C(30), C(33) & C(36)) (Cimd(5)), 126.46 (C(8))
(2-napthalene), 125.60 (C(31), C(34) & C(37)) (Cimd(4)), 118.56 (C(3)) (2-napthalene), 106.14 (C(7))
(2-napthalene), 55.55 (C(1) & C(28)) (CH3-O), 47.28 (C(12) & C(16)) (CH-COO), 20.63 (C(13) &
C(17)) (CH3-C-COO).
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 ed
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Scheme 1: The Synthetic pathway for obtaining the complex [Cd(nap)2(imd)3]

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2.3 Instrumentation and physical determinations

FTIR spectra were obtained using a Bruker Alpha-II Platinum ATR spectrometer within a

range 4000 - 400 cm-1. The electronic absorption spectra were meaured in a Perkin Elmer lambda 25
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UV/VIS spectrophotometer. NMR spectra were obtained using a Bruker Avance III spectrometer

using TMS as an internal standard with chemical shifts (δ) presented in ppm. The percentage of
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Carbon, Hydrogen and Nitrogen present was obtained using a Thermoscientific Flash 2000 organic

elemental CHNSO Analyzer.

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2.4 Determination of crystal structure

X-ray diffraction data from a single crystal of [Cd(nap)2(imd)3] was collected on a Bruker
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APEX-II X-ray diffractometer that has a Mo IμS microfocus X-ray source (λ = 0.71073 Å) and a CCD

detector. The measurement was conducted at 100 K utilizing an Oxford Cryosystems low-temperature
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device. The APEX-IV software suite was utilized for data collection, cell refinement, and data

reduction. Absorption adjustments were implemented with using SADABS [42]. The space group

assignments were determined by the investigation of systematic absences, E-statistics, and iterative
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refinement of the structures. The structure was identified by determined using a dual-space technique

using SHELXT [43] and then improved through full-matrix least squares with SHELXL [44].
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Anisotropic displacement parameters were used to refine all atoms except hydrogen. The C-H atoms

were positioned based on idealized geometry and adjusted with fixed isotropic displacement

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 parameters using a riding model. CCDC 2323501 contains the supplementary crystallographic data

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for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk.

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2.5 Computational Study

2.5.1 DFT Approach

The structure under investigation in calculations utilizing density functional theory (DFT) was shown

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using Gauss View 6.0.16. [45], while the Gaussian 16 suite of programs was utilized in conducting all

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computations [46]. The ωB97XD/def2svp method was employed for structural optimization, as

illustrated in Fig.4. By using Chemcraft 3.0, the optimized structure as well as the molecular orbital

were visualized. er
Furthermore, the NBO 7.0 module was integrated into Gaussian 16 program to conduct Natural Bond

Orbitals (NBO) analysis [47]. This allowed for the exploration of orbital contributions, distribution of
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atomic charge as well as contributions to stabilization energy and charge transfer. The examination of

non-covalent interactions (NCI) was done using the Multiwfn 3.7 package [48]. To provide a visual

representation, 3-dimensional iso-surfaces were generated via VMD [49], along with 2-dimensional
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RDG maps presented using GNU plots. A delve into crystallographic analysis ensured the

investigation of both inter and intra-molecular interactions. Visualization of the crystal structure was
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done using Hirshfield surface analysis by the generation of fingerprint and Hirshfield surface plots

carefully crafted with a 3.0 Version of Crystal Explorer [50].

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2.5.2 Molecular Docking Protocol

Molecular docking was used to simulate how a small molecule interacts with proteins at the atomic
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level. This allowed us to observe how these molecules behave inside the target protein’s binding site

while helping to deduce the essential biological processes [51]. The three primary objectives of
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molecular docking include predicting the structure of the ligand-receptor, visualizing the

conformation as well as ranking such conformations using a scoring algorithm. The selected protein

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 from Chloridoids difficile (PDB:6v1s) The ADP-ribosyl transferase binding component (ARC) is a

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protein that is essential for the virulence of Chloridoids difficile and belonging to the ADP-ribosyl

transferase protein class, which are responsible for the ADP-ribosylation of other proteins [52]. ADP-

ribosylation is a post-translational modification that can alter the function of a protein. In the case of

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C. difficile, ARC is responsible for ADP-ribosylations in the Rho family of GTPases. This ADP-

ribosylation leads to the activation of Rho, which in turn causes the actin cytoskeleton to reorganize

[53]. This reorganization of the actin cytoskeleton is essential for the formation of the C. difficile

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biofilm, which is a protective layer that allows the bacteria to survive in the environment. Also, a

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protein from Homo sapiens, Prostaglandin reductase 2(PDB: 2zb7), is a pro-inflammatory mediator

that is involved in the initiation and perpetuation of inflammation. PGD2R activation leads to the

release of inflammatory cytokines and chemokines, which recruit inflammatory cells to the site of
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inflammation. PGD2R also promotes the production of prostaglandin E2 (PGE2), which is another

pro-inflammatory mediator [54], was obtained from Protein Data Bank (PDB) (www.RSCPDB.org)
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and assembled on Biovia Discovery Studio 21 for analysis [55]. This included deleting native ligands

linked to the proteins from the PDB, adding missing hydrogen atoms, and removing water molecules.

The produced proteins, our chemical, and reference medications were then entered into Pyrx [56] for
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docking. Transformation of the proteins into macromolecular layout, while grid box argument helps in

centrally defining the crystal structures. The results of docking were estimated based on binding
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affinity, and conformations exhibiting some interactions via the active-site residues were carefully

selected through extensive research utilizing PyMOL and Discovery Studio. [57]. In increasing the

validity of the results, unique attention was given to elucidating the target protein’s interaction with
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the compounds. Crucially, Discovery Studio was used to do a thorough investigation of these

interactions, which included alkyl interactions, hydrogen and halogen bonds and Van der Waals
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forces. An important component of biological systems, hydrogen bonding, was specifically addressed

[58]. The tendency of the protein ligand interactions to recover from perturbations was inferred from

the bond length of H-atom; with shorter lengths suggesting stronger interaction between the ligand
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and the protein. The thorough molecular docking method offered insightful information about the

complex molecular interactions in the compound.

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 2.6 Biological studies

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2.6.1 Antioxidant activity

(a) DPPH Assay

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Each 2 mL containing 1000, 500, 250, 125, 62.5 µg/mL of the test sample and ascorbic acid

(standard) was added to a methanolic solution of DPPH (2.0 mL of 0.3 mM solution). The mixture

obtained was left to remain in the dark room for 30 mins after which absorbance was read at 517 nm

[59]. The experiments were done in triplicate, and average readings were taken. The percentage

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scavenging activity for the radical (RSA) is calculated using formulae

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Where Ac =absorbance of the control and As =absorbance of the sample
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To determine the IC50 (half-maximal inhibitory concentration) values [60], a plot of the Log of

concentration (μg/mL) against percentage inhibition of the samples was generated, and IC50 values

evaluated from the equation of the line obtained.

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(b) Phosphomolybdate Assay

The phosphomolybdate assay was employed in evaluating the total antioxidant capacity of the
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compound [61]. Briefly, the method involves the addition of 3.0 mL of the phosphomolybdate reagent

(4.0 mM (NH4)2MoO4, 0.6 M H2SO4, and 28 mM Na3(PO4)) into a test tube containing 0.3 mL of test
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sample. The test tube and its content were after that enclosed with aluminium foil and incubated for

90 mins at 95 °C. Following its cooling to ambient temperature using ice, each solution’s absorbance

was recorded against a blank at 765 nm. All measurements were done in triplicate using ascorbic acid
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as a standard.

2.6.2 Antimicrobial screening

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 The antibacterial and antifungal activity of the compounds was evaluated using the

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agar well diffusion technique. The inhibitory action of the samples was evaluated against

(gram +) (Bacillus anthracis and Staphylococcus aureus), (gram –) (Salmonella typhi and

Escherichia coli) and fungal (Aspergillus niger and Candida albicans) strains. The samples

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were dissolved in DMSO. Accordingly, following the incubation at 37 °C, 24 and 48 hrs for

the bacteria and fungi, the inhibition zone diameters (mm) formed around each well

containing the test compound were accurately recorded in millimeters [62,63].

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3.0 Results and Discussion

3.1 Crystal structure description of [Cd(nap)2(imd)3]

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The compound [Cd(nap)2(imd)3] exhibited a monoclinic crystal structure with the P21 space group.

The asymmetric unit comprises three neutral imidazole units and two units of ligands contributing -2
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charges to a Cd(II) ion with the atoms situated in crystallographically separate locations. The Cd(II)

ion is a 7-coordinate system with a distorted pentagonal bipyramidal geometry. The distance between

carboxylate oxygen atoms and Cd(II) ranges from 2.42 to 2.498 Å. The naphthyl rings of both ligands
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are situated almost perpendicular to each other [∠C22–C23–C18–C9: 168.3(11)º]. Despite the non-

existence of significant π–π stacking interactions, [Cd(nap)2(imd)3] exhibits strong classical and non-
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classical intermolecular hydrogen bonding interactions. The N–H groups in all three imidazoles can

play the role of potential H-bond donors, whereas the oxygen atoms of the carboxylate group can act
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as acceptors [N1–H1⋯O5(-x+1, y+1/2, -z+1): 2.739(15) Å; N3–H3⋯O2(-x, y-1/2, -z+1): 2.756(14)

Å; N5–H5⋯O4(x, y-1, z): 2.839(15) Å]. The crystallographic information is presented in Table
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Table 1. Crystal data and structure refinement for [Cd(nap)2(imd)3]

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Empirical formula C37H38CdN6O6

Formula weight 775.13

Temperature 100(2) K

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Wavelength 0.71073 Å

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Crystal system Monoclinic

Space group P 21 er
Unit cell dimensions a = 13.581(8) Å a= 90°.
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b = 8.290(5) Å b= 109.352(18)°.

c = 16.693(10) Å g = 90°.

Volume 1773.1(18) Å3
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Z 2
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Density (calculated) 1.452 Mg/m3

Absorption coefficient 0.670 mm-1

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F(000) 796

Crystal size 0.350 x 0.120 x 0.080 mm3

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Theta range for data collection is 1.589 to 26.653°.

Index ranges -17<=h<=17, -10<=k<=10, -21<=l<=21

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Reflections collected 39672

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 Independent reflections 7399 [R(int) = 0.2030]

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Completeness to theta = 25.242°100.0 %

Refinement method Full-matrix least-squares on F2

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Data/restraints/parameters 7399 / 915 / 455

Goodness-of-fit on F2 1.031

Final R indices [I>2sigma(I)] R1 = 0.0716, wR2 = 0.1511

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R indices (all data) R1 = 0.1268, wR2 = 0.1766

Absolute structure parameter -0.06(5)

Extinction coefficient n/a

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Largest diff. peak and hole 1.905 and -0.950 e.Å-3
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CCDC 2323501
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 Fig. 2: An ORTEP diagram for the asymmetric unit of [Cd(nap)2(imd)3] with atom numbering. H -
atoms are omitted for clarity.

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Fig.3: The crystal packing of [Cd(nap)2(imd)3]

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3.2 Molecular structure investigation

3.2.1 Geometry optimization

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 It is established that shorter bond lengths indicate better reactivity between the atoms involved

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compared to longer bond lengths, which are more stable [64]. In this study, the various atoms in this

complex are studied based on their bond lengths and are compared to experimental values calculated

from the ChemDraw 3D PDB file. From our analysis, Cd43 is being used as the central metal atom,

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whereas experimentally, Cd1 is used. The closest atoms to the Cd central metal atom, which are

nitrogen and oxygen are being studied closely. The bond length of Cd43-O20 is 2.416 Å according to

Table 2, however the experimental bond Cd1-O3 has a bond length of 2.42 Å, which closely aligns

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with our study results. Cd43-N58 has a bond length of 2.413 Ǻ while experiment Cd1-N10 has a value of

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2.348 Ǻ, which is somewhat less compared to our obtained theoretical values results. The bond

lengths indicate that the link between Cd and N and O atoms is about equal in magnitude. The bond

between both atoms and the Cd bond length is at least 2.0 Ǻ, which signifies a double bond. Secondly,
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other bonds that the analyzed system has in common with the experiment are also being studied. N51-

C53 has a magnitude of 1.318 Ǻ while the experimental N11-C17 is 1.316 Ǻ, which shows a very
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minimal difference of 0.002 Ǻ. The H82-O79 has a value of 2.085 Ǻ, and the experimental H82-O72 is

2.905 Ǻ, which is a very large difference from our result. This significant disparity is likewise

comparable to the C-H bond designations and the N-H bonds. Now, in terms of magnitude, the Cd-O
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bond has the highest magnitude, while the N66-H57 has the smallest magnitude of 1.013 Ǻ. Also, it can

be deduced that N-C, C-H and N-H bonds are single bonds, while Cd-O and Cd-N are double bonds.
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Table 2 presents the selected theoretical and experimental bond lengths of the synthesized

[Cd(nap)2(imd)3] complex.
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Table 2. Examined bond lengths of the complex via theoretical and experimental.

Complex Bond label Theoretical Bond Experimental

Length (A)
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Bond Length (A)

[Cd(nap)2(imd)3] Cd43-O20 2.416 Cd1-O3 2.420
Cd43-N58 2.413 Cd1-N10 2.348
N51-C53 1.318 N11-C17 1.316
H82-O79 2.085 H82-O72 2.905
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C14-H44 1.408 C17-H20 0.981

N66-H57 1.013 N11-H12 0.880

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 ed
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Fig. 4: Optimized structure of [Cd(nap)2(imd)3] illustrating the lengths of the bond

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connecting the doped metal and the surrounding atoms.

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3.3 Bonding analysis

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 3.3.1 Hirshfeld Surface Analysis

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Hirshfeld surface analysis is a computational approach used in drug design to understand the

intermolecular interactions between a therapeutic molecule and its target. [65]. This method relies on

the Hirshfeld partitioning of a crystal structure's electron density, enabling the visualization and

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quantification of individual atoms' contributions to intermolecular interactions [66]. The research

offers useful insights into the characteristics and intensity of several contacts, including electrostatic,

hydrogen, and van der Waals interactions such as hydrogen, van der Waals, and electrostatic

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interactions. Moreover, it aids in discovering possible binding sites on the target protein that are not

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easily visible in the crystallographic structure. It helps in defining the arrangement of molecules and

recognizing possible variations or combined crystal structures that may affect the drug's effectiveness

[67]. Therefore, it improves the logical development of potential drugs.

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The crystal packing interactions of the [Cd(nap)2(imd)3] are analyzed using Hirshfeld surface analysis,
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along with the fingerprint plot. The Hirshfeld surface maps in Fig.5 show that intermolecular

interactions with distances less than the sum of van der Waals radii are represented by red patches.

Van der Waals interactions are shown by white areas, whereas lengthier contacts are represented by
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blue areas [68]. Fig.5 shows that the red color represents N-H…O intermolecular interaction. The

distances from a location on the Hirshfeld surface to the closest atoms outside and within the surface
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are labeled as de and di, as seen in Fig.6. The interactions in the complex and their percentage

abundance are as follows: C…C 0.6 %, C…H 15%, C…O 0.1%, C…N 0.3%, H…C 12.9%, H…H

51.2%, H…N 1.7%, H…O 7.4%, N…H 1.9%, N…N 0.3%, N…O 0.2% and O…H 7.9%. The data
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obtained so far indicate that the H…H interaction is the prevalent force in the compound, suggesting

high selectivity, potency and binding specificity towards the target protein.
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Fig. 5: Visualization of the intermolecular interactions in [Cd(nap)2(imd)3] using the d norm,

d i, shape index, and fragment patch-mapped Hirshfeld surface.
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 ed
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Fig.6: Fingerprint plots showing the distribution of different interactions for

[Cd(nap)2(imd)3]
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 ed
3.4 Vibrational analysis

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Vibrational analysis is a significant spectroscopic technique used in numerous scientific domains like

chemistry, physics, and materials science. This method involves examining the oscillatory patterns

within molecules and materials to gain valuable insights into their arrangement, composition, and

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behavior [69]. Vibrational spectroscopy provides scientists with precise instruments for identifying

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and characterizing molecules, offering detailed information about their structural characteristics. By

analyzing these vibrational modes, scientists can infer details such as bond lengths, angles, and

symmetry within a molecule. The crucial role of vibrational analysis lies in unraveling the
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complexities of chemical bonding within molecules, enabling the differentiation between different

types of chemical bonds (single, double, or triple) and the identification of functional groups. This
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information is fundamental for understanding chemical reactions and reactivity [70]. Vibrational

analysis is commonly utilized in drug research and development within the pharmaceutical sector. It

aids in assessing the purity of drug compounds, elucidating the structures of complex biomolecules,
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and monitoring the progress of chemical reactions in drug synthesis processes. Vibrational

spectroscopy also extends its application to biomedical research and diagnostics, proving invaluable
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in studying biological entities such as proteins, DNA, and lipids. Additionally, it serves as a reliable

tool for detecting abnormalities in tissues, thereby significantly contributing to disease diagnosis and

advancements in medical research [71]. The theoretical vibrational frequencies and assignments for
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the [Cd(nap)2(imd)3] complex is presented in Table S14 in the supplementary materials.

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C-H Vibration

Previous studies have recorded that the spectral range of 3000-3100 cm-1 encompasses aromatic and

Sp2 C-H stretching vibrations, whereas Sp3 C-H stretch vibrations typically occur in the range 3000 -
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2850 cm-1 [72]. Notably, the aromatic and Sp2 C-H vibrations, as observed in this compound, span

3100.87-3314.88 cm-1. Similarly, the Sp3 C-H stretching vibrations occurred within the range

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 3030.72-3185.57 cm-1. Crucially, one can infer that the theoretically calculated C-H stretching

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vibrations match the values reported in previous researches.

N-H Vibrations

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The N-H stretching vibrations usually falls between 3500 - 3300 cm-1 in the infrared spectrum [73].

Observably, the theoretical N-H stretching vibrational frequency was observed around 3640.35-

3679.79 cm-1. The estimated frequencies somewhat exceed the stated values, although they are in

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close alignment. This confirms the stable geometry conformation of the study complex.

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C=C Vibrations

The documented literature indicates that the range for C=C stretching vibrations in IR spectroscopy
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usually ranges from 1680 - 1600 cm-1 [74]. The theoretical C=C vibrations were observed around

1734.40 - 1656.24 cm-1. Notably, the theoretical values align with the reported values.
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C=O Vibrations

The stretching vibration frequency range for the C=O bond (also known as carbonyl stretching)
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typically falls between 1600 and 1800 cm⁻¹ [75]. In this present study, the C=O stretching vibrations

in this investigation falls within 1688.60 - 1681.14 cm-1. The calculated C=O vibrations fall within the
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range of IR spectroscopy as reported from existing literature.

C=N Vibrations
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The characteristic region for the C-N stretching vibrations in IR spectroscopy, as reported by existing

literature, typically falls between 1400 - 1200 cm-1. Observably, the C-N stretching vibrations were
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seen around 1559.45-1605.91 cm-1 [76]. The reported range for the C-N stretching vibrations is

slightly lower than the theoretical values. However, the result of the calculated vibrational frequencies

for all functional groups present in the study metal complex agrees with reported values from the
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literature. Hence, the compound's selectivity, potency and high binding specificity towards the target

protein is affirmed.

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 3.5 Investigation of electronic property

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3.5.1 HOMO-LUMO and Quantum Descriptor Parameters

Research is being conducted on FMO analysis to comprehend the electronic characteristics of a

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system. Various molecular properties such as HOMO, LUMO, energy gap, ionization energy, electron

affinity, electronegativity, hardness, chemical potential, electrophilicity, and Fermi energy were

analyzed to understand the level of stability and reactivity of the studied complex [77]. The HOMO

energy is determined to be -7.60 eV, and the LUMO energy is determined to be -0.36 eV based on the

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data in Table 3. The energy gap (Eg) is a parameter that measures the conductivity of a system, telling

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us if the system is metallic, semi-metallic or possesses insulating properties [78]. The compound's

energy gap is determined to be 7.24 eV, indicating that it belongs to the category of a semiconductor
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or an insulator. This indicates that the electron transfer from the HOMO to the LUMO is inefficient,

resulting in a system that is less reactive and more stable. The ionization potential (IP) is 7.6 eV,
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signifying that a significant quantity of energy is needed to ionize an electron from the atom. The

electron affinity (EA) is low at 0.36 eV, indicating that the system does not readily attract electrons.

The electronegativity (σ) of 0.13 eV is very low. The hardness (η), which is the degree to which a

system can withstand distortion, has a magnitude of 3.98 eV, indicating a moderate ability to
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withstand pressure and other factors. The electrophilicity (ω) with magnitude 1.64 eV is also very
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low. Lastly, the Fermi energy level (EFL) of 3.62 eV is explained with respect to the energy gap. The

gap between the Fermi energy level and the energy gap is around 4.35 eV, which is a very wide gap,

further confirming the limited electron transport separating the VBM and the CBM.
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Table 3: The HOMO energy, LUMO energy, energy gap (Eg), and quantum descriptor
characteristics in electron volts (eV) of the analyzed complex.
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Complex HOMO- LUMO- Eg IP EA Σ η μ ω EFL

eV eV

[Cd(nap)2(imd)3] -7.60 -0.36 7.24 7.60 0.36 0.13 3.98 -3.62 1.64 3.62
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 3.5.2 Natural Bond Orbital (NBO) Analysis

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The analysis of Natural bond orbital (NBO) is commonly used to understand the computational

solution of the Schrödinger equation and simplify chemical bonding ideas. NBO analysis is the most

successful method for identifying inter- and intra-molecular orbital exchanges within a complex.

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Furthermore, NBO research offers a clear insight into the delocalization of electron density occurring

between filled donor (Lewis) and unfilled acceptor (non-Lewis) natural bond orbitals, highlighting a

more stable donor-acceptor interaction. [79]. The transitions were recorded based on the atomic

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composition of the transition without taking into account their perturbation energy. Second order

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perturbation energy refers to the energy needed in breaking a bond in a system. From Table S15, the

C-C donor to C-C acceptor possesses the highest perturbation of 30.99 kcal/mol. This single transition

can partially account for the fact that C-C transfer in both donors and acceptors are bonds that are
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harder to break compared to other transitions. The transition of lone pair nitrogen donor to lone pair

cadmium has a disturbance of 20.7 kcalmol-1, which is seconds to the C-C transition. The transition
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LP(2)O20-LP*(6) Cd43 has a perturbation energy of 16.49 kcal/mol, followed by the transition from

O42 to the same cadmium atom at an almost similar energy of 14.61 kcal/mol. The least perturbation

energy is recorded in the transition from C-O donor to Cd lone pair, which is 4.72 kcal/mol. In
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conclusion, these transitions, bonds and energies are studied to give in-depth insight into the

electronic properties of [Cd(nap)2(imd)3].

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3.5.3 Non-Covalent Interaction (NCI)

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Non-covalent interactions (NCI), or Reduced Density Gradient (RDG) analysis, is the study of the

forces and interactions between atoms in a molecule, including both intra and intermolecular

interactions [80]. The main examples of NCI include hydrogen bonding, van der Waals forces,
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hydrophobic interactions and electrostatic interactions [81]. In the case of our [Cd(nap)2(imd)3]

complex, both top and side views are captured to facilitate a more comprehensive visual examination.
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The structural maps' green iso-surfaces show non-directional attraction, a symptom of weak

interactions brought on by van der Waals dispersion forces [82]. Strong contacts, primarily due to

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 steric repulsion, are represented by the red iso-surfaces and have a significant impact on the

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conformation and reactivity of ions and molecules. Analysis of Fig.S16 reveals that green surfaces are

dispersed throughout the compound, suggesting relatively weak forces holding it together. This

outcome is advantageous as such weak attraction facilitates the compound's easy dissolution in

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various biological systems, enabling faster diffusion into the bloodstream.

3.5.4 Molecular Electrostatic Potential (MESP)

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Understanding molecular interactions and locating potential sites for electrophilic and nucleophilic

assaults in a molecular system depend on the knowledge of the molecular electrostatic potential, or

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MESP. [83]. This possible map is visually represented by a variety of colors. The red tint on the

MESP map indicates the most negative region, which is favorable to electrophilic attacks, according
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to results in the literature [68]. Conversely, the blue color represents the most positive area,

encouraging nucleophilic assaults. Lighter shades of blue indicate slightly less positivity than deeper
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shades. Yellow regions on the map denote areas with less negative potential relative to the red areas.

Analysis of Fig.6 reveals that compound [Cd(nap)2(imd)3] exhibits greater nucleophilic tendencies

than electrophilic ones. The MESP color scheme aids in distinguishing between electrophilic and
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nucleophilic regions, clearly showing that the electrophilic portion of [Cd(nap)2(imd)3] is significantly

smaller than its nucleophilic counterpart. The observation is backed by data gathered from the FMO
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table, showing an estimated electrophilicity value of 1.64 eV, which is significantly low and aligns

with the results obtained from the MESP analysis.

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Fig.6: Molecular electrostatic potential map showing preferred locations for nucleophilic and
electrophilic attacks.
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3.6 Molecular docking (Antimicrobial and Anti-inflammation)

Molecular docking aims to identify the ligand's conformation that reduces the system's energy. A

scoring function is utilized, which is a mathematical formula that considers the many forms of
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interactions between the two molecules [58]. The scoring function is typically based on the principles

of quantum mechanics, but it can also be based on more empirical methods. Once the scoring function
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has been defined, the docking program will generate a number of possible conformations of the ligand

and then score each conformation [83]. The conformation with the lowest score is typically
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considered to be the most likely to bind to the receptor. Table S17 presents the docking outcomes,

revealing that when the structure [Cd(nap)2(imd)3] is docked with the ADP-ribosyl transferase binding

component protein (PDB: 6v1s), it shows a binding affinity of -9.8 kcalmol-1, forming eight hydrogen
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bonds, with serine having the shortest bond length. This notable abundance of hydrogen bonds may be

attributed to the compound's polarity and shape, suggesting promising antibacterial properties.
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By contrast, the common antibiotic azithromycin creates three hydrogen bonds and has a binding

affinity of -9.5 kcal/mol. After examining the many interactions between [Cd(nap)2(imd)3] and 6v1s,

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 it was discovered that the stabilization of the ligand-protein complex is aided by hydrophobic pi-

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sigma, hydrophobic pi-alkyl contacts, and electrostatic pi-anion interactions with the amino acid

glutamine. Docking using [Cd(nap)2(imd)3] for the protein prostaglandin reductase 2 (PDB: 2zb7)

results in a binding affinity of -8.6 kcal/mol and six detected hydrogen bond interactions, with

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tyrosine A:100 exhibiting the shortest bond length (2.2931 Å). In comparison, ibuprofen creates two

H-bonds with a binding affinity of -7.6 kcal/mol. Additionally, electrostatic pi-anion interactions are

evident in the docking between [Cd(nap)2(imd)3] and prostaglandin reductase. The molecular docking

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results strongly indicate that [Cd(nap)2(imd)3] exhibits high binding affinities with both ADP-ribosyl

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transferase binding component and prostaglandin reductase 2. This suggests that [Cd(nap)2(imd)3]

holds promise as a potential candidate for treating bacterial infections and inflammation.

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Fig.7. 3D image of the studied complex and proteins obtained from the protein databank
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3.7 FTIR

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 The FTIR spectra of the ligands and complex generated in the solid state are presented (Figs.S1-S3).

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Fig.8 represents the overlaid FTIR spectra of naproxen, imidazole and [Cd(nap)2(imd)3]. Some

characteristic spectra data (cm-1) are presented in Table 4. The stretching vibration of the carboxylic

group of free naproxen is represented by the medium band at 3384 cm-1 in its spectra. This band

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vanishes from the complex produced with the Cd(II) ion's spectra, signifying the carboxylate group's

deprotonation. The intense band at 1161 cm-1 corresponds to the ⱱ(C-O) stretching vibration of the

methoxy group (Ar-O-C) [84,85]. Two prominent bands at 1680 cm-1 and 1384 cm-1 were identified

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as the vibrations of the C=O and C-O bonds in the carboxylic acid (-COOH) group. These bands in

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the spectra of the complex, were replaced by strong bands at 1554 cm-1 due to the antisymmetric

ⱱas(CO2) and 1399 cm-1 assigned to the symmetric ⱱs(CO2) stretching vibrations of the naproxenato

ligand. The difference ∆v = [ⱱas(CO2) - ⱱs(CO2)] is a crucial tool for identifying the coordination
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modes in a carboxylate ligand. As shown in Table 4, ∆v = 155 cm-1 corresponding to bidentate mode

of coordination, of the _COOˉ group [86,87]. This conclusion aligns with the findings from the X-ray
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investigations. The ⱱ(N-H) band at 3109 cm-1 in the unbound imidazole ligand shifted to 3126 cm-1

upon coordination in the complex. The binding of the imidazole ligands to the Cd(II) ion was verified

by the presence of a moderate band at 751 cm-1. This band is typically associated with the out-of-
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plane ρ(C-H) vibration [88,89]. The new bands observed at 650 cm-1 and 471 cm-1 in the spectra of

[Cd(nap)2(imd)3] were identified as the vibrations related to (Cd-N) and (Cd-O) bonds, respectively.
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These bands were not present in the free ligands. All assignments have been completed based on the

existing literature data [90,91].

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Fig.8: Superimposed FTIR spectra of naproxen, imidazole and [Cd(nap)2(imd)3]
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Table 4: Selected FTIR absorption bands (cm-1) of the ligands and complex

Compound ⱱ(N-H) v(C=N) ⱱas(CO2) ⱱs(CO2) ∆v ⱱ(Cd-N) ⱱ(Cd-O)

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=(ⱱas - ⱱs)

nap ― ― 1680 1461 219 ― ―

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imd 3109 1545 ― ― ― ― ―

[Cd(nap)2(imd)3] 3126 1492 1554 1399 155 650 471

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3.8 Electronic Absorption Spectra

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In a DMSO solution, the ligands and the Cd(II) complex's absorption spectra were obtained between

200 and 700 nm. The spectrum of naproxen displays two pairs of bands at 264 and 274 nm, and 319

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 and 333 nm, which were identified as corresponding to the 𝝿 → 𝝿* and n → 𝝿* transitions,

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respectively. The peak at 275 nm in the free imidazole ligand corresponds to the 𝝿 → 𝝿* transition of

the aromatic ring. The electronic spectra of [Cd(nap)2(imd)3] displays absorptions that closely

resemble those of the individual ligands. A small change in the absorption peak is observed, possibly

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resulting from the ligands binding to the Cd(II) metal core. This verifies the lack of d - d transitions,

as anticipated for d10 ions such as Cd(II), where all d-electrons are paired up [87, 92].

3.9 NMR

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NMR spectroscopy is used to analyze the behavior of the complex in solution, confirming the

formula and purity of the chemical. The ligands and complex’s 1H-NMR spectra were obtained in a

DMSO-d6 solution and are shown in Fig.S7-S9. The lack of a signal at 9.25 ppm, which corresponds
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to the carboxylic hydrogen of the free naproxen in the 1H-NMR spectra of the complex, may indicate

the presence of the deprotonated ligand in the complex [93,94]. The additional signals of the
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naproxenato ligand exhibit upfield or downfield shifts after interacting with the Cd(II) ion, as

anticipated. Aromatic proton multiplets are seen between 7.71 and 7.81 ppm [95]. A singlet peak at

12.03 ppm is attributed to the N-H proton, while three more signals at 7.73, 7.24, and 7.01 ppm are
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assigned to the protons of the coordinated imidazole ligand [96].

The ligands and complex’s 13C-NMR spectra were obtained in a DMSO-d6 solution and are
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shown in Fig.S10-S12. The absorption signal of the carboxylic carbon (C14) shifted slightly from 175

ppm in the free ligand to 176 ppm in the complex, suggesting electron transfer from the carboxylate
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anion COO- to the cadmium metal center, resulting in de-shielding of the carboxylate carbon.

Additionally, the following carboxylate carbons have a noteworthy downfield chemical shift in

relation to naproxen: (C(12)) (CH-COO) (45.15 to 47.28 ppm), (C(13)) (CH3-C-COO) (18.94 to 20.63
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ppm) in the complex, indicating the interaction of the carboxyl group with cadmium due to

complexation [94].
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3.10 In vitro biological studies

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 3.10.1 Antioxidant activity

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The radical scavenging activity (RSA) of the compounds was screened using DDPH and

phosphomolybdate assays. In the DPPH assay (Table S18), the RSA was concentration-dependent,

with the complex performing better than the free ligands. This agrees closely with the results obtained

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for similar compounds [97-100]. The antioxidant ability of the tested compounds has been compared

holistically using their IC50 values (the sample concentration in µg/mL required to scavenge 50 % of

DPPH radical) (Fig. 9a). In comparison with ascorbic acid, the complex compared favorably with an

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IC50 value of 24.41 µg/mL as against 20.55 µg/mL for the standard. The order of scavenging power

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for the DPPH radical of the compounds is: nap < imd < [Cd(nap)2(imd)3] < AsA.

The result of the total antioxidant capacity of the compounds from the phosphomolybdate assay is
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presented in Table S19. A similar trend to that of the DPPH assay was noticed, wherein the complex

appeared to have a better TAC value compared to the ligands. In the presence of the compound
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(antioxidants), a green coloration is observed, which is due to the formation of a phosphomolybdenum

(V) complex following the reduction of Mo(VI) to Mo(V) with an absorption maxima occurring at

765 nm [101-102]. Fig. 9b shows a comparison of the IC50 values of Ascorbic acid (37.59 µg/mL),
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[Cd(nap)2(imd)3] (112.09 µg/mL), naproxen (168.74 µg/mL) and imidazole (182.56 µg/mL) resulting

in a total antioxidant capacity order: AsA > [Cd(nap)2(imd)3] > nap > imd. Generally, the ascorbic
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acid standard possessed stronger antioxidant activity compared to the synthesized complex. However,

the complex performed far better than the parent ligands and can, therefore, be said to be a promising

lead for further exploration.

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Fig. 9a&b: A Comparison of IC50 values of the ligands, complex and Ascorbic Acid
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Standard

3.10.2 Antimicrobial Screening Results

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The inhibitory action of the ligands and complex against the tested organisms is expressed as the

diameter of inhibition zones (mm). The results in Figs. 10a&b and Table 5 show that the free

naproxen was inactive while imidazole was moderately active against all the tested organisms in this
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study. However, the synthesized complex showed remarkable activity, especially against S. aureus

and B. anthracis, where higher activity was recorded in comparison to Ciprofloxacin. Against the
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fungal strains, the complex also presents a superior activity compared to the standard drug

Ketoconazole. Generally, the complex showed better activity compared to the unbound ligands. The
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improved activity of the complex when compared to the ligand could be due to the chelation effect

upon complexation with the metal ion. Chelation has been reported to increase the lipophilicity of

metal complexes causing their enhanced penetration of the membrane cells of the organisms
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[103,104].
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 Table 5: Antibacterial and antifungal activities of associated ligands and the complex

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Gram (+) Bacteria Gram (-) Bacteria Fungi

S. aureus B. anthracis E. coli S. typhi C. albicans A. niger

Compounds

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imd 18 16 13 16 14 12
nap 0 0 0 0 0 0
[Cd(nap)2(imd)3] 28 26 20 18 22 24
Ciprofloxacin 26 22 32 26 ─ ─
Ketoconazole ─ ─ ─ ─ 20 16

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KEY: (─) = Not Tested

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Fig.10a&b: Antimicrobial activity of ligands and the complex

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4.0 Conclusion

The synthesis characterization with spectroscopic, physicochemical, DFT and single crystal X-ray
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diffraction studies of a novel Cd(II) complex bearing naproxen ligand have been carried out

successfully, and the structure has been established. Utilizing experimental and theoretical methods,
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including DFT computation and molecular docking, we characterized the complex's low reactivity,

high stability, and structural features, validated by close agreement between experimental and

theoretical data. Analysis of crystal packing interactions highlighted strong binding specificity
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facilitated by dominant H…H interactions. Molecular docking studies revealed [Cd(nap)2(imd)3]'s

promising antimicrobial and anti-inflammatory potential, supported by higher binding affinities

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 compared to standard drugs. These findings underscore [Cd(nap)2(imd)3]'s candidacy for future

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therapeutic applications targeting bacterial infections and inflammation. The biological capabilities of

the compound were assessed in vitro for its antioxidant, antibacterial, and antifungal properties. The

complex demonstrated enhanced scavenging of the DPPH free radical at varying concentrations

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compared to the free ligands, however its effectiveness was lower than that of the ascorbic acid

standard. A similar trend was obtained for the total antioxidant capacity. The in-vitro antimicrobial

testing against specific bacterial and fungal strains indicated that the naproxen ligand did not exhibit

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any inhibitory effects. The combination exhibited significant antimicrobial activity against the studied

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pathogens, particularly against S. aureus and B. anthracis, surpassing the activity of ciprofloxacin.

Hence, the compound shows promise as an antibacterial candidate that could help prevent diseases

related to oxidative stress. er

List of Abbreviations
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DPPH - 1,1-diphenyl-2-picrylhydrazyl) DMF- N'N'-DimethylformamideN'N'-Dimethylformamide,

DMSO-Dimethylsulfoxide, MHz-Mega Hertz, IR- Infrared, NMR- Nuclear Magnetic Resonance,

TMS - Tetramethylsilane, FMO - Frontier Molecular Orbital, HOMO - Highest occupied molecular
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orbital, LUMO - Lowest unoccupied molecular orbital, VBM - Valence band maximum, CBM -

Conduction band minimum AsA-Ascorbic Acid, SC-XRD- Single crystal X-ray diffraction
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5.0 Declaration

5.1 Authors' contributions

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Abdulbasit A Aliyu: Investigation, Methodology, Funding acquisition, Validation, Formal analysis,

Writing original draft. Joshua Ayoola Obaleye: Conceptualization, Visualization, Supervision and
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draft correction. Abdullahi Ola Rajee: Interpretation and discussion of results Rawlings A. Timothy

and Favour A. Nelson: Computational studies & analysis. Monu Joy: SC-XRD and structural
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analysis.

5.2 Declaration of Conflicting Interest

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 The authors declare no conflicting interest in the course of this research.

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5.3 Acknowledgments

Abdulbasit A Aliyu is grateful to the Tertiary Education Trust Fund (TETFUND) of Nigeria for the

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Award of Bench Work Fellowship. The authors acknowledge the support of the World Bank STEP-B

Laboratory of the University of Ilorin, Nigeria and also the School of Chemistry and Physics,

University of Kwazulu-Natal, South Africa, for providing bench space. The authors would like to

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acknowledge the Centre for High-Performance Computing (CHPC) in South Africa for providing

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computational resources for this research project.

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4937275