Synthesis of New Organotin(IV) N-methyl-N-benzyldithiocarbamate Compounds and Cytotoxicity Assessment on Human Lung Carcinoma Cell Line (A549)

Introduction

In developing and developed nations, a major cause of death is cancer. Cancer was responsible for nearly 10 million deaths in 2020. Worldwide, in statistical terms, most of these occurred due to lung cancer, after which came colorectal cancer, cancers of the liver and stomach, and breast cancer in females¹. Meanwhile, in Malaysia, patients with lung cancer have a low survival rate in comparison to those with different forms of cancer since nearly one in ten generally obtain a diagnosis when their situation is critical, at stages III or IV². This leads to an urgent study to discover useful anticancer drugs for lung cancer patients.

Chemotherapy, surgery, radiotherapy, and targeted therapy are commonly used for lung cancer treatment ³. Nevertheless, when treating patients with lung cancer, particularly if they have NSCLC, the typical form of care remains platinum-based chemotherapy [4], with the standard drug utilized generally being cisplatin ^5,6. The action of cisplatin is to bind to the N7 reactive center on purine residues, resulting in damage to the deoxyribonucleic acid of the cancer cells and apoptotic cell death⁷. Although cisplatin is an effective anticancer agent, its side effects and resistance limit its clinical use in cancer treatment ⁸. Certain patients can experience side effects such as nephrotoxicity, nausea, hepatotoxicity, cardiotoxicity and neurotoxicity from cisplatin. Meanwhile, damage to DNA can be repaired to a greater extent and the cisplatin’s accumulation intracellular and cytosolic inactivation can be reduced, which are the principal causes of the development of resistance to cisplatin ⁹.

As a result, scientists have conducted several studies to replace existing treatments, including using non-platinum metals, such as organotin(IV). The anti-tumor properties of the first organotin(IV) compounds have been studied, and they have shown properties almost identical to cisplatin ¹⁰. Recent studies have highlighted the therapeutic potential of the organotin(IV) dithiocarbamate compounds ^11–13. At even a low concentration, an organotin(IV) compound has high toxicity and, in cancer cells, they display anticancer activity through gene-mediated pathways ¹⁴. The coordination number as well as the characteristics of groups bonded to the centre of tin atom are responsible for the ability to bind to this type of compound’s DNA ¹⁴. The complexes formed from the binding of organotin (IV) compounds with stable ligands like dithiocarbamate might cause them to have greater lipophilic properties, thus creating reactions with the components of the cells, which might result in the cells dying ^15–17. Therefore, the synthesizing, characterizing, and evaluating the cytotoxic effects of novel organotin(IV) dithiocarbamate compounds against carcinoma cells in the human lung (A549) will be conducted in the study.

Materials And Methods

Reagents

The following suppliers sold all the chemicals and reagents involved, which were utilized precisely as received: N-methylbenzylamine, dibutyltin(IV) dichloride, tricyclohexyltin(IV) chloride, and cisplatin (Sigma-Aldrich, Germany); ethanol and chloroform (Systerm, Malaysia); carbon disulfide and ammonia solution 25% were supplied by Merck; DMSO (Sigma-Aldrich, USA).

Synthesis of organotin(IV) N-methyl-N-benzyldithiocarbamate

Two compounds were synthesized via the in situ method by the reaction between organotin(IV) salt and secondary amines. According to the molar ratio of 1:1 and 2:1 for triorganotin(IV) and diorganotin(IV), respectively, dibutyltin(IV) dichloride and tricyclohexyltin(IV) chloride was allowed to react with the secondary amines; N-methylbenzylamine and carbon disulfide in ethanolic solution. For 120 mins at a temperature under 4 ^oC, stirring of the reaction mixture was performed. After filtering, cold ethanol was used to wash the mixture. Upon the formation of white precipitate, it was left to dry in a desiccator over several days.

Physical Measurement

Both of synthesized compounds were characterized by using analytical techniques and basic spectroscopies, including CHNS elemental analysis, FTIR spectroscopy, NMR spectroscopy, and an X-ray single crystallography study. MPA120 EZ-Melt automated melting point apparatus was used to measure the melting points of each compound. The melting point of a pure compound should be in the range of 1–3°C. Next, the CHNS Elemental Analyzer model Perkin Elmer 2400 was used to elementally analyze the carbon, hydrogen, nitrogen, and sulfur, whereby a comparison was made between the analytical value and theoretical percentage. Next, the infrared spectra of each compound were determined by using a Bruker (Vertex 70v) FTIR Spectrometer in the spectral range of 4000–80 cm^–1. Functional groups presence in each compound could be detected through FT-IR analysis. The chemical shifts of ¹H, ¹³C, and ¹¹⁹ Sn NMR spectra were obtained by using an NMR spectrophotometer model Bruker AVANCE 400 III HD in CdCl₃, with tetramethylsilane as an internal standard.

A Rigaku single-crystal X-ray diffractometer was used to determine compound’s crystal structure. Both FTIR and X-ray single crystallography study was conducted at Sunway University. The measurements of CHNS analysis were conducted at the Organic Synthesis Research Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM) Puncak Alam, whereby the NMR spectroscopies were conducted in Centre For Research And Instrumentation Management (CRIM), UKM.

Recrystallization and Crystallographic Study

To perform the stages of crystallization, the compound was dissolved at room temperature in a solution of ethanol and chloroform at a 1:2 v/v ratio. Then, the mixture was slowly evaporated for three to four days until colorless crystals formed. The formed crystals were harvested and then examined using X-ray crystallography in a cold liquid nitrogen stream.

Cell and Cell Culture

Human lung carcinoma cells (A549) were purchased from the American Type Culture Collection (ATCC). A549 cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) (Sigma USA). The L-glutamine-enriched media were supplemented with 1% penicillin/streptomycin and 10% fetal bovine serum (FBS).

MTT Cytotoxicity Assay

By using the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay ¹⁸, the synthesized compounds were screened against the A549 cell line. Six concentrations of the serial dilution of each compound were formulated, including 0.16 µM, 0.31 µM, 0.63 µM, 1.25 µM, and 2.5 µM, with the highest being 5.00 µM. In the MTT assay, the positive control utilized was cisplatin; meanwhile, a negative control was provided by the untreated cells. The A549 cells were seeded in a 96-well plate at a density of 5×10⁴ mL^-1 and Incubated overnight at 37 ^oC in 5% CO₂. Following incubation for 24 hours, the removal of the media from each well occurred, with each compound used to replace them. After the cells had been treated for 24 hours, 20 µL of MTT was added to each well in a dark environment because MTT is light-sensitive. Following this, a four-hour incubation of the cells took place, after which the removal from each well of 180 µL of supernatant occurred. Then, the newly formed formazan crystal were dissolved with the addition of 180 uL of DMSO. Once DMSO had been introduced, a 15-minute incubation of the 96-well plate was performed again. At 570 nm, a Multiskan GO microplate reader (Thermo Fisher Scientific) was used to detect the compounds’ cytotoxicity effects. To plot the cytotoxicity graphs, the viable-cell percentages and compound concentrations were set against each other. Once the graphs had been plotted, the IC₅₀ values could be ascertained, indicating that in comparison to the cells that had not been treated, the cell population in the treated cells had been halved.

Statistical Analysis

The data obtained from this study was analyzed using one-way ANOVA by using IBM Statistical Package for Social Sciences (SPSS). The data is statistically significant when p < 0.05.

Results and Discussion

Synthesis of Compounds 1 and 2

Two new organotin(IV) dithiocarbamate compounds were synthesized by using the in situ method in this study. Both compounds were synthesized through the reactions of organotin IV salt [dibutyltin(IV) dichloride or tricyclohexyltin(IV) chloride] and secondary amines [N-methylbenzylamine] in the presence of carbon disulphide in ethanol. The compounds were synthesized in an ice bath at temperatures below 4°C to prevent the dithiocarbamate ligand from decomposing. Two hours later, after filtration, cold ethanol was used to wash the mixture three times. The mixture was left to dry in a desiccator up to the point at which a white powder of the compounds had been produced.

Table 1 shows the compounds’ physical characteristics and the data related to the analysis. Based on Table 1, the percentage yields of both compounds were in the range of 57.6–75.3 %, which is higher than 50 % of the theoretical yield. Both compounds can be assumed to be pure compounds because their melting points were less than 3°C. Found to be white solids, at room temperature, each compound (1 and 2) was stable in the atmosphere. Using the recommended formula, the values from the experiment and the theory demonstrated good agreement with the data from the C, H, N, and S elemental analysis.

The results of two newly synthesized organotin(IV) N-methyl-N-benzyldithiocarbamate compounds are confirmed to be similar to the suggested structural formula. The structural formulas for these compounds are dibutyltin (IV) N-methyl-N-benzyldithiocarbamate (C₄H₉)₂Sn[S₂CN(CH₃(C₆H₅)(CH₂)]₂ (Compound 1) (Figure1) and tricyclohexyltin(IV) N-methyl-N-benzyldithiocarbamate (C₆H₁₁)₃Sn[S₂CN(CH₃(C₆H₅)(CH₂)] (Compound 2) (Fig 2).

Figure 1: The chemical structure of Compound 1 Click here to View Figure

Figure 2: The chemical structure of Compound 2 Click here to View Figure

Table 1: The Physical Properties and Elemental Analytical Data of Compounds 1 and 2

				Experimental (Theory), %
Molecular formula	Color	Yield (%)	Melting Point (°C)	C	H	N	S
Compound 1 (C4H9)2Sn[S2CN(CH3(C6H5)(CH2)]2	White	75.3	92.4–94.4	48.66 49.92	5.98 6.12	4.31 4.48	20.08 20.50
Compound 2 (C6H11)3Sn[S2CN(CH3(C6H5) (CH2)]	White	57.6	72.6–74.6	57.35 57.45	8.12 7.68	1.55 2.48	8.79 11.36

*Bold: Theoretical value

Infrared Spectroscopy Analysis

The key vibrational bands obtained using Fourier-transform infrared (FTIR) spectroscopy for compounds 1 and 2 are shown in Table 2. The important absorbance peaks that identify the presence of dithiocarbamate ligands were based on the presence of ν(C—N) and ν(C—S) . The ν(C—N) band, also known as the thiouride band, was discovered in the 1475–1481 cm^–1 range. The thiouride band is usually observed in the range of wavelengths between 1450 and 1550 cm^{–1 19,20}. Adeyemi et al. (2019) reported the existence of the thiouride band at wavelengths ranging from 1443 to 1488 cm^{–1 21}.

Meanwhile, the ν(C—S) band was discovered at 971–975 cm^–1. The presence of the ν(C—S) absorption band in the infrared spectrum indicates the mode of coordination of the ligand with the central metal, either monodentate or bidentate ²². The bonding between the Sn atom and the organotin(IV) compound can be determined by the presence of ν(Sn-C). The ν(Sn-C) band was found in the spectral range of 496–552 cm^{–1 11,23}. Therefore, as revealed in the analysis, dithiocarbamate groups and organotin (IV) compounds were present, which were comprised of the recommended formulae for each compound and fulfilled the criteria proposals of prior researchers.

Table 2: Infrared Absorption Bands of Compounds 1 and 2

Compound	Wavelength (cm–1)
	ν (C-H)	ν (C—N)	ν (N-C)	ν (C—S)	ν (Sn-C)	ν (Sn-S)
1	3057	1481	1239	975	552	382
2	2915	1475	1246	971	496	379

Nucleus Magnetic Resonance (NMR) Spectroscopy Analysis

Apart from FTIR analysis, NMR analysis has also been carried out to identify the molecular structure, ¹H, ¹³C, and ¹¹⁹Sn atoms in each of the synthesized compounds. Based on Table 3, the ¹H proton NMR of Compounds 1 and 2 shows the presence of a single signal for the methyl proton directly bound to the N atoms in dithiocarbamate at 3.328 ppm and 3.388 ppm ²⁴, respectively. Besides, the methylene proton of methylene group attached directly to the N atom of dithiocarbamate ligands were observed in the range of 5.148 – 5.255 ppm ²⁵.  A broad signal for the butyl group attached to the Sn atom was found in the range of 0.972–2.127 ppm ^11,26, confirming that it’s attached to the Sn atom, which is electropositive, through the nuclei of carbon. This causes shielding, which occurs through the carbon chain ²⁷.

Meanwhile, in Compound 2, proton signals in a range of 1.374–2.047 ppm were assigned for the tricyclohexyl group on the tin(IV) atom ²⁸. The aromatic multiplet signal of the proton of the phenyl group bound to Compounds 1 and 2 was observed in the chemical shift range of 7.249–7.374 ppm and 7.270–7.385 ppm, respectively. Consistently, the chemical shifts of 7.27 to 8.07 ppm were reported for the proton of the phenyl group (C₆H₅-N) ^17,29. Furthermore, for bis(p-substituted-N-methylbenzyldithiocarbamate) compound that was synthesized by Khan et al. (2015), the chemical shift of the aromatic proton of the phenyl group were observed in a range of 7.14–7.94 ppm ²⁷.

Table 3: ¹H NMR Spectra Data of Compound 1 and Compound 2

Compound		Chemical shifts, δ (ppm)
	N-R” (R” = CH3)	-NR’ (R’ = CH2)	-NR’R aromatic	Sn-R (R=C4H9, C6H11)
1	3.328	5.148	7.249–7.374	CH2: 2.127 CH2: 1.986 CH2: 1.512 CH3: 0.972
2	3.388	5.255	7.270–7.385	1.374–2.047

 

Next, the presence of each carbon signal in the synthesized compound can be identified through the ¹³C NMR spectra. Table 4 shows the data spectra of ¹³C NMR. An important chemical shift in characterizing organotin(IV) dithiocarbamate compounds is the CS₂ carbon signal. The carbon atom signal in N-CS₂ of Compounds 1 and 2, appears in the chemical shift range between 200.66 and 202.32 ppm. The signal is usually observed in the chemical shift range of 185–220 ppm ³⁰ . Through the CS₂ signal, it shows that the sulfur atom has formed a bond with the central metal of the Sn atom in the compound ¹³.

Furthermore, carbon signals for other carbon-containing substances were also observed in the ¹³C NMR spectroscopy. Signals derived from the methylene carbon near the electronegative atom of nitrogen appeared to range from 59.95 to 60.70 ppm ^11,31. The resonation between 13.89 ppm and 34.46 ppm was observed for the dibutyltin(IV) compound ³², where the chemical shift in the range of 26.20–34.76 ppm was assigned for the tricyclohexyltin(IV) compound ²⁸. The diphenyl complex was obtained within the δ 127.45 to 135.83 ppm region, which corresponded to the information provided by Haezam et al. ¹³ that showed resonation in the range of 119.0–136.75 ppm.

Table 5 shows the data spectra of the ¹¹⁹Sn NMR of Compounds 1 and 2. The coordination number of the synthesized compound’s Sn atom was determined through analysis using ¹¹⁹Sn NMR spectroscopy. The result shows the ¹¹⁹Sn spectra for Compounds 1 and 2 are in the range of –338.75 to –22.55 ppm. It explains that Compounds 1 and 2 have the expected coordination geometry of hepta ³³ and tetra ³⁴ around the tin center, respectively. The signal of the complex can have the same coordination and various chemical shifts in ¹¹⁹Sn due to its dependence on the R group’s number and characteristics, as well as the characteristics of the dithiocarbamate ligand to which the Sn atom is bound ³⁵. This may be due to the sensitivity of the chemical environment of tin ^36,37.

Table 4: ¹³C NMR Spectra Data of Compounds 1 and 2

Compound	Chemical shifts, δ (ppm)
	N‒CS2	Sn‒R (R=C4H9, C6H11 )	N- CH2C6H5	N-CH3	N‒CH2 C6H5
(1)	202.32	13.89 (CH2), 26.48 (CH2), 28.70 (CH2), 34.46 (CH3)	59.95	41.77	127.55, 127.92, 128.83, 135.36
(2)	200.66	26.20–34.76	60.70	42.52	127.45, 127.71, 128.74, 135.83

 

Table 5: ¹¹⁹Sn NMR Spectra Data of Compounds 1 and 2

Compound	Chemical shifts 119Sn, δ (ppm)
1	–338.75
2	–22.55

 

X-ray Single Crystallography Study

The data related to crystallography and refinement are shown in Table 6 , while compound 1’s chosen bond lengths and angles are shown in Table 7. The recrystallization process was carried out for both synthesized compounds through an evaporation process at room temperature using a mixture of two solvents: ethanol and chloroform at a certain ratio (1:2 v/v). Once evaporation at room temperature over a number of days had taken place, colorless crystals had been formed by only compound 1. Compound 1 (dibutyltin(IV) N-methyl-N-benzyldithiocarbamate) has a colorless crystal structure with dimensions of 0.27 ´ 0.20 ´ 0.11 mm and a molecular mass of 625.57 g. Compound 1’s single crystal is in the triclinic system and the P1 space, where a = 9.6272(1) Å, b = 12.1043(2) Å, c = 13.3584(2) Å, α = 82.296(1) Å, and β = 86.611(1)° ³⁸.

A significant difference can be detected in the bond distance of the four sulfur atoms that coordinate with the Sn atom, which is Sn‒S1 = 2.5334(4) and Sn‒S3 = 2.5497(4). The central metal, Sn (IV) is covalently bonded to S1 and S3 within a normal Sn-S bond distance of 2.48–2.57 Å ²³. The asymmetric coordination of the dithiocarbamate ligands results in a large disparity of C–S bond lengths, with C1-S1 bonds being shorter than S2-bonds [C1–S1, S2 = 1.7477(19) & 1.6910(19) Å and 1.7528(19) & 1.6944(19) Å]. The crystal structure of Compound 1 shows the coordination mode by anisobidentate between the central metal of the Sn atom and the dithiocarbamate ligands. The C19–Sn–C23 for this compound is 137.83(7)° which is larger than the ideal angle for a tetrahedron (109.5°) ^17,34, resulting in a distorted tetrahedron geometry. However, the S1–Sn–S3 bond angle which falls at 80.289(14)° was parallel to the S_short-Sn-S_short bond angles reported in previous studies (78°–88°) ²³.

Figure 3 portrays the plotted ORTEP of Compound 1. The coordinate geometry depicted in the X-ray single crystal crystallographic analysis results is described as a skewed trapezoidal-bipyramidal geometry with a short trapezoidal edge formed through strong bonds between S1 and S3, while S2 and S4 bonds affect the length of the sides of the geometry.

Table 6: Crystallographic Data and Refinement Parameters for Compound 1 ³⁸

Chemical formula	C26H38N2S4Sn
Molar mass (g)	625.57
a (Å)	9.6272 (1)
b (Å)	12.1043 (2)
c (Å)	13.3584 (2)
α (o)	82.296 (1)
β (o)	86.611 (1)
y (o)	66.912 (1)
V (Å3)	1419.02 (4)
Z	2
Rgt (F)	0.0235
wRref(F2)	0.0612
Suhu (K)	100
μ (mm–1)	10.0
Wavelength	Cu Kα radiation (1.54184 Å)
Diffractometer, scan mode	XtaLAB Synergy, ω
θmax, completeness	75.3º, >99%
N(hkl)measured, N(hkl)unique, Rint	37,119, 5854, 0.033
Criterion for lobs, N(hkl)gt	lobs > 2 ơ (lobs), 5841
N(param)refined	302
Programs	CrysAlisPRO, SHELX, WINGX/ORTEP

Table 7: Selected bond length (Å) and angles (º) for Compound 1

Bond lengths (Å)		Bond angles (°)
Sn-C19	2.1479(18)	C19-Sn-C23	137.83(7)
Sn-C23	2.1530(18)	C19-Sn-S1	109.80(5)
Sn-S1	2.5334(4)	C23-Sn-S1	103.99(5)
Sn-S3	2.5497(4)	C19-Sn-S3	104.60(5)
S1-C1	1.7477(19)	C23-Sn-S3	105.32(5)
S2-C1	1.6910(19)	S1-Sn-S3	80.29(14)
S3-C10	1.7528(19)	C1-S1-Sn	94.16(6)
S4-C10	1.6944(19)	C10-S3-Sn	95.34(6)
N1-C1	1.337(2)	C1-N1-C2	122.40(16)
N1-C2	1.463(2)	C1-N1-C9	119.73(16)
N1-C9	1.465(2)	C2-N1-C9	117.72(15)
N2-C10	1.335(2)	C10-N2-C18	120.59(16)
N2-C18	1.467(2)	C10-N2-C11	124.05(15)
N2-C11	1.475(2)	C18-N2-C11	115.35(15)
C2-C3	1.519(3)	N1-C1-S2	122.35(14)
C3-C8	1.391(3)	N1-C1-S1	118.35(14)
C3-C4	1.391(3)	S2-C1-S1	119.30(11)
C4-C5	1.388(3)	N1-C2-C3	114.04(15)
C5-C6	1.391(3)	N2-C10-S4	122.09(14)
C6-C7	1.384(3)	N2-C10-S3	118.89(14)
C7-C8	1.392(3)	S4-C10-S3	119.01(10)
C11-C12	1.514(3)	N2-C11-C12	112.93(15)
C12-C13	1.388(3)	C20-C19-Sn	112.43(13)

 

Figure 3: ORTEP plot of Compound 1 Click here to View Figure

Cytotoxicity of organotin(IV) N-methyl-N-benzyldithiocarbamate compounds in A549 cells

Table 8 shows the IC₅₀ values for Compound 1 (dibutyltin(IV) N-methyl-N-benzyldithiocarbamate) and Compound 2 (tricyclohexyltin(IV) N-methyl-N-benzyldithiocarbamate). As shown by the the MTT assay findings, each compound had a major cytotoxic effect on carcinoma cell lines in the human lung (A549). However, based on the inhibitory IC₅₀ values of Compounds 1 and 2 at 0.80 µM (0.50 g/cm³) and 2.77 µM (1.56 g/cm³), it is observed that Compound 1 is highly toxic. Moreover, when compared with a standard drug, cisplatin, both compounds exhibit higher cytotoxicity activity toward A549 cell lines. As shown in Figure 4, after being treated for 24 hours, the cytotoxic effects against A549 cells of organotin(IV) N-methyl-N-benzyldithiocarbamate compounds could be identified.

Compound 1, which is dibutyltin(IV) N-methyl-N-benzyldithiocarbamate, has a stronger cytotoxic effect than tricyclohexyltin(IV) N-methyl-N-benzyldithiocarbamate because the toxicity is dependent on the structure of the compound. Study by Pellerito et al. (2006) stated that certain elements or functional groups in a compound provide different proliferative effects to treated cells ³⁹. Furthermore, the cytotoxic effect can be influenced by the length and count of the alkyl groups connected to the metal tin atom in the center ⁴⁰. Greater toxicity is evident in organotin compounds that are highly substituted; meanwhile, compounds’ cytotoxic effects are enhanced by shorter alkyl substituents ^41–43. Thus, the conclusion was that these published data demonstrated the generally greater anticancer activity of the diorganotin compound, compared to the triorganotin (IV) compound.

Table 8: IC₅₀ values of Compound 1 and Compound 2 against A549 cells.

Compound	IC50(μM)±S.E.M
1	0.80  0.09
2	2.77  0.34
Cisplatin	32.00  0.29

 

Figure 4: The cytotoxicity of organotin(IV) N-methyl-N-benzyldithiocarbamate compounds against A549 cells upon a 24-hour treatment. Click here to View Figure

Conclusion

Utilizing the in-situ method enabled the successful synthesis of two novel organotin(IV) obtained via N-methyl-N-benzyldithiocarbamate. Elemental and spectroscopies analysis, namely CHNS analysis, FT-IR, and NMR spectroscopies were then employed to characterize these compounds. In general, the theoretical CHNS values were exhibited by the experimental CHNS values of each compound. Moreover, each compound displayed the presence of crucial absorbance peaks: ν(C—N), ν(C—S), ν(Sn-S) and ν(Sn-C) which indicates that the organotin(IV) dithiocarbamate compounds have formed. Furthermore, the presence of significant nuclear magnetic resonance (NMR) signals confirms the structure of compounds obtained. An X-ray single crystallography study was also used to determine the crystal structure of dibutyltin(IV) N-methyl-N-benzyldithiocarbamate (Compound 1). The result showed that the geometry of Compound 1 is a skewed trapezoidal bipyramidal with a short trapezoidal edge. Both compounds showed strong toxicity against A549 cells compared to cisplatin, with Compound 1 being more potent than Compound 2.

Acknowledgement

We would like to thank the Ministry of Higher Education (FRGS/1/2021/STG04/UKM/02/5) for the financial support given to this study. We would also like to acknowledge the Faculty of Health Sciences of Universiti Kebangsaan Malaysia and Sunway University for the technical support provided in this study. Additionally, we would like to thank the Center for Research and Instrumentation Management (CRIM), UKM and Organic Synthesis Research Laboratory, Institute of Science (UiTM) for the laboratory services given.

Conflicts of Interest

The authors declare that they have no conflict of interest.

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