Physicochemical Properties, Antimicrobial activity and Docking Study of Carboxymethyl Cellulose (CMC)

doi:10.21203/rs.3.rs-3403243/v1

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Physicochemical Properties, Antimicrobial activity and Docking Study of Carboxymethyl Cellulose (CMC)

https://doi.org/10.21203/rs.3.rs-3403243/v1

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Carboxymethyl Cellulose (CMC), a renowned natural polymer, finds versatile applications, especially in medicine. This study explores the effect of 4-(2-chloroethyl)morpholine hydrochloride, a biologically active compound, on polymer properties and biological activity. Various concentrations (1%, 5%, 10%, and 15%) from 4-(2-chloroethyl) morpholine hydrochloride in CMC were examined to assess the changes in the polymer properties and the biological impact. The results indicated that elevated antimicrobial agent percentages amplify the zone of inhibition and markedly change the polymer's thermal and optical characteristics. A higher concentration of 4-(2-chloroethyl)morpholine hydrochloride also reduces CMC degradation and scanning electron microscopy (SEM) reveals significant surface modifications. Remarkably, our compound displayed good antibacterial and antifungal activities and the suggested mechanism studies proposed that our compound could act as a potential succinate dehydrogenase inhibitor (SDHIs), which was proved by the agreeable molecular docking study. The current study could help the title compound to be a lead compound for exploring highly bioactive antimicrobial and antifungal substrates, especially the potential SDHIs.

Carboxymethyl Cellulose (CMC)

4-(2-chloroethyl)morpholine hydrochloride

Characterization

Antimicrobial agent

Cellulose, one of the most abundant biopolymers on Earth, has garnered significant attention for its diverse applications in various fields, including the biomedical and environmental sectors (Heinze 2016). Among its derivatives, carboxymethyl cellulose (CMC) has emerged as a versatile material due to its water-solubility, biocompatibility, and biodegradability (Zia et al. 2017). The carboxymethylation of cellulose imparts it with unique properties that are attractive for applications in drug delivery, wound healing, tissue engineering, and environmental remediation (Eyley and Thielemans 2014).

Promoting the principles of green chemistry to enhance sustainable and reusable materials stands as a pivotal goal across nations. Among these materials, CMC a biodegradable natural polymer, has emerged as a versatile contender, finding applications as a viscosity modifier in both food and non-food sectors (Mourya and N. Inamdara;Ashutosh Tiwari 2010; Sheng et al. 2019; Kundu et al. 2022). Notably recognized for its non-toxic and hypoallergenic nature, CMC serves as an economical derivative of cellulose that spans diverse industries (Pushpamalar et al. 2016). Its role ranges from being a disintegrant in pharmaceutical formulations, aiding in tablet disintegration within the gastrointestinal tract post-oral administration, to safeguarding food products against microbial, chemical, and mechanical threats through packaging in the food sector (Roy et al. 2009). Moreover, CMC's appeal extends to medical applications and antimicrobial agent delivery techniques, underpinned by its affordability, ease of reaction, processability, and non-toxic human-use properties (Roy et al. 2009; Jain et al. 2010; Kumar et al. 2014; Gaikwad et al. 2019; Klein and Poverenov 2020). Its contribution to wound dressing, with proven antibacterial efficacy against various types of injuries, underscores its importance (Hebeish and Sharaf 2015; Yang et al. 2018; Kanikireddy et al. 2020; Zhang et al. 2021).

Grafting, a common modification technique, involves the attachment of functional groups or polymers onto the backbone of CMC, thus enhancing its properties and expanding its utility (Ivanovic et al. 2016). The grafting of various compounds onto CMC has been explored extensively to tailor its characteristics for specific applications. Such modifications can provide controlled drug release (Wang et al. 2017), improved mechanical strength (Naderahmadian et al. 2023), and increased adsorption capacity for environmental pollutants (Eltaweil et al. 2020).This comprehensive study delves into the grafting of diverse moieties onto CMC, aiming to elucidate the structural changes, physicochemical properties, and biological performance of these grafted materials. By characterizing the grafted CMC derivatives, their potential for biomedical and environmental applications can be better understood and harnessed (Pettignano et al. 2019; Hosseini et al. 2022).

In this article, morpholine derivatives, known for their robust antibacterial and antifungal properties, have garnered attention (Durcik et al. 2023). These derivatives show activity against enzymes essential for DNA synthesis, along with influencing cellular stress response, rendering them valuable for combating a wide spectrum of bacteria and fungi (Ohui et al. 2019). This article delves into the realm of chemical reactions by grafting 4-(2-chloroethyl)morpholine hydrochloride, a representative morpholine derivative, onto CMC. This grafting is executed through a water-based medium. The resulting polymer products, synthesized at different percentages, are then studied to discern the alterations in polymer properties and their subsequent antimicrobial activities. Furthermore, the biological evaluation of these materials will be explored, providing valuable insights into their suitability for biomedical applications.

Materials

Sodium carboxymethyl cellulose from Thermo Fisher. 4-(2-chloroethyl)morpholine hydrochloride from Sigma Aldrich, Germany. Citric acid from Loba Chemical, Mumbai, India. All chemicals are used with no further purification.

Synthesis of of 4-(2-Chloroethyl)morpholine Hydrochloride on Carboxymethyl Cellulose (CMC)

In five beakers of 250 ml, 1g of the CMC was added to each beaker and then (5%, 0.05g) of citric acid was added to each beaker in 100 ml of distilled water. Hereafter, different weight percentages of the 4-(2-chloroethyl)morpholine hydrochloride were added (1%, 0.01g), (5%, 0.05 g), (10%, 0.1 g), and (15%, 0.15g). The reaction mixture was stirred at room temperature for 24 hours and the resulting viscous products were poured into nine-inch glass Petri dishes and were kept in the oven for 2–3 days at 40°C to remove the residue of water. The films were peeled out for instrument testing.

Physicochemical characterization

The examination of sample morphological features in high vacuum mode was conducted using the Thermo Scientific Quattro field emission scanning electron microscope (FESEM) (Thermo Scientific Quattro, Waltham, MA, USA). Additionally, the FESEM was equipped with an Oxford energy dispersive X-ray system to determin the elemental composition of the samples. To assess the thermal properties of the samples, Shimadzu Thermogravimetric Analyzers TGA (Shimadzu TGA-51, Japan) and a differential scanning calorimeter (DSC) (Shimadzu DSC-60 Plus, Japan) were employed, covering a temperature range of 25–600°C. Structural analysis of the samples was also carried out using an ATR-FT-IR spectrometer (Shimadzu IR–Tracer 100 Fourier Transform Infrared Spectrophotometer, Shimadzu, Japan). The X-ray diffraction (XRD) analysis of CMC was performed on a membrane sample using a XRD Shimadzu, Japan XRD-7000.

Antibacterial Activity

The antimicrobial sensitivity testing (AST) of six CMC polymers with the biologically active comound 4-(2-chloroethyl)morpholine hydrochloride was tested against five microorganisms. Two gram-positive (Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA)) and two gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and one fungus (Candida albicans) were used to study the inhibitory effects of the different CMC Polymer’s. All five isolates were maintained in the Department of Biology, Faculty of Science, Jazan University. The identification of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Candida albicans was done by standard biochemical tests and was maintained on sterile Nutrient agar plates in a refrigerator at 4 ⁰C till further use.(Alamier et al. 2023b, a) Escherichia coli was identified by Molecular analysis of its 16 sDNA gene sequencing (Essa et al. 2018). A 24-hours fresh culture of all five microorganisms was used to study the AST of CMC polymer with antimicrobial agent 4-(2-chloroethyl)morpholine hydrochloride. Kirby Bauer’s agar disc diffusion method was used. Six thin layers of CMC polymers with different antimicrobial agent concentrations were provided. Sample 1 was CMC with crosslink without antimicrobial agent (Negative control), sample 2 was CMC with 10% of antimicrobial agent with no crosslink (positive control), sample 3 was CMC with 1% of antimicrobial agent, sample 4 was CMC with 5% of antimicrobial agent, sample 5 was CMC with 10% of antimicrobial agent and sample 6 was CMC with 15% of antimicrobial agent. Antibiotic control (Streptomycin 10 µg) was used as another positive control. Sterile 5 mm discs of different polymer samples were prepared by using a sterile paper punch for all the 6 CMC polymer samples. Fresh 24 H microbial culture was prepared to match the McFarland’s 0.5 turbidity standard tubes (1.5 x 108 colony forming units/mL). They were spread on sterile Muller and Hinton’s agar (MHA) plates then different CMC polymers with antimicrobial agent and standard discs were transferred on these plates. Two plates were used per isolate. The polymer samples were labelled 1 to 6 and a standard antibiotic disc was used as control. The plates were incubated at 37 ⁰C for 24 H. The zone of inhibition was measured using a zone measuring scale in millimeters. All the tests were carried out in triplicates.

Docking Procedure

MOE-Dock, Chemical Computing Group Inc. was utilized to perform the docking studies(Zhou et al. 2011; Yang et al. 2019). All testified SDHs are substantially reserved in their spatial structure, subunit, and electron transport pathway and the ubiquinone binding site in the prokaryotes and eukaryotes. So, avian (Gallus gallus) respiratory complex II with carboxin bound (PDB code: 2FBW) was selected for the molecular docking study(Gul et al. 2012; Yang et al. 2019). The crystal structure was adjusted to remove water and was added to MOE, and polar hydrogen atoms were added to the structure with their standard geometry followed by their energy minimization. A systematic conformational search at default parameters with an RMS gradient of 0.001 kcal/mol using Site Finder was carried out on the resulting model. SDH Active site was recognized, and dummy atoms were established from the resulting alpha spheres.(Alamier et al. 2023a,b) The backbone and residues were fixed while performing the energy minimization. The RMSD was used to confirm the docking of the ligand into the SDH crystal structure. The smallest energy-minimized pose was selected for further analysis. The monomer was docked by the same method and ten conformations were chosen carefully while all other parameters were kept at their default settings. The best conformation of the monomer-enzyme complex was designated based on their energy. The resulting docked complex model was then used for calculating the energy parameters usingMMFF94x force field energy calculation and predicting the docked interactions at the active site.

In this study, carboxymethylcellulose (CMC) and varying weight ratios of the 4-(2-Chloroethyl) morpholine Hydrochloride films were prepared using citric acid as a non-toxic crosslinking agent. This lets us explore the attributes of antimicrobial agent-grafted CMC as well as its thermal characteristics. To facilitate this reaction, we employed citric acid as a crosslinking agent, which contributed to the creation of a seamless, colorless, and cohesive polymer film. Illustrating the procedural framework, Scheme 1 outlines the probabilistic course of the CMC grafting process involving the antimicrobial agent.

FTIR Study

The Fourier transform infrared (FTIR) analysis plays a crucial role in substantiating the chemical grafting of the antimicrobial agent into the polymer chain, offering insight into the intricate molecular interactions. Through the FTIR spectra, the behavior of carboxymethyl cellulose (CMC) emerges with distinctive peaks, each signifying specific molecular groups and their transformations upon antimicrobial agent incorporation. In the FTIR spectra, the characteristic features of CMC reveal the underlying chemistry. A broad peak centered around 3200 cm^− 1 signifies the stretching of the hydroxyl (OH) groups within the CMC molecule, underpinning its hydrogen bonding potential. Concurrently, the CH group is reflected by a peak positioned at about 2800 cm^− 1, indicative of the aliphatic hydrocarbon moieties present. The COOH group, denoting carboxyl functional groups, manifests as a distinctive peak around 1600 cm^− 1, echoing the presence of acidic components within CMC's structure. The C-O-C stretching frequency, vital for the ester groups, is discerned at around 1060 cm^− 1, representing the intricate arrangements of these groups within the polymer matrix.

After the introduction of the antimicrobial agent, these spectral features undergo subtle yet significant shifts. Specifically, the peak associated with C-N bonds, a sign of the antimicrobial agent's integration, becomes prominent within the range of 1250 to 1300 cm^− 1. This heightened presence of C-N bonds can be attributed to the successful grafting of the antimicrobial agent onto the polymer chain, resulting in a detectable change in the FTIR spectra. For a comprehensive depiction of these variations and their correlation with different antimicrobial agent concentrations, consult Fig. 1, which showcases the FTIR spectra of CMC samples, both in their pristine form and after being subjected to varying antimicrobial agent quantities. The intricate changes in peak intensities and positions serve as a testament to the successful grafting process and offer valuable insights into the molecular transformations within the CMC polymer.

Thermal and DSC Analysis

The investigation into thermal stability involved Thermal Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) under a nitrogen atmosphere. TGA and DSC curves, as in Fig. 3, unveiled essential insights into the behavior of CMC and its interaction with the incorporated antimicrobial agent. All the samples show a small (5–15%) mass loss for the first decomposition step and more significant mass loss (39–75%) for the second step The TGA curves highlighted a significant shift in behavior with the introduction of the antimicrobial agent.Notably, the temperature at which a 10% weight loss occurred was about 250°C for pristine CMC. This temperature steadily increased with increasing antimicrobial agent content. A key observation emerged at the point of 50% weight loss, suggesting that the degradation of the loaded CMC diminished progressively as the concentration of the antimicrobial agent within the polymer increased. This finding has significant implications for the material's potential durability and longevity in diverse applications (Sugama and Pyatina 2015). Therefore the higher values of the mass loss in the second decomposition step may be attributed to the degradation of side chain and the loss of CO₂ in the case of CMC (El-Sayed et al. 2011).

DSC analysis further illuminated the interplay between the polymer and the antimicrobial agent. The decomposition profile of pristine CMC showed higher thermal stability than CMC integrated with the antimicrobial agent. This difference stemmed from the inherent thermal stability discrepancy between the two components. Intriguingly, DSC curves showcased that the endothermic peak for CMC with 1% of the antimicrobial agent was marginally elevated compared to pristine CMC. However, CMC grafting with 5%, 10%, and 15% of the antimicrobial agent exhibited progressively enhanced thermal stability. This augmentation in thermal stability was attributed to the heightened presence of the antimicrobial agent molecules within the polymer matrix.(de Britto and Assis 2009) It's important to delve further into the degradation behavior of CMC. Incorporating the antimicrobial agent not only altered thermal characteristics but also influenced the degradation process. The reduction in the degradation temperature and rate as antimicrobial agent concentration increased implies the antimicrobial agent's ability to stabilize the polymer matrix. This phenomenon could be linked to the antimicrobial agent molecules acting as reinforcing agents, hindering the mobility of polymer chains during degradation. Additionally, the antimicrobial agent's interaction with the polymer chains might alter the accessibility of degradative agents, further affecting the degradation kinetics.

3.3. X-ray diffraction (XRD) analysis

Figure 3 shows the XRD spectrum of the CMC and CMC with varying antimicrobial agent concentrations respectively. depicted in Fig. 4, illuminated the structural shifts resulting from antimicrobial agent integration.The pure CMC has a broad peak at 19.92ᵒ which shows CMC has partially crystalline similar to previous study reported by (Kanafi et al. 2019). There were destructive decrease in the intensity of all peaks observed for cross-linked CMC film and CMC with varying antimicrobial agent concentrations which implied that the composite has mainly became amorphous which give a soft and flexible structure. These changes were ascribed to the interactions between the antimicrobial agent and the polymer chain, which affected the overall arrangement of the molecular structure. The broader curves exhibited by polymers containing various antimicrobial agent amounts pointed towards shifts in crystalline behavior due to antimicrobial agent-induced variations.

Morphological features

The characterization of morphological features through Scanning Electron Microscopy (SEM) was pivotal in deciphering alterations at the structural level. The SEM images in Fig. 5 offered a visual representation of the morphological transformations at the surface level. The surface of CMC without the antimicrobial agent, depicted in picture (a), stood in stark contrast to the morphologies observed after antimicrobial agent incorporation. Picture (b) displayed marginal surface changes for CMC with 1% antimicrobial agent, but significant alterations emerged with higher antimicrobial agent content. The polymer's surface became notably rougher as antimicrobial agent concentration increased. This phenomenon could be attributed to progressively integrating antimicrobial agent molecules, leading to alterations in surface characteristics. Particularly, picture (d) showcased the most substantial roughness due to the higher concentration of the grafted antimicrobial agent.

Antimicrobial Evaluation

As seen in Fig. 5, Six CMC polymers with antimicrobial agent 4-(2-chloroethyl)morpholine hydrochloride were applied to five microorganisms to study their antibacterial and antifungal activities. As shown in Table 1, sample 1, carboxy methyl cellulose with crosslink without antimicrobial agent (negative control) showed no inhibitory activity while CMC without crosslink but with 10% antimicrobial agent showed inhibitory activity against all the microorganisms (Positive antimicrobial agent control). Samples 2 to 5 containing increasing concentrations of antimicrobial agent 4-(2-chloroethyl)morpholine hydrochloride, showed increasing antimicrobial activity against all five microorganisms. Sample No 2 (CMC with 1% antimicrobial agent) showed the least zone of inhibition towards the microorganisms tested. The zone of inhibition increased as the concentration of the antimicrobial agent increased from 5% (sample 3) to 15% (sample 5).

Table 1

Antimicrobial sensitivity testing of different concentrations of antimicrobial agent 4-(2-chloroethyl)morpholine hydrochloride added to carboxy methyl cellulose polymer.
Sample number	Polymer sample	Zone of Inhibition (mm)
Sample number	Polymer sample	EC	PA	SA	MRSA	CA
1	CMC with crosslink without the antimicrobial agent	0	1	0	0	0
2	CMC with 1% antimicrobial agent	0	2	4	4	3
3	CMC with a 5% antimicrobial agent	10	9	8	10	10
4	CMC with a 10% antimicrobial agent	11	9	11	12	12
5	CMC with a 15% antimicrobial agent	13	10	12	13	13
6	Antibiotic Control Streptomycin 10 µg	15	12	18	16	17
7	Control (antimicrobial agent only)	20	22	23	26	32
Key: mm–Millimeter, CMC– carboxy methyl cellulose, EC– Escherichia Coli, PA– Pseudomonas aeruginosa, SA – Staphylococcus aureus, MRSA – Methicillin-resistant Staphylococcus aureus, CA-Candida albicans

A graphical representation of the action of CMC polymer with different antimicrobial agent concentrations is shown in Fig. 6. The first two groups indicated the controls used, and the 3rd group to the 6th group indicated the inhibition zone for CMC with antimicrobial agent concentration of 1% up to 15%. The last group indicated the positive antibiotic control of 10 µg Streptomycin.

3.6. Molecular Docking Studies

Molecular docking is a trustworthy procedure used to expect binding poses for protein-ligand interactions and could be exploited to explore molecular interaction and the most favorable binding site. The interactions that depend on the distance between the amino acid and ligand might also be established. We tried to study the interactions of our synthetic polymer with avian (Gallus gallus) respiratory complex II with carboxin bound (PDB code: 2FBW) via oligomeric model compounds. In silico studies of these were expected to play a key role in determining chemical diversity and ligand-receptor interaction(Zhang and Wu 2006; Abdel-Hamid et al. 2007; Jakupec et al. 2008; Gul et al. 2013) .The monomer was docked into the active site of 2FBW. The diverse position of the monomer was aimed at predicting the significance of the binding site and mode of ligand-protein interactions. The valuable conformation for the monomer was picked based on the lowest binding energy. A favorable docked complex with the target was proved from the binding free energy data obtained after the docking procedure (Tables 2 and 3).

Table 2

Hydrogen bonds interaction of docked monomer with 2FBW.
Ligand	Receptor	Interaction	Distance	E (kcal/mol)
O22	OG SER 55 (A)	H-donor	2.66	-1.8
O26	O ALA 212 (A)	H-donor	2.60	-0.5
O1	OG1 THR 228 (A)	H-acceptor	2.81	-1.6
O16	OG1 THR 57 (A)	H-acceptor	2.88	-1.3
O22	N ALA 26 (A)	H-acceptor	3.02	-1.8
O24	N GLU 397 (A)	H-acceptor	3.20	-0.9
O25	N ALA 29 (A)	H-acceptor	2.95	-2.5
O33	NH2 ARG 297 (A)	H-acceptor	2.98	-3.8

Table 3

Binding interactions of monomer unit with 2FBW.
Material	Binding Energy	RMSD	Amino Acid
monomer	-12.554	1.89	SER55, ALA212, THR 228, THR57, ALA26, GLU397, ALA29, ARG 297
Native Ligand	-14.221

The calculations were also used to establish the SDH protein-monomer structure and to study possible interactions, based on H-bonding, π-π, and arene-π interactions, within the 5Å range. The monomer was found to bind in the same pocket of the active site of SDH and displayed interactions with amino acid residues of SDH, suggesting that the monomer might be potential SDHIs. For our monomer, the oxygen atoms from the morpholine moiety formed the strongest hydrogen bonds with the key residue ARG297 with bond lengths of 2.98 Å and there are 7 more hydrogen bonds with the active site which shows the favorability of our monomer to SDH enzyme (Fig. 1A, B), suggesting that morpholine moiety could be a functional tool to promote the interactions targeting SDH.

CMC polymer with different concentrations of antimicrobial agent 4-(2-choloroethyl)morpholine hydrochloride 1–15% was prepared and its antibacterial and antifungal activity was measured by agar disc diffusion method. The increasing antimicrobial agent concentrations showed an increasing trend in inhibiting the different microorganisms used. It showed the best activity against Escherichia coli, MRSA, and Candida albicans. The CMC polymer with 15% antimicrobial agent showed similar activity to the commercial antibiotic Streptomycin (10 µg) indicating strong antimicrobial activity. The consequent molecular docking studies exhibited that the title compound could form 8 hydrogen bonds with the amino acid residues of SDH, which yielded similar binding sites with the commercial SDHI Boscalid, suggesting the synthesized compound could be a potential SDHIs. The CMC polymer with an antimicrobial agent can be a promising candidate for antibacterial and antifungal activity.

Acknowledgment

The authors extend their appreciation to the Deputyship for Research& Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number ISP23-95.

Author contributionsAll authors made substantial contributions to the conception of the work, Synthesis and Characterization, A.A., H.S, A.F, and M.R,E.; Molecular docking part, D.A; Antimicrobial Investigation, S.K; Validation, W.M.A. and N.A.; Formal analysis, A.A, H.S, and M.R.E Visualization, A.A, and A.F Writing — original draft, A.A Writing — review & editing, A.A, H.S, A.F, M.R.E, S.K, and D.A; All authors have read and agreed to the published version of the manuscript

Funding Funding for open access publishing: University of Jazan. This publication has been co-financed by the Deputyship for Research& Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number ISP23-95.

Data availability Data is contained within the article.

Conflict of interest Authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval and consent to participate Not applicable.

Consent for publication All authors gave their consent for publication.

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Scheme 1 is available in the Supplementary Files section

No competing interests reported.

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Scheme 1: The probability scheme reaction of CMC grafting with an antimicrobial agent.

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Physicochemical Properties, Antimicrobial activity and Docking Study of Carboxymethyl Cellulose (CMC)

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Abstract

Figures

Introduction

Experimental Part

Materials

Synthesis of of 4-(2-Chloroethyl)morpholine Hydrochloride on Carboxymethyl Cellulose (CMC)

Physicochemical characterization

Antibacterial Activity

Docking Procedure

Result and discussion

FTIR Study

Thermal and DSC Analysis

3.3. X-ray diffraction (XRD) analysis

Morphological features

Antimicrobial Evaluation

3.6. Molecular Docking Studies

Conclusion

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

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