Next Article in Journal
A Deep Learning-Based Integration Method for Hybrid Seismic Analysis of Building Structures: Numerical Validation
Next Article in Special Issue
Special Issue on Polysaccharides: From Extraction to Applications
Previous Article in Journal
Morphological, Histological and Ultrastructural Changes in Hordeum vulgare (L.) Roots That Have Been Exposed to Negatively Charged Gold Nanoparticles
Previous Article in Special Issue
The Improvement of Reserve Polysaccharide Glycogen Level and Other Quality Parameters of S. cerevisiae Brewing Dry Yeasts by Their Rehydration in Water, Treated with Low-Temperature, Low-Pressure Glow Plasma (LPGP)
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Applied Sciences
Volume 12
Issue 7
10.3390/app12073267
applsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Novel Chitosan Derivatives and Their Multifaceted Biological Applications

by
Iyyakkannu Sivanesan
1,
Nazim Hasan
2,
Syed Kashif Ali
2,
Juhyun Shin
3,
Judy Gopal
4,
Manikandan Muthu
4,* and
Jae-Wook Oh
3,*
1
Department of Bioresources and Food Science, Institute of Natural Science and Agriculture, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea
2
Department of Chemistry, Faculty of Science, Jazan University, Jazan P.O. Box 114, Saudi Arabia
3
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 143-701, Korea
4
Laboratory of Neo Natural Farming, Chunnampet 603 401, Tamil Nadu, India
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2022, 12(7), 3267; https://doi.org/10.3390/app12073267
Submission received: 17 February 2022 / Revised: 9 March 2022 / Accepted: 22 March 2022 / Published: 23 March 2022
(This article belongs to the Special Issue Polysaccharides: From Extraction to Applications)
Browse Figure
Versions Notes

Abstract

:
Chitosan is a rather attractive material, especially because of its bio-origins as well as generation from exoskeletal waste. As the mantle has been effectively transferred from chitin to chitosan, so has it been extrapolated to in-house synthesized novel chitosan derivatives. This review comprehensively lists the available novel chitosan derivatives (ChDs) and summarizes their biological applications. The fact that chitosan derivatives do comprise multifaceted biological applications is attested by the voluminous reports on their varied contributions. However, this review points out to the fact that there has been selective focus on bio functions such as antifungal, antioxidant, antibacterial, whereas other biomedical applications and antiviral applications remain relatively less explored. With their current functionality record, there is definitely no doubt that the plethora of synthesized ChDs will have a profound impact on the unexplored biological aspects. This review points out this lacuna as room for future exploration.

1. Introduction

Chitosan is a versatile linear amino-polysaccharide, exploited for its diversified biological applications. It is a polycationic polymer obtained from marine crustacean waste via partial deacetylation of chitin [1]. Chitosan has gained attention in the decades, because of its abundance, easy extraction from waste sources, renewability, low cost, anti-bacterial activity, non-toxicity, excellent biocompatibility and biodegradability [2,3]. Chitosan is obtained from chitin by deacetylation and consists of randomly distributed deacetylated β-(1→4)-linked d-glucosamine and acetylated N-acetyl-d-glucosamine units [4]. The deacetyl amine groups on the polymer backbone are key to its various functions. The unique biological properties of chitosan as a drug carrier [5], antimicrobial [6], antioxidant [7], antitumor agent [8] and a wound dressing agent [9,10], are well recorded. Other unique biological attributes include immunomodulatory, immunoregulatory, anti-inflammatory and blood cholesterol-limiting effects.
Despite the above advantages, chitosan exhibits insolubility in water due to its pKa value being 6.5. The reason for its low solubility in the acidic environment is because the primary amine of chitosan is protonated, resulting in positively charged polycations [11]. It is in this direction that chemical modifications were sought after in order to enhance the solubility of chitosan. As is known, increase in the number of free amino and hydroxyl groups leads to it complexing with polyanions [12]. Chemical modifications of chitosan simplify its transformation through NH2 and OH− groups and become the basis for the formation of several functional derivatives such as sulfonation [13], amination [14], and carboxymethylation [15] and the like. In addition to these, chitosan is also chemically modified through grafting with functionalized monomers [16,17] and via complexing with other anionic polymers [18].
Chitosan is a rather attractive option as a biomedical substrate, since it is extracted from natural sources and given the fact that it has recyclable origins, making it highly regarded. There is no question of its credentials, as research is underway to expand its applicability and especially dig into breaking the limitations of this biopolymer. In this direction, chemical modifications, derivatives, grafts, nanomaterials become increasingly important. The present review focuses on briefly consolidating the various novel chitosan derivatives (ChDs) and summarizing their accomplishments. The milestones reached through their biofunctionality as antimicrobials, antioxidants, anticancer agents as well as others of clinical importance were reviewed. The areas needing focus and research expansion, have been discussed under future perspectives.

2. Novel ChDs

Chitosan contains three nucleophilic functional groups: C2-NH2, C3-OH, and C6−OH. The modification does not initiate changes on the fundamental chitosan skeleton, but results in derivatives that are characterized by new or improved properties. Chitosan can be modified at the amino or C6-OH sites; the C3−OH groups are not that easy to modify, owing to large steric hindrance. The two-amino groups are easily modified because of their excellent chemical reactivity. Additionally, amino groups of chitosan are more prone to nucleophilic reactions than the OH groups; moreover, both active groups react with electrophilic moieties such as acyl chlorides, acids and halogenated alkanes, which further modify the amino and OH groups non-selectively [19,20]. Phthaloyl groups and Schiff bases protect the amino group of chitosan [21,22,23,24], and triphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl are used to protect the OH groups of chitosan [24,25]. Alkylation (carboxymethylation), acylation (phthaloylation), quaternization, sulfation, thiolation, graft copolymerization, etc. are the predominantly reported modifications tailor-made for specific applications [26]. The major classes of chitosan modifications and what has been achieved through these modifications are briefly summarized below.
N-alkylated ChDs comprise diethylmethyl, trimethyl, triethyl and dimethyl ethyl chitosans which emerge following alkylation of the primary amines of chitosan (with suitable aldehyde and reducing agents added). N-trimethyl chitosan (TMC) is prepared via methylation of amine groups with methyl iodide [27]. Its water solubility depends on its degree of methylation [28]. An improvement in the mucoadhesive trait, followed by enhanced absorption (at neutral pH), has been observed in the case of soluble TMC [29,30,31]. Quaternized, thiolated, hydrophobic and chemically grafted ChDs are reported to improve or impart novel properties to chitosan. Quaternary ChDs of the N-alkyl or quaternary ammonium types could increase the solubility of chitosan in water and are able to keep its solubility stable over a wide range of pH values. This modification is reported to exhibit enhanced mucoadhesive, drug penetration attributes [32]. N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) is synthesized by incorporating a quaternary ammonium moiety, such as glycidyl trimethyl ammonium, into the amine groups of chitosan. This is also what has been used to formulate albumin-loaded chitosan derivative nanoparticles [33].
Other derivatives rise from the addition of hydrophobic groups to chitosan via acylation. Caprylic, lauric and capric acids are the notable fatty acids used to increase the permeability [34,35]. Oleoyl and octanoyl ChDs are N-acylated ChDs, formed using fatty acyl chlorides; these are resistant to gastric enzymatic degradation and show enhanced mucoadhesiveness and permeability [36].
Thiolated chitosans are produced by modifying the chitosan amine groups with cysteine, 2-iminothiolane, thiobutylamidine or thioglycolic acid. These derivatives possess high drug permeation, improved oral as well as nasal mucoadhesive drug delivery and also displayed in situ gelling behavior in physiological fluids [37,38,39]. Trimethyl chitosan–cysteine (TMC–Cy) is a modified chitosan conjugate that combines TMC and thiolated derivatives. This derivative positively impacts chitosan’s mucoadhesive and permeation properties. TMC–Cy insulin-loaded nanoparticles are reported to have high insulin encapsulation efficiency and mucoadhesion, compared to TMC–insulin nanoparticles [40]. Chitosan chemically modified through the introduction of carboxylic acid is highly hydrophilic in basic environments. Chitosan succinate and chitosan phthalate showed an insulin-loading capacity of nearly 60% and protection from gastric enzyme degradation [41,42]. Lauryl succinyl chitosan possesses negatively charged mucoadhesive properties as well as hydrophilic and hydrophobic traits [43]. Chitosan derivatives containing Schiff-bases are formed by the conjugation of a primary amine on chitosan with an active carbonyl group [44]. The substitution reactions are comparatively easier and produce imine-containing Schiff bases [45]. The relation between chitosan Schiff-bases and pharmacological activities are well known [11,45,46].
Carboxymethyl chitosan (CMCS) is one of the most important ChDs that are widely reported for their varied biological properties [47,48]. CMCS are prepared by reacting chitosan with chloroacetic acid in water under microwave irradiation [49,50]. Compared to chitosan, CMCS possesses good water solubility, which greatly expands the applications of chitosan [51]. CMCS is well established for its enhanced antibacterial ability against Staphylococcus aureus and Escherichia coli [52]. It also has been reported for its anti-tumor activity because it has stronger electrostatic interaction with negatively charged tumor cells, thus inhibiting the growth of tumor cells [49,51]. Antifungal and antioxidant properties are represented by this compound. Synthesis of mono-N-carboxymethyl chitosan (MCC) is obtained via chemical modification with glyoxylic acid in the presence of sodium borohydride, decreasing the transepithelial electrical resistance of Caco-2 cell monolayers [31].
Chemical grafting of chitosan is a process by which one or more species are connected as a side chain to the main chitosan chain [16]. Chitosan can be grafted via radiation, free radical, or enzymatic and cationic copolymerization. Chitosan-poly(ethylene glycol) diacrylate and chitosan derivatives with galactose groups are notable examples. Figure 1 gives an overview of the chitosan derivatives predominantly known for their bio-applications.
As much as the biological properties of chitosan are dependent on the degree of deacetylation (DD), the degree of substitution (DS) depends on the percentage of newly added groups into chitosan. These influence the biological functionality of ChDs. The DS of ChDs have a profound impact on their solubility and biological activity at neutral pH [53]. Poor dissolution of chitosan and reduced solubility limit the application of chitosan in drug delivery [54]. Chitosan is chemically modified to overcome these barriers. The outcome of these chemical modification in the form of various ChDs helps overcome the limitations of chitosan for biological applications.

3. Biological Applications of ChDs

Table 1 and Table 2 summarizes all the various biological applications of the novel ChDs reported in the literature. The applications are discussed below under antimicrobial, antioxidant, and miscellaneous subcategories in Section 3.1, Section 3.2 and Section 3.3.

3.1. Antimicrobial Applications

Eight novel ChDs bearing urea groups were synthesized, and their antioxidant activities were explored. In vitro fungicidal activity of these derivatives was further tested against Phomopsis asparagus, Fusarium oxysporum f. sp. niveum, Botrytis cinerea and F. oxysporum f. sp. cucumebrium. The results showed that most of the derivatives exhibited significant control at concentrations of 1.0 mg mL−1 and showed low cytotoxicity [106]. Two antimicrobial phenolic chitosan Schiff bases (I) and (II) were synthesized and the antimicrobial activities of Schiff base (I) were significantly higher than Schiff base (II). High concentrations of Schiff base (I) inhibited 99% of Gram-positive bacteria and Schiff base (II) led to 82% inhibition. The cytotoxicity of these derivatives was tested against fibroblast cells [70]. New ChDs bearing guanidinium, N-guanidinium chitosan acetate and N-guanidinium chitosan chloride were synthesized and found to show high antimicrobial activity [75].
Botrytis cinerea, Phytophthora capsici and Fusarium solani are notorious plant pathogenic fungi that lead to huge losses of crops worldwide. Novel water-soluble functional ChDs were synthesized and tested against the three fungi and the cytotoxicity were estimated in vitro; the ChDs exhibited better antifungal activities and water solubility than chitosan and better biocompatibility [98]. In another study, authors synthesized a novel cationic ChD possessing 1,2,3-triazolium and pyridinium groups via cuprous-catalyzed azide-alkyne cycloaddition (CuAAC) and methylation. The antifungal efficiencies and their biocompatibility were confirmed [99].
Packialakshmi et al. [123] investigated the effect of chitosan on SARS-CoV-2. β-ChDs were screened against the HepG2and MCF-7 (breast) cancer cell lines and found to be effective. They also investigated the ChDs (1a–1j) docking against SARS coronavirus via in silico docking analysis. The results showed this to be a promising alternative antiviral agent for SARS-CoV2.
Alkyl groups were introduced into amine groups of chitosan via Schiff’s base intermediates to obtain N-alkyl ChDs. The antibacterial activity against S. aureus was explored and was found to increase with the increase in the chain length of the alkyl substituent [125]. Novel N,O-acyl chitosan (NOAC) derivatives were synthesized and their fungicidal activity against Botrytis cinerea and the rice leaf blast fungus Pyricularia oryzae was assessed [88]. CS Schiff bases (CSSBs) (CS-P1, CS-P2, and CS-P3) were synthesized and their antimicrobial activity and antifungal activity was confirmed [82].
Authors have also reported a study using chitosan acylation with linoleic (LA) and dilinoleic acid (DLA) for fabrication of polymer films and further assessment of antimicrobial properties of the polymer films against E. coli and the fungi Candida albicans [60]. Several novel ChDs bearing benzenoid/heterocyclic moieties displayed significant enhancement in superoxide-radical scavenging activity and DPPH radical scavenging activity and antifungal activity against plant pathogens, Colletotrichum lagenarium and Phomopsis asparagi. Moreover, they also showed low cytotoxicity on L929 cells [107]. A series of 6-O-imidazole-based quaternary ammonium ChDs, were successfully synthesized. Their antioxidant property was evaluated in vitro. Most of the quaternized ChDs with long length alkyl chains and primary amino groups showed >85% inhibition at 1.0 mg/mL against Botrytis cinerea. Another group reported an antimicrobial effect on crop-threatening bacteria by benzyl moiety-grafted or quaternized ChDs. Three novel thiosemicarbazone ChDs were obtained via condensation reaction of thiosemicarbazide chitosan with phenylaldehyde, o-hydroxyphenylaldehyde, and p-methoxyphenylaldehyde, respectively. Antifungal activity against the plant pathogenic fungi Stemphylium solani weber, Alternaria solani, Rhizoctonia solani, and Phomopsis asparagi Sacc. was demonstrated [102].
Kandile et al. [85] reported the synthesis of ChD-inspired heterocyclic anhydride and the antibacterial activity of the ChDs and their use against S. aureus and B. subtilis. Three heteroaryl pyrazole derivatives, namely 1-phenyl-3-(thiophene-2-yl)-1H-pyrazole-4-carbaldehyde, 1-phenyl-3-(furan-2-yl)-1H-pyrazole-4-carbaldehyde and 1-phenyl-3-(pyridine-3-yl)-1H-pyrazole-4-carbaldehyde, were synthesized and reacted to form Schiff bases of chitosan. These were tested for their antibacterial effect against Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia), Gram-positive bacteria (Staphylococcus aureus and Streptococcus mutans) and fungi (Aspergillus fumigatus and Candida albican). The derivatives also showed no cytotoxicity [81].
Novel water-soluble ChDs (TQCSPX) were synthesized; antifungal results indicated that the quaternized derivatives showed enhanced antifungal activity [101]. Four novel coumarin-functionalized ChDs 4a–4d were synthesized via condensation reactions of thiosemicarbazide chitosan with coumarin derivatives. Their antifungal activities against three kinds of phytopathogens: Fusarium oxysporum f.sp. vasinfectum, Alternaria solani Sorauer and Fusarium moniliforme was confirmed [100]. A novel O-quaternary ammonium N-acyl thiourea chitosan (OQCATUCS) with different degrees of substitution was synthesized by Li et al. [23]. The antimicrobial activities of the ChDs were assessed against Staphyloccocus aureus, Escherichia coli, Aspergillus niger, Pseudomonas aeruginosa and Bacillus subtilis. Diethyl dithiocarbamate chitosan (EtDTCCS) was used against Alternaria porri, Gloeosporium theae sinensis Miyake, and Stemphylium solani Weber as tested. Compared with native chitosan, EtDTCCS showed a better inhibitory effect [23].
Three novel quaternary ChDs were synthesized by reacting chloracetylchitosan (CACS) with pyridine (PACS), 4-(5-chloro-2-hydroxybenzylideneamino)-pyridine (CHPACS), and 4-(5-bromo-2-hydroxybenzylideneamino)-pyridine (BHPACS). Their antifungal activity against Monilinia fructicola, Cladosporium cucumerinum, Colletotrichum lagenarium, and Fusarium oxysporum was found to be superior compared to native chitosan [90]. Novel water-soluble ChDs containing 1,3,4-thiadiazole group were synthesized including 1,3,4-thiadiazole (TPCTS), 2-methyl-1,3,4-thiadiazole (MTPCTS), and 2-phenyl-1,3,4-thiadiazole (PTPCTS). MTPCTS inhibited Colletotrichum lagenarium, Phomopsis asparagi and Monilinia fructicola at 1.0 mg/mL [92].
Tan et al. [97] reported the synthesis of two novel cationic ChDs modified with quaternary phosphonium salts via trimethylation, chloride acetylation and quaternization with tricyclohexylphosphine and triphenylphosphine. The antifungal activities of ChDs against Phomopsis asparagi, Watermelon fusarium, Colletotrichum lagenarium, and Fusarium oxysporum showed significant antifungal efficiency compared to native chitosan. A chitosan derivative of 2-thiophene carboxaldehyde was found to be active against Escherichia coli. Novel chitosan oligosaccharide derivatives (COS-All-Tio) have been employed for shrimp preservation. Six dominant spoilage bacteria Shewanella putrefaciens (RMS1), S. putrefaciens (S2), Pseudomonas weihenstephanensis (P1), P. gessardii (P2), Aeromonas bestiarum (A1) and Aeromonas molluscorum (A2) that are actively involved in spoilage of prawns were used. COS-All-Tio ChDs could inhibit the growth of all these bacteria. It was observed that COS-All-Tio could inhibit bacterial growth by influencing their membrane integrity, resulting in the leakage of the bacterial intracellular substances [87].
Si et al. [86] report a new biodegradable and biocompatible chitosan-derived cationic antibacterial polymer, 2,6-diamino chitosan (2,6-DAC). 2,6-DAC demonstrated excellent broad-spectrum antimicrobial activity against clinically relevant and multidrug-resistant (MDR) bacteria, including Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. In vivo biocompatibility of 2,6-DAC was also tested; 2,6-DAC did not cause any weight loss nor significant changes in liver and kidney biomarkers or blood electrolytes. 2,6-DAC was also used together with novobiocin and rifampicin to inhibit A. baumannii in murine intraperitoneal and lung infection models.

3.2. Antioxidant Applications

A new class of ChD-possessing thiourea salts has been reported that could successfully enhance the solubility and the antioxidant activity. Their antioxidant properties were tested and an increase in thiourea salt groups in ChDs showed enhanced scavenging effect. The scavenging activity of the ChDs against DPPH-radical and superoxide-radical was more than 90% at 1.6 mg/mL. No cytotoxicity was observed for the L929 cells at all testing concentrations [114]. Quaternized N-pyridylurea ChDs were prepared and the antioxidant activity of the synthesized ChDs was assessed in vitro. Enhanced antioxidant capacity compared with N-pyridylurea ChDs was observed and high biocompatibility with L929 cells demonstrated [113].
A group of novel chitosan quaternary ammonium derivatives containing pyridine or amino-pyridine were successfully synthesized. This showed improved antifungal activity and better water solubility and stronger antioxidant activity than chitosan. The synergistic effect of the amino group and pyridine improved the antioxidant activity of ChDs [110]. A new class of ChDs possessing 1,2,3-triazolium charged units by “click reaction” with efficient 1,2,3-triazole quaternization were synthesized and possessed enhanced radical-scavenging activity [112].

3.3. Miscellaneous Bio-Applications

N,O-selenized N-(2-carboxyethyl) chitosan (sNCCS) was synthesized through carboxyethylation and selenylation. In vitro assessment confirmed that sNCCS has excellent bile acid binding capacity. Moreover, higher selenium content significantly enhanced the antioxidant properties of the sNCCS. No cytotoxic effect was observed on Caco-2 cells [115]. Novel water soluble phosphonium ChDs (WSPCSs) with two different degrees of substitution (3.6% and 4.2%) of quaternary phosphonium were synthesized in a homogeneous system. The derivatives could be easily dissolved in water. MTT (methyl thiazolyltetrazolium) assay indicated that they had low cytotoxicity to L929 cells [119]. The pharmaceutical performance of an innovative chitosan derivative, methyl acrylate chitosan-bearing p-nitrobenzaldehyde (MA*CS*pNBA) Schiff base, was studied by Ali et al. [71]. The antibacterial activity of MA*CS*pNBA was used against multi-drug resistant (MDR) Gram-negative and Gram-positive bacteria. It also exhibited anti-biofilm, antioxidant and anti-inflammatory biomaterial, evidencing hemocompatibility and no cytotoxicity [71].
N-substituted ChDs were synthesized via condensation with a number of selected aryl and heteroaryl aldehydes. The antimicrobial activity of chitosan Schiff’s base (CSB) derivatives was confirmed against four types of bacteria, and two crop-threatening pathogenic fungi. The triazolo-Schiff’s base derivative 3c was tested against human breast adenocarcinoma cells (MCF-7), human colon carcinoma cells (HCT-116), and human hepatocellular liver carcinoma cells (HepG-2), showed growth inhibitory effects [64]. A series of N,N,N-trimethyl-O-(ureidopyridinium)acetyl ChDs were synthesized. This modification developed the water solubility and biological properties of chitosan. The prepared ChDs exhibited improved antioxidant activity compared to chitosan. The ChDs also showed antifungal activity on Phomopsis asparagus as well as Botrytis cinerea, and they showed significant inhibitory effect on the selected phytopathogen as well as low cell toxicity [108]. In another study, Schiff bases of chitosan (CS) were synthesized using citronellal, citral, containing selenium and sulfur. Biological assays were conducted using films prepared by blending ChDs and poly(vinyl alcohol). The film inhibited Escherichia coli, Staphylococcus aureus and Candida albicans. In vivo assays revealed that the ChDs film attenuates atopic dermatitis-like symptoms in mice, by suppressing the increase in myeloperoxidase (MPO) activity and reactive species (RS) levels induced by 2,4-dinitrochlorobenzene (DNCB), indicative of the potent use of ChDs in skin infection treatments [73]. The ChDs modified with poly(ethylene glycol) (PEG) were soluble in neutral water, interacted with acrylic polymer having carboxy groups and gave a more stable emulsion. The N-carboxymethylated, N,O-sulfated, and N-trimethylated ChDs showed reasonable low electric resistance. Carbohydrate-branched ChDs were synthesized to obtain increased water solubility and attain novel biological properties. The specific interaction with lectins or bacterium and the activation of canine polymorpho nuclear leukocyte (PMN) cells were biological activities made possible by the synthesized carbohydrate-branched ChDs [126].
Chitosan with phenolic hydroxyl groups (Chit-Ph), were soluble at neutral pH and gellable via a peroxidase catalyzed reaction within seconds and compatible with L929 cells [117]. Soluble, antibacterial ChDs were prepared by Liu et al. via region selective chemical modification. Water-solubility increased and the results of the platelet adhesion and the activated partial thromboplastin time (APTTs) assays indicate that grafting hydroxyethyl could improve anticoagulation of chitosan. The antibacterial activity of HC against Enterococcus and E. coli was also demonstrated [57]. A novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed. Overall, their study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for synergistic tumor inhibition [127]. A reactive antibacterial compound (4-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-benzyl)-triphenyl-phosphonium bromide (NHS-QPS) was synthesized for chemical modification of CS, and a series of antibacterial N quaternary phosphonium ChDs were obtained. The water solubility and antibacterial activities of N-QPCSxy against Escherichia coli and Staphylococcus aureus were evaluated and confirmed along with its low cytotoxicity [67]. New novel chitosan-sulfonamide derivatives have been designed to develop new wound dressing biomaterials. The antimicrobial assay evidenced that chitosan-based sulfadiazine, sulfadimethoxine and sulfamethoxazole derivatives were the most active. The MTT assay showed that some of the ChDs are nontoxic. Additionally, in vivo studies on a burn wound model induced in Wistar rats demonstrated an improved healing effect and enhanced epithelialization of chitosan-sulfonamide derivatives. The obtained results strongly recommend the use of the developed ChDs as antimicrobial wound dressing biomaterials [109]. In terms of ChD-assisted anticancer therapy, an excellent review by Shakil et al. [128] is available. Table 3 gives the list of anticancer milestones achieved using ChDs

4. Future Perspectives

The journey of chitosan began from marine shell waste, has meandered from chitin to chitosan and is now diverging into multiple modifications to result in novel ChDs. As observed from the ocean of applications of these chitosan derivatives, much has been accomplished. The wisdom behind modifying chitosan to obtain derivatives that break the limitations of native chitosan is an attractive research direction. As has been described, there have been ample accomplishments in terms of antimicrobial activity, antioxidant activity and biocompatibility. However, this review does envision scope for further expansion.
With as many as close to a hundred chitosan derivatives synthesized and tested for selective biological properties, it is strange that only a few biomedical applications have been seldom tested. As has been reviewed, very few novel chitosan derivatives have been applied to cancer therapy as compared to the voluminous reports with native chitosan. Chitosan is already well accomplished for cancer treatment [135,136,137,138,139,140] and, with the ChDs showing much advanced features compared to native chitosan, more positive outcomes are expected through implementing novel ChDs. This review urges the practical implementation of the novel ChDs for anticancer research, phototherapy, bioimaging and diagnostics. There are definitely huge possibilities and prospects in this direction that need research focus.
The most worked on biological property, where ChDs have been elaborately worked on, is their antimicrobial properties. Yet here too there exists an evident bias. Antibacterial and antifungal applications have been researched with respect to numerous novel abundant ChDs. However, it was observed that selective novel ChDs were applied to specific strains of bacteria and fungi. As can be observed from Table 1, the strains tested were more or less repetitive. Moreover, almost nothing regarding antiviral applications has been attempted. Being in the COVID era, seeing what these viruses are capable of, it is strange that a system so well understood for its antimicrobial activity, will not be put to test for its antiviral activity. This strong bias (there being more antibacterial reports) towards the implementation of novel ChDs within microbial applications was observed. This review stresses the need for more focus towards implementing the synthesized novel ChDs for diverse antibacterial (especially clinical isolates) and antiviral testing. Additionally, biomedical applications, such as antibacterial coatings, wound dressing, drug delivery and pharmaceutical options, have not been attempted with novel ChDs.
Chitosan nanoparticles have their own unique properties, combining chitosan derivatives with chitosan nanomaterials will be a whole new avenue of possibilities, which is yet to be explored. As always, nanomaterials have always exceeded the abilities and limits of their bulk counterparts; chemical modification of chitosan nanoparticles and chitosan nanofibers could unleash numerous possibilities and satisfy extended biological functions. This could be the future of novel ChDs.

5. Conclusions

This review summarized the innumerable biological applications of novel chitosan derivatives. The need to expand the available chitosan derivative resources into various other facets of biological applications is stressed as a future perspective. There are few biological functions that lie never attempted, which need to be investigated. From the magnitude of the plethora of novel ChDs available, to that of those which have been applied, there is a solid gap. This review seeks to encourage of readers to bridge this gap through their future input.

Author Contributions

I.S., J.G. and M.M. preparation of original draft; N.H., S.K.A. and J.S. review and revisions; J.-W.O. participated in review and revisions. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

This article was supported by the KU Research Professor Program of Konkuk University.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Grotz, E.; Tateosian, N.; Amiano, N.; Cagel, M.; Bernabeu, E.; Chiappetta, D.A.; Moretton, M.A. Nanotechnology in tuberculosis: State of the art and the challenges ahead. Pharm. Res. 2018, 35, 213. [Google Scholar] [CrossRef] [PubMed]
  2. Mi, F.L.; Tan, Y.C.; Liang, H.F.; Sung, H.W. In vivo biocompatibility and degradability of a novel injectable-chitosan-based implant. Biomaterials 2002, 23, 181–191. [Google Scholar] [CrossRef]
  3. Tamer, M.T.; Valachova, K.; Hassan, M.A.; Omer, A.M.; El-Shafeey, M.; Mohy Eldin, M.S.; Soltes, L. Chitosan/hyaluronan/edaravone membranes for anti-inflammatory wound dressing: In vitro and in vivo evaluation studies. Mater. Sci. Eng. C 2018, 90, 227–235. [Google Scholar] [CrossRef] [PubMed]
  4. Rinaudo, M. Chitin and chitosan: Properties and applications. Prog. Polym. Sci. 2006, 31, 603–632. [Google Scholar] [CrossRef]
  5. Omer, A.; Tamer, T.; Hassan, M.; Rychter, P.; Eldin, M.M.; Koseva, N. Development of amphoteric alginate/aminated chitosan coated microbeads for oral protein delivery. Int. J. Biol. Macromol. 2016, 92, 362–370. [Google Scholar] [CrossRef]
  6. Yildirim-Aksoy, M.; Beck, B.H. Antimicrobial activity of chitosan and a chitosan oligomer against bacterial pathogens of warmwater fish. J. Appl. Microbiol. 2017, 122, 1570–1578. [Google Scholar] [CrossRef]
  7. Valachová, K.; Tamer, T.M.; Eldin, M.M.; Šoltés, L. Radical-Scavenging activity of glutathione, chitin derivatives and their combination. Chem. Pap. 2016, 70, 820–827. [Google Scholar] [CrossRef]
  8. Xie, F.; Ding, R.L.; He, W.F.; Liu, Z.J.; Fu, S.Z.; Wu, J.B.; Yang, L.L.; Lin, S.; Wen, Q.L. In vivo antitumor effect of endostatin-loaded chitosan nanoparticles combined with paclitaxel on Lewis lung carcinoma. Drug Deliv. 2017, 24, 1410–1418. [Google Scholar] [CrossRef] [Green Version]
  9. Archana, D.; Dutta, J.; Dutta, P.K. Evaluation of chitosan nano dressing for wound healing: Characterization, in vitro and in vivo study. Int. J. Biol. Macromol. 2013, 57, 193–203. [Google Scholar] [CrossRef]
  10. Tamer, T.M.; Collins, M.N.; Valachová, K.; Hassan, M.A.; Omer, A.M.; Eldin, M.S.M.; Švík, K.; Jurčík, R.; Ondruška, Ľ.; Biró, C.; et al. MitoQ loaded chitosan-hyaluronan composite membranes for wound healing. Materials 2018, 11, 569. [Google Scholar] [CrossRef] [Green Version]
  11. Morsy, R.; Ali, S.S.; El-Shetehy, M. Development of hydroxyapatite-chitosan gel sunscreen combating clinical multidrug-resistant bacteria. J. Mol. Struct. 2017, 1143, 251–258. [Google Scholar] [CrossRef]
  12. Mahmoudzadeh, M.; Fassihi, A.; Dorkoosh, F.; Heshmatnejad, R.; Mahnam, K.; Sabzyan, H.; Sadeghi, A. Elucidation of molecular mechanisms behind the self-assembly behavior of chitosan amphiphilic derivatives through experiment and molecular modeling. Pharm. Res. 2015, 32, 3899–3915. [Google Scholar] [CrossRef] [PubMed]
  13. Rwei, S.P.; Lien, C.C. Synthesis and Rheological Characterization of Sulfonated Chitosan Solutions. Colloid Polym. Sci. 2014, 292, 785–795. [Google Scholar] [CrossRef]
  14. Afshar, H.A.; Ghaee, A. Preparation of aminated chitosan/alginate scaffold containing hallosyte nanotubes with improved cell attachment. Carbohydr. Polym. 2016, 151, 1120–1131. [Google Scholar] [CrossRef]
  15. Bukzem, A.L.; Signini, R.; Dos Santos, D.M.; Liao, L.M.; Ascheri, D.P. Optimization of carboxymethyl chitosan synthesis using response surface methodology and desirability function. Int. J. Biol. Macromol. 2016, 85, 615–624. [Google Scholar] [CrossRef]
  16. Jayakumar, R.; Prabaharan, M.; Reis, R.L.; Mano, J.F. Graft copolymerized chitosan—Present status and applications. Carbohydr. Polym. 2005, 62, 142–158. [Google Scholar] [CrossRef] [Green Version]
  17. Tamer, T.M.; Omer, A.M.; Hassan, M.A.; Hassan, M.E.; Sabet, M.M.; Eldin, M.M. Development of thermo-sensitive poly N-isopropyl acrylamide grafted chitosan derivatives. J. Appl. Pharm. Sci. 2015, 5, 1–6. [Google Scholar]
  18. Luo, Y.; Wang, Q. Recent development of chitosan-based polyelectrolyte complexes with natural polysaccharides for drug delivery. Int. J. Biol. Macromol. 2014, 64, 353–367. [Google Scholar] [CrossRef]
  19. Sahariah, P.; Maásson, M. Antimicrobial chitosan and chitosan derivatives: A review of the structure–activity relationship. Biomacromolecules 2017, 18, 3846–3868. [Google Scholar] [CrossRef]
  20. Sashiwa, H.; Aiba, S. Chemically modified chitin and chitosan as biomaterials. Prog. Polym. Sci. 2004, 29, 887–908. [Google Scholar] [CrossRef]
  21. Chen, C.; Tao, S.; Qiu, X.; Ren, X.; Hu, S. Long-Alkane-Chain modified N-phthaloyl chitosan membranes with controlled permeability. Carbohydr. Polym. 2013, 91, 269–276. [Google Scholar] [CrossRef] [PubMed]
  22. Hu, L.; Meng, X.; Xing, R.; Liu, S.; Chen, X.; Qin, Y.; Yu, H.; Li, P. Design, synthesis and antimicrobial activity of 6- N -substituted chitosan derivatives. Bioorgan. Med. Chem. Lett. 2016, 26, 4548–4551. [Google Scholar] [CrossRef] [PubMed]
  23. Li, Z.; Yang, F.; Yang, R. Synthesis and characterization of chitosan derivatives with dual-antibacterial functional groups. Int. J. Biol. Macromol. 2015, 75, 378–387. [Google Scholar] [CrossRef] [PubMed]
  24. Kurita, K.; Sugita, K.; Kodaira, N.; Hirakawa, M.; Yang, J. Preparation and evaluation of trimethylsilylated chitin as a versatile precursor for facile chemical modifications. Biomacromolecules 2005, 6, 1414–1418. [Google Scholar] [CrossRef]
  25. Benediktsdottir, B.E.; Gaware, V.S.; Runarsson, O.V.; Jonsdottir, S.; Jensen, K.J.; Masson, M. Synthesis of N,N,N-trimethyl chitosan homopolymer and highly substituted N-alkyl-N,N-dimethyl chitosan derivatives with the aid of di-tert-butyldimethylsilyl chitosan. Carbohydr. Polym. 2011, 86, 1451–1460. [Google Scholar] [CrossRef]
  26. Jain, A.; Gulbake, A.; Shilpi, S.; Jain, A.; Hurkat, P.; Jain, S.K. A new horizon in modifcations of chitosan: Syntheses and applications. Crit. Rev. Ther. Drug Carrier Syst. 2013, 30, 91–181. [Google Scholar] [CrossRef]
  27. Sieval, A.B.; Thanou, M.; Kotzé, A.F.; Verhoef, J.C.; Brussee, J.; Junginger, H.E. Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride. Carbohydr. Polym. 1998, 36, 157–165. [Google Scholar] [CrossRef]
  28. Verheul, R.J.; Amidi, M.; van der Wal, S.; van Riet, E.; Jiskoot, W.; Hennink, W.E. Synthesis, characterization and in vitro biological properties of O-methyl free N,N,N-trimethylated chitosan. Biomaterials 2008, 29, 3642–3649. [Google Scholar] [CrossRef]
  29. Hamman, J.H.; Stander, M.; Kotze, A.F. Effect of the degree of quaternisation of N-trimethyl chitosan chloride on absorption enhancement: In vivo evaluation in rat nasal epithelia. Int. J. Pharm. 2002, 232, 235–242. [Google Scholar] [CrossRef]
  30. Thanou, M.; Verhoef, J.C.; Marbach, P.; Junginger, H.E. Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J. Pharm. Sci. 2000, 89, 951–957. [Google Scholar] [CrossRef]
  31. Thanou, M.; Nihot, M.T.; Jansen, M.; Verhoef, J.C.; Junginger, H.E. Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 2001, 90, 38–46. [Google Scholar] [CrossRef]
  32. Ahmed, T.A.; Aljaeid, B.M. Preparation, characterization and potential application of chitosan, chitosan derivatives and chitosan metal nanoparticles in pharmaceutical drug delivery. Drug Des. Dev. Ther. 2016, 10, 483–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Xu, Y.M.; Du, Y.M.; Huang, R.H.; Gao, L.P. Preparation and modification of N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride nanoparticle as a protein carrier. Biomaterials 2003, 24, 5015–5022. [Google Scholar] [CrossRef]
  34. Tomita, M.; Hayashi, M.; Horie, T.; Ishizawa, T.; Awazu, S. Enhancement of colonic drug absorption by transcellular permeation route. Pharm. Res. 1988, 5, 786–789. [Google Scholar] [CrossRef]
  35. Tien, C.L.; Lacroix, M.; Ispas-Szabo, P.; Mateescu, M.A. N-Acylated chitosan: Hydrophobic matrices for controlled drug release. J. Control. Release 2003, 93, 1–13. [Google Scholar] [CrossRef]
  36. Sonia, T.A.; Sharma, C.P. Chitosan and Its Derivatives for Drug Delivery Perspective. Adv. Polym. Sci. 2011, 243, 23–54. [Google Scholar]
  37. Schnurch, A.B.; Hornof, M.; Zoidl, T. Thiolated polymers–thiomers: Synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates. Int. J. Pharm. 2003, 260, 229–237. [Google Scholar] [CrossRef]
  38. Hornof, M.D.; Kast, C.E.; Bernkop-Schnürch, A. In Vitro Evaluation of the Viscoelastic Properties of Chitosan-Thioglycolic Acid Conjugates. Eur. J. Pharm. Biopharm. 2003, 55, 185–190. [Google Scholar] [CrossRef]
  39. Roldo, M.; Hornof, M.; Caliceti, P.; Bernkop-Schnürch, A. Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: Synthesis and in vitro evaluation. Eur. J. Pharm. Biopharm. 2004, 57, 115–121. [Google Scholar] [CrossRef]
  40. Yin, L.; Ding, J.; He, C.; Cui, L.; Tang, C.; Yin, C. Biomaterials Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials 2009, 30, 5691–5700. [Google Scholar] [CrossRef]
  41. Ubaidulla, U.; Khar, R.K.; Ahmad, F.J.; Sultana, Y.; Panda, A.K. Development and characterization of chitosan succinate microspheres for the improved oral bioavailability of insulin. J. Pharm. Sci. 2007, 96, 3010–3023. [Google Scholar] [CrossRef] [PubMed]
  42. Ubaidulla, U.; Sultana, Y.; Ahmed, F.J.; Khar, R.K.; Panda, A.K. Chitosan phthalate microspheres for oral delivery of insulin: Preparation, characterization, and in vitro evaluation. Drug Deliv. 2007, 14, 19–23. [Google Scholar] [CrossRef]
  43. Rekha, M.R.; Sharma, C.P. Synthesis and evaluation of lauryl succinyl chitosan particles towards oral insulin delivery and absorption. J. Control. Release 2009, 135, 144–151. [Google Scholar] [CrossRef] [PubMed]
  44. Casettari, L.; Castagnino, E.; Stolnik, S.; Lewis, A.; Howdle, S.M.; Illum, L. Surface Characterisation of Bioadhesive PLGA/Chitosan Microparticles Produced by Supercritical Fluid Technology. Pharm. Res. 2011, 28, 1668–1682. [Google Scholar] [CrossRef] [PubMed]
  45. Tamer, A.M.; Hassan, M.A.; Omer, M.A.; Baset, W.M.A.; Hassan, M.E.; El-Shafeey, M.E.A.; Mohy Elding, M.S. Synthesis, characterization and antimicrobial evaluation of two aromatic chitosan Schiff base derivatives. Process Biochem. 2016, 51, 1721–1730. [Google Scholar] [CrossRef]
  46. Malik, S.; Nema, B. Antimicrobial activities of schiff bases: A review. Int. J. Theor. Appl. Phys. 2016, 8, 28–30. [Google Scholar]
  47. Rui, L.; Xie, M.; Hu, B.; Zhou, L.; Saeeduddin, M.; Zeng, X. Enhanced solubility and antioxidant activity of chlorogenic acid-chitosan conjugates due to the conjugation of chitosan with chlorogenic acid. Carbohydr. Polym. 2017, 170, 206–216. [Google Scholar] [CrossRef]
  48. Wang, Y.-L.; Zhou, Y.-N.; Li, X.-Y.; Huang, J.; Wahid, F.; Zhong, C.; Chu, L.-Q. Continuous production of antibacterial carboxymethyl chitosan-zinc supramolecular hydrogel fiber using a double-syringe injection device. Int. J. Biol. Macromol. 2020, 156, 252–261. [Google Scholar] [CrossRef]
  49. Lei, M.; Huang, W.; Sun, J.; Shao, Z.; Duan, W.; Wu, T.; Wang, Y. Synthesis, characterization, and performance of carboxymethyl chitosan with different molecular weight as additive in water-based drilling fluid. J. Mol. Liq. 2020, 310, 113135. [Google Scholar] [CrossRef]
  50. Shieh, Y.; Chen, Y.; Don, T. Carboxymethyl chitosan has sensitive two-way CO2-responsive hydrophilic/hydrophobic feature. Carbohydr. Polym. 2020, 241, 116408. [Google Scholar] [CrossRef]
  51. Lyu, R.L.; Xia, T.; Liang, C.; Zhang, C.; Li, Z.Q.; Wang, L.C.; Wang, Y.; Wu, M.; Luo, X.G.; Ma, J.Y.; et al. MPEG grafted alkylated carboxymethyl chitosan as a high-efficiency demulsifier for O/W crude oil emulsions. Carbohydr. Polym. 2020, 241, 116309. [Google Scholar] [CrossRef] [PubMed]
  52. Zhang, C.; Yang, X.; Li, Y.; Qiao, C.; Wang, S.; Wang, X.; Xu, C.; Yang, H.; Li, T. Enhancement of a zwitterionic chitosan derivative on mechanical properties and antibacterial activity of carboxymethyl cellulosebased films. Int. J. Biol. Macromol. 2020, 159, 1197–1205. [Google Scholar] [CrossRef]
  53. Li, J.; Cai, C.; Li, J.; Li, J.; Li, J.; Sun, T.; Wang, L.; Wu, H.; Yu, G. Chitosan-Based Nanomaterials for Drug Delivery. Molecules 2018, 23, 2661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Wang, W.; Meng, Q.; Li, Q.; Liu, J.; Zhou, M.; Jin, Z.; Zhao, K. Chitosan Derivatives and Their Application in Biomedicine. Int. J. Mol. Sci. 2020, 21, 487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Kumar, S.; Dutta, P.K.; Koh, J. A physico-chemical and biological study of novel chitosan-chloroquinoline derivative for biomedical applications. Int. J. Biol. Macromol. 2011, 49, 356–361. [Google Scholar] [CrossRef] [PubMed]
  56. Patale, R.L.; Patravale, V.B. O,N-carboxymethyl chitosan-zinc complex: A novel chitosan complex with enhanced antimicrobial activity. Carbohyd. Polym. 2011, 85, 105–110. [Google Scholar] [CrossRef]
  57. Liu, H.; Zhao, Y.; Cheng, S.; Huang, N.; Leng, Y. Syntheses of Novel Chitosan Derivative with Excellent Solubility, Anticoagulation, and Antibacterial Property by Chemical Modification. J. Appl. Polym. Sci. 2012, 124, 2641–2648. [Google Scholar] [CrossRef]
  58. Kumar, S.; Koh, J. Physiochemical, optical and biological activity of chitosan-chromone derivative for biomedical applications. Int. J. Mol. Sci. 2012, 13, 6102–6116. [Google Scholar] [CrossRef] [Green Version]
  59. Kumar, S.; Koh, J.; Kim, H.; Gupta, M.K.; Dutta, P.K. A new chitosan-thymine conjugate: Synthesis, characterization and biological activity. Int. J. Biol. Macromol. 2012, 50, 493–502. [Google Scholar] [CrossRef]
  60. Niemczyk, A.; El Fray, M. Novel chitosan derivatives as films with an antimicrobial effect. Prog. Chem. Appl. Chitin Its Deriv. 2013, XVIII, 59–66. [Google Scholar]
  61. Mohamed, N.A.; Mohamed, R.R.; Seoudi, R.S. Synthesis and characterization of some novel antimicrobial thiosemicarbazone O-carboxymethyl chitosan derivatives. Int. J. Biol. Macromol. 2014, 63, 163–169. [Google Scholar] [CrossRef] [PubMed]
  62. Badawy, M.E.; Rabea, E.I.; Taktak, N.E. Antimicrobial and inhibitory enzyme activity of N-(benzyl) and quaternary N-(benzyl) chitosan derivatives on plant pathogens. Carbohydr. Polym. 2014, 111, 670–682. [Google Scholar] [CrossRef] [PubMed]
  63. Sarwar, A.; Katas, H.; Samsudin, S.N.; Zin, N.M. Regioselective Sequential Modification of Chitosan via Azide-Alkyne Click Reaction: Synthesis, Characterization, and Antimicrobial Activity of Chitosan Derivatives and Nanoparticles. PLoS ONE 2015, 10, e0123084. [Google Scholar] [CrossRef] [Green Version]
  64. Abdelwahab, H.; Hassan, S.; Yacout, G.; Mostafa, M.; El Sadek, M. Synthesis and biological evaluation of new imine- and amino-chitosan derivatives. Polymers 2015, 7, 2690–2700. [Google Scholar] [CrossRef]
  65. Pathania, D.; Gupta, D.; Kothiyal, N.C.; Sharma, G.; Eldesoky, G.E.; Naushad, M. Preparation of a novel chitosan-g-poly(acrylamide)/Zn nanocomposite hydrogel and its applications for controlled drug delivery of ofloxacin. Int. J. Biol. Macromol. 2016, 84, 340–348. [Google Scholar] [CrossRef]
  66. Moghadas, B.; Dashtimoghadam, E.; Mirzadeh, H.; Seidi, F.; Hasani-Sadrabadi, M.M. Novel chitosan-based nanobiohybrid membranes for wound dressing applications. RSC Adv. 2016, 6, 7701–7711. [Google Scholar] [CrossRef]
  67. Zhu, D.; Cheng, H.; Li, J.; Zhang, W.; Shen, Y.; Chen, S.; Ge, Z.; Chen, S. Enhanced water-solubility and antibacterial activity of novel chitosan derivatives modified with quaternary phosphonium salt. Mater. Sci. Eng. C Mater. Biol. Appl. 2016, 61, 79–84. [Google Scholar] [CrossRef]
  68. Dragostin, O.M.; Samal, S.K.; Dash, M.; Lupascu, F.; Pânzariu, A.; Tuchilus, C.; Ghetu, N.; Danciu, M.; Dubruel, P.; Pieptu, D.; et al. New antimicrobial chitosan derivatives for wound dressing applications. Carbohydr. Polym. 2016, 141, 28–40. [Google Scholar] [CrossRef]
  69. Martins, D.B.; Nasario, F.D.; Silva-Goncalves, L.C.; Oliveira Tiera, V.A.; Arcisio-Miranda, M.; Tiera, M.J.; Dos Santos Cabrera, M.P. Chitosan derivatives targeting lipid bilayers: Synthesis, biological activity and interaction with model membranes. Carbohydr. Polym. 2018, 181, 1213–1223. [Google Scholar] [CrossRef] [Green Version]
  70. Hassan, M.A.; Omer, A.M.; Abbas, E.; Baset, W.M.A.; Tamer, T.M. Preparation, physicochemical characterization and antimicrobial activities of novel two phenolic chitosan Schiff base derivatives. Sci. Rep. 2018, 8, 11416. [Google Scholar] [CrossRef] [Green Version]
  71. Ali, S.S.; Kenawy, E.R.; Sonbol, F.I.; Sun, J.; Al-Etewy, M.; Ali, A.; Huizi, L.; El-Zawawy, A.N. Pharmaceutical Potential of a Novel Chitosan Derivative Schiff Base with Special Reference to Antibacterial, Anti-Biofilm, Antioxidant, Anti-Inflammatory, Hemocompatibility and Cytotoxic Activities. Pharm. Res. 2018, 36, 5. [Google Scholar] [CrossRef] [PubMed]
  72. Kritchenkov, A.S.; Egorov, A.R.; Kurasova, M.N.; Volkova, O.V.; Meledina, T.V.; Lipkan, N.A.; Tskhovrebov, A.G.; Kurliuk, A.V.; Shakola, T.V.; Dysin, A.P.; et al. Novel non-toxic high efficient antibacterial azido chitosan derivatives with potential application in food coatings. Food Chem. 2019, 301, 125247. [Google Scholar] [CrossRef] [PubMed]
  73. Gularte, M.S.; Anghinoni, J.M.; Abenante, L.; Voss, G.T.; de Oliveira, R.L.; Vaucher, R.A.; Luchese, C.; Wilhelm, E.A.; Lenardão, E.J.; Fajardo, A.R. Synthesis of chitosan derivatives with organoselenium and organosulfur compounds: Characterization, antimicrobial properties and application as biomaterials. Carbohydr. Polym. 2019, 219, 240–250. [Google Scholar] [CrossRef] [PubMed]
  74. Saud, R.; Pokhrel, S.; Yadav, P.N. Synthesis, characterization and antimicrobial activity of maltol functionalized chitosan derivatives. J. Macromol. Sci. Part A 2019, 56, 375–383. [Google Scholar] [CrossRef]
  75. Salama, A.; Hasanin, M.; Hesemann, P. Synthesis and antimicrobial properties of new chitosan derivatives containing guanidinium groups. Carbohydr. Polym. 2020, 241, 116363. [Google Scholar] [CrossRef]
  76. Menazea, A.A.; Eid, M.M.; Ahmed, M.K. Synthesis, characterization, and evaluation of antimicrobial activity of novel chitosan/tigecycline composite. Int. J. Biol. Macromol. 2020, 147, 194–199. [Google Scholar] [CrossRef]
  77. Affes, S.; Maalej, H.; Aranaz, I.; Acosta, N.; Heras, Á.; Nasri, M. Enzymatic production of low-Mw chitosan-derivatives: Characterization and biological activities evaluation. Int. J. Biol. Macromol. 2020, 144, 279–288. [Google Scholar] [CrossRef]
  78. Sedghi, R.; Gholami, M.; Shaabani, A.; Saber, M.; Niknejad, H. Preparation of Novel Chitosan Derivative Nanofibers for Prevention of Breast Cancer Recurrence. Eur. Polym. J. 2020, 123, 109421. [Google Scholar] [CrossRef]
  79. Kritchenkov, A.S.; Egorov, A.R.; Artemjev, A.A.; Kritchenkov, I.S.; Volkova, O.V.; Kiprushkina, E.I.; Zabodalova, L.A.; Suchkova, E.P.; Yagafarov, N.Z.; Tskhovrebov, A.G. Novel heterocyclic chitosan derivatives and their derived nanoparticles: Catalytic and antibacterial properties. Int. J. Biol. Macromol. 2020, 149, 682–692. [Google Scholar] [CrossRef]
  80. Kritchenkov, A.S.; Egorov, A.R.; Artemjev, A.A.; Kritchenkov, I.S.; Volkova, O.V.; Kurliuk, A.V.; Shakola, T.V.; Rubanik, V.V.; Tskhovrebov, A.G.; Yagafarov, N.Z.; et al. Ultrasound-assisted catalyst-free thiol-yne click reaction in chitosan chemistry: Antibacterial and transfection activity of novel cationic chitosan derivatives and their based nanoparticles. Int. J. Biol. Macromol. 2020, 143, 143–152. [Google Scholar] [CrossRef]
  81. Hamed, A.A.; Abdelhamid, I.A.; Saad, G.R.; Elkady, N.A.; Elsabee, M.Z. Synthesis, characterization and antimicrobial activity of a novel chitosan schiff bases based on heterocyclic moieties. Int. J. Biol. Macromol. 2020, 153, 492–501. [Google Scholar] [CrossRef] [PubMed]
  82. Nadia, Q.H.; Mohsin, O.M.; Luqman, E.M. Synthesis and Biological Evaluation of Three New Chitosan Schiff Base Derivatives. ACS Omega 2020, 5, 13948–13954. [Google Scholar]
  83. Iqbal, D.N.; Shafiq, S.; Khan, S.M.; Ibrahim, S.M.; Abubshait, S.A.; Nazir, A.; Abbas, M.; Iqbal, M. Novel chitosan/guar gum/PVA hydrogel: Preparation, characterization and antimicrobial activity evaluation. Int. J. Biol. Macromol. 2020, 164, 499–509. [Google Scholar] [CrossRef] [PubMed]
  84. Yadav, M.K.; Pokhrel, S.; Yadav, P.N. Novel chitosan derivatives of 2-imidazolecarboxaldehyde and 2-thiophenecarboxaldehyde and their antibacterial activity. J. Macromol. Sci. A 2020, 57, 703–710. [Google Scholar] [CrossRef]
  85. Kandile, N.G.; Mohamed, H.M. New chitosan derivatives inspired on heterocyclic anhydride of potential bioactive for medical applications. Int. J. Biol. Macromol. 2021, 182, 1543–1553. [Google Scholar] [CrossRef] [PubMed]
  86. Si, Z.; Hou, Z.; Vikhe, Y.S.; Thappeta, K.R.V.; Marimuthu, K.; De, P.P.; Ng, O.T.; Li, P.; Zhu, Y.; Pethe, K.; et al. Antimicrobial effect of a novel chitosan derivative and its synergistic effect with antibiotics. ACS Appl. Mater. Interfaces 2021, 13, 3237–3245. [Google Scholar] [CrossRef]
  87. Wei, X.Y.; Xia, W.; Zhou, T. Antibacterial activity and action mechanism of a novel chitosan oligosaccharide derivative against dominant spoilage bacteria isolated from shrimp Penaeus vannamei. Lett. Appl. Microbiol. 2021, 74, 268–276. [Google Scholar] [CrossRef]
  88. Badawy, M.E.I.; Rabea, E.I.; Rogge, T.M.; Stevens, C.V.; Smagghe, G.; Steurbaut, W.; Hofte, M. Synthesis and fungicidal activity of new N,O-acyl chitosan derivatives. Biomacromolecules 2004, 5, 589–595. [Google Scholar] [CrossRef]
  89. Badawy, M.E. Chemical modification of chitosan: Synthesis and biological activity of new heterocyclic chitosan derivatives. Polym. Int. 2008, 57, 254–261. [Google Scholar] [CrossRef]
  90. Li, R.; Guo, Z.; Jiang, P. Synthesis, characterization, and antifungal activity of novel quaternary chitosan derivatives. Carbohydr. Res. 2010, 345, 1896–1900. [Google Scholar] [CrossRef] [Green Version]
  91. Qin, Y.; Xing, R.; Liu, S.; Li, K.; Meng, X.; Li, R.; Cui, J.; Li, B.; Li, P. Novel thiosemicarbazone chitosan derivatives: Preparation, characterization, and antifungal activity. Carbohydr. Polym. 2012, 87, 2664–2670. [Google Scholar] [CrossRef]
  92. Li, Q.; Ren, J.; Dong, F.; Feng, Y.; Gu, G.; Guo, Z. Synthesis and antifungal activity of thiadiazole-functionalized chitosan derivatives. Carbohydr. Res. 2013, 373, 103–107. [Google Scholar] [CrossRef] [PubMed]
  93. Qin, Y.; Xing, R.; Liu, S.; Li, K.; Hu, L.; Yu, H.; Chen, X.; Li, P. Synthesis of chitosan derivative with diethyldithiocarbamate and its antifungal activity. Int. J. Biol. Macromol. 2014, 65, 369–374. [Google Scholar] [CrossRef] [PubMed]
  94. Li, Y.; Liu, S.; Qin, Y.; Xing, R.; Chen, X.; Li, K.; Li, P. Synthesis of novel pyrimethanil grafted chitosan derivatives with enhanced antifungal activity. BioMed Res. Int. 2016, 2016, 8196960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Li, Q.; Tan, W.; Zhang, C.; Gu, G.; Guo, Z. Synthesis of water soluble chitosan derivatives with halogeno-1,2,3-triazole and their antifungal activity. Int. J. Biol. Macromol. 2016, 91, 623–629. [Google Scholar] [CrossRef]
  96. Tan, W.; Zhang, J.; Luan, F.; Wei, L.; Chen, Y.; Dong, F.; Li, Q.; Guo, Z. Design, synthesis of novel chitosan derivatives bearing quaternary phosphonium salts and evaluation of antifungal activity. Int. J. Biol. Macromol. 2017, 102, 704–711. [Google Scholar] [CrossRef]
  97. Tan, W.; Li, Q.; Dong, F.; Chen, Q.; Guo, Z. Preparation and characterization of novel cationic chitosan derivatives bearing quaternary ammonium and phosphonium salts and assessment of their antifungal properties. Molecules 2017, 22, 1438. [Google Scholar] [CrossRef] [Green Version]
  98. Fan, Z.; Qin, Y.; Liu, S.; Xing, R.; Yu, H.; Chen, X.; Li, K.; Li, P. Synthesis, characterization, and antifungal evaluation of diethoxyphosphoryl polyaminoethyl chitosan derivatives. Carbohydr. Polym. 2018, 190, 1–11. [Google Scholar] [CrossRef]
  99. Tan, W.; Li, Q.; Dong, F.; Zhang, J.; Luan, F.; Wei, L.; Chen, Y.; Guo, Z. Novel cationic chitosan derivative bearing 1,2,3-triazolium and pyridinium: Synthesis, characterization, and antifungal property. Carbohydr. Polym. 2018, 182, 180–187. [Google Scholar] [CrossRef]
  100. Yang, G.; Jin, O.; Xu, C.; Fan, S.; Wang, C.; Xie, P. Synthesis, characterization and antifungal activity of coumarin-functionalized chitosan derivatives. Int. J. Biol. Macromol. 2018, 106, 179–184. [Google Scholar] [CrossRef]
  101. Liu, W.; Qin, Y.; Liu, S.; Xing, R.; Yu, H.; Chen, X.; Li, K.; Li, P. Synthesis, characterization and antifungal efficacy of chitosan derivatives with triple quaternary ammonium groups. Int. J. Biol. Macromol. 2018, 114, 942–949. [Google Scholar] [CrossRef] [PubMed]
  102. Wei, L.; Li, Q.; Chen, Y.; Zhang, J.; Mi, Y.; Dong, F.; Lei, C.; Guo, Z. Enhanced antioxidant and antifungal activity of chitosan derivatives bearing 6-O-imidazole-based quaternary ammonium salts. Carbohydr. Polym. 2019, 206, 493–503. [Google Scholar] [CrossRef]
  103. Zhang, J.; Tan, W.; Wei, L.; Chen, Y.; Mi, Y.; Sun, X.; Li, Q.; Dong, F.; Guo, Z. Synthesis of urea-functionalized chitosan derivatives for potential antifungal and antioxidant applications. Carbohydr. Polym. 2019, 215, 108–118. [Google Scholar] [CrossRef] [PubMed]
  104. Wei, L.; Tan, W.; Wang, G.; Li, Q.; Dong, F.; Guo, Z. The antioxidant and antifungal activity of chitosan derivatives bearing Schiff bases and quaternary ammonium salts. Carbohydr. Polym. 2019, 226, 115256. [Google Scholar] [CrossRef]
  105. Tan, W.; Zhang, J.; Mi, Y.; Dong, F.; Li, Q.; Guo, Z. Enhanced Antifungal Activity of Novel Cationic Chitosan Derivative Bearing Triphenylphosphonium Salt via Azide-Alkyne Click Reaction. Int. J. Biol. Macromol. 2020, 165, 1765–1772. [Google Scholar] [CrossRef]
  106. Zhang, J.J.; Mi, Y.Q.; Sun, X.; Chen, Y.; Miao, Q.; Tan, W.Q.; Li, Q.; Dong, F.; Guo, Z.Y. Improved antioxidant and antifungal activity of chitosan derivatives bearing urea groups. Starch-Stärke 2020, 72, 5–6. [Google Scholar] [CrossRef]
  107. Mi, Y.; Zhang, J.; Chen, Y.; Sun, X.; Tan, W.; Li, Q.; Guo, Z. New synthetic chitosan derivatives bearing benzenoid/heterocyclic moieties with enhanced antioxidant and antifungal activities. Carbohydr. Polym. 2020, 249, 116847. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, J.; Tan, W.; Li, Q.; Dong, F.; Guo, Z. Synthesis and Characterization of N,N,N-trimethyl-O-(ureidopyridinium)acetyl Chitosan Derivatives with Antioxidant and Antifungal Activities. Mar. Drugs 2020, 18, 163. [Google Scholar] [CrossRef] [Green Version]
  109. Dragostin, O.M.; Samal, S.K.; Lupascu, F.; Pânzariu, A.; Dubruel, P.; Lupascu, D.; Tuchiluș, C.; Vasile, C.; Profire, L. Development and Characterization of Novel Films Based on Sulfonamide-Chitosan Derivatives for Potential Wound Dressing. Int. J. Mol. Sci. 2015, 16, 29843–29855. [Google Scholar] [CrossRef] [Green Version]
  110. Li, Q.; Zhang, C.; Tan, W.; Gu, G.; Guo, Z. Novel Amino-Pyridine Functionalized Chitosan Quaternary Ammonium Derivatives: Design, Synthesis, and Antioxidant Activity. Molecules 2017, 22, 156. [Google Scholar] [CrossRef] [Green Version]
  111. Wei, L.; Li, Q.; Tan, W.; Dong, F.; Luan, F.; Guo, Z. Synthesis, Characterization, and the Antioxidant Activity of Double Quaternized Chitosan Derivatives. Molecules 2017, 22, 501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Li, Q.; Sun, X.; Gu, G.; Guo, Z. Novel water soluble chitosan derivatives with 1,2,3-triazolium and their free radical-scavenging activity. Mar. Drugs 2018, 16, 107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Zhang, J.; Tan, W.; Wei, L.; Dong, F.; Li, Q.; Guo, Z. Synthesis, Characterization, and Antioxidant Evaluation of Novel Pyridylurea-Functionalized Chitosan Derivatives. Polymers 2019, 11, 951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Sun, X.; Zhang, J.; Chen, Y.; Mi, Y.; Tan, W.; Li, Q.; Dong, F.; Guo, Z. Synthesis, characterization, and the antioxidant activity of carboxymethyl chitosan derivatives containing thiourea salts. Polymers 2019, 11, 1810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Chen, W.W.; Cheng, H.; Jiang, Q.X.; Xia, W.S. The characterization and biological activities of synthetic N, O-selenized chitosan derivatives. Int. J. Biol. Macromol. 2021, 173, 504–512. [Google Scholar] [CrossRef] [PubMed]
  116. Meng, Q.; Su, W.; He, C.; Duan, C. Novel chitosan-based fluorescent materials for the selective detection and adsorption of Fe in water and consequent bio-imaging applications. Talanta 2012, 97, 456–461. [Google Scholar] [CrossRef]
  117. Sakai, S.; Yamada, Y.; Zenke, T.; Kawakami, K. Novel chitosan derivative soluble at neutral pH and in-situ gellable via peroxidase-catalyzed enzymatic reaction. J. Mater. Chem. 2009, 19, 230–235. [Google Scholar] [CrossRef]
  118. Rasad, M.S.B.A.; Halim, A.S.; Hashim, K.; Rashid, A.H.A.; Yusof, N.; Shamsuddin, S. In vitro evaluation of novel chitosan derivatives sheet and paste cytocompatibility on human dermal fibroblasts. Carbohydr. Polym. 2010, 79, 1094–1100. [Google Scholar] [CrossRef]
  119. Wang, L.; Xu, X.; Guo, S.; Peng, Z.; Tang, T. Novel water soluble phosphonium chitosan derivatives: Synthesis, characterization and cytotoxicity studies. Int. J. Biol. Macromol. 2011, 48, 375–380. [Google Scholar] [CrossRef]
  120. Xu, X.; Li, Y.; Shen, Y.; Guo, S. Synthesis and in vitro cellular evaluation of novel anti-tumor norcantharidin-conjugated chitosan derivative. Int. J. Biol. Macromol. 2013, 62, 418–425. [Google Scholar] [CrossRef]
  121. Samadi, F.Y.; Mohammadi, Z.; Yousefi, M.; Majdejabbari, S. Synthesis of raloxifene-chitosan conjugate: A novel chitosan derivative as a potential targeting vehicle. Int. J. Biol. Macromol. 2016, 82, 599–606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Hakimi, S.; Mortazavian, E.; Mohammadi, Z.; Samadi, F.Y.; Samadikhah, H.; Taheritarigh, S.; Tehrani, N.R.; Rafiee-Tehranig, M. Thiolated methylated dimethylaminobenzyl chitosan: A novel chitosan derivative as a potential delivery vehicle. Int. J. Biol. Macromol. 2017, 95, 574–581. [Google Scholar] [CrossRef] [PubMed]
  123. Packialakshmi, P.; Gobinath, P.; Ali, D.; Alarifi, S.; Alsaiari, N.S.; Idhayadhulla, A.; Surendrakumar, R. Synthesis and Characterization of Aminophosphonate Containing Chitosan Polymer Derivatives: Investigations of Cytotoxic Activity and in Silico Study of SARS-CoV-19. Polymers 2021, 13, 1046. [Google Scholar] [CrossRef] [PubMed]
  124. Yao, Z.; Zhang, C.; Ping, Q.; Yu, L. A series of novel chitosan derivatives: Synthesis, characterization and micellar solubilization of paclitaxel. Carbohydr. Polym. 2007, 68, 781–792. [Google Scholar] [CrossRef]
  125. Kim, C.H.; Choi, J.W.; Chun, H.J.; Choi, K.S. Synthesis of chitosan derivatives with quaternary ammonium salt and their antibacterial activity. Polym. Bull. 1997, 38, 387–393. [Google Scholar] [CrossRef]
  126. Morimoto, M.; Saimoto, H.; Usui, H.; Okamoto, Y.; Minami, S.; Shigemasa, Y. Biological activities of carbohydrate-branched chitosan derivatives. Biomacromolecules 2001, 2, 1133–1136. [Google Scholar] [CrossRef]
  127. Yin, T.; Liu, Y.; Yang, M.; Wang, L.; Zhou, J.; Huo, M. Novel Chitosan Derivatives with Reversible Cationization and Hydrophobicization for Tumor Cytoplasm-Specific Burst Co-delivery of siRNA and Chemotherapeutics. ACS Appl. Mater. Interfaces 2020, 12, 14770–14783. [Google Scholar] [CrossRef]
  128. Shakil, M.S.; Mahmud, K.M.; Sayem, M.; Niloy, M.S.; Halder, S.K.; Hossen, M.S.; Uddin, M.F.; Hasan, M.A. Using Chitosan or Chitosan Derivatives in Cancer Therapy. Polysaccharides 2021, 2, 795–816. [Google Scholar] [CrossRef]
  129. Salahuddin, N.; Elbarbary, A.A.; Salem, M.L.; Elksass, S. Antimicrobial and antitumor activities of 1,2,4-triazoles/polypyrrole chitosan core shell nanoparticles. J. Phys. Org. Chem. 2017, 30, e3702. [Google Scholar] [CrossRef]
  130. Cui, Z.; Ni, N.C.; Wu, J.; Du, G.Q.; He, S.; Yau, T.M.; Weisel, R.D.; Sung, H.W.; Li, R.K. Polypyrrole-Chitosan conductive biomaterialsynchronizes cardiomyocyte contraction and improves myocardial electrical impulse propagation. Theranostics 2018, 8, 2752–2764. [Google Scholar] [CrossRef]
  131. Jiang, M.; Ouyang, H.; Ruan, P.; Zhao, H.; Pi, Z.; Huang, S.; Yi, P.; Crepin, M. Chitosan derivatives inhibit cell proliferation andinduce apoptosis in breast cancer cells. Anticancer Res. 2011, 31, 1321–1328. [Google Scholar] [PubMed]
  132. Jiang, Z.; Han, B.; Li, H.; Yang, Y.; Liu, W. Carboxymethyl chitosan represses tumor angiogenesis in vitro and in vivo. Carbohydr. Polym. 2015, 129, 1–8. [Google Scholar] [CrossRef] [PubMed]
  133. Huang, R.; Mendis, E.; Rajapakse, N.; Kim, S.K. Strong electronic charge as an important factor for anticancer activity of chitooligosaccharides (COS). Life Sci. 2006, 78, 2399–2408. [Google Scholar] [CrossRef] [PubMed]
  134. Li, X.; Wang, J.; Chen, X.; Tian, J.; Li, L.; Zhao, M.; Jiao, Y.; Zhou, C. Effect of chitooligosaccharides on cyclin D1, bcl-xl and bcl-2 mRNA expression in A549 cells using quantitative PCR. Chin. Sci. Bull. 2011, 56, 1629. [Google Scholar] [CrossRef] [Green Version]
  135. Adhikari, H.S.; Yadav, P.N. Anticancer Activity of Chitosan, Chitosan Derivatives, and Their Mechanism of Action. Int. J. Biomater. 2018, 2018, 2952085. [Google Scholar] [CrossRef] [Green Version]
  136. Harish Prashanth, K.; Tharanathan, R. Depolymerized products of chitosan as potent inhibitors of tumor-induced angiogenesis. Biochim. Biophys. Acta Gen. Subj. 2005, 1722, 22–29. [Google Scholar] [CrossRef]
  137. Maeda, Y.; Kimura, Y. Antitumor effects of various low-molecular-weight chitosans are due to increased natural killer activity of intestinal intraepithelial lymphocytes in sarcoma 180-bearing mice. J. Nutr. 2004, 134, 945–950. [Google Scholar] [CrossRef]
  138. Qin, C.; Du, Y.; Xiao, L.; Gao, X. Enzymic preparation of water-soluble chitosan and their antitumor activity. Int. J. Biol. Macromol. 2002, 31, 111–117. [Google Scholar] [CrossRef]
  139. Wang, S.L.; Lin, H.T.; Liang, T.W.; Chen, Y.J.; Yen, Y.H.; Guo, S.P. Reclamation of chitinous materials by bromelain for the preparation of antitumor and antifungal materials. Bioresour. Technol. 2008, 99, 4386–4393. [Google Scholar] [CrossRef]
  140. Yamada, S.; Ganno, T.; Ohara, N.; Hayashi, Y. Chitosan monomer accelerates alkaline phosphatase activity on human osteoblastic cells under hypofunctional conditions. J. Biomed. Mater. Res. A 2007, 83, 290–295. [Google Scholar] [CrossRef]
Applsci 12 03267 g001 550
Figure 1. Overview of various chitosan derivatives that are applied for biological applications.
Figure 1. Overview of various chitosan derivatives that are applied for biological applications.
Applsci 12 03267 g001
Table
Table 1. Antibacterial, antifungal and cytotoxic applications of various novel chitosan derivatives.
Table 1. Antibacterial, antifungal and cytotoxic applications of various novel chitosan derivatives.
Novel Chitosan Derivative TypeBiological
Application		Bio-FunctionalityReference
Chitosan–chloroquinoline derivativeAntibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus, moderate AF activity against Candida albicans.[55]
Antifungal (AF)
O,N-carboxymethyl chitosan–zinc complex chitosan–zinc complexAntibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus.[56]
Hydroxyethyl chitosanAntibacterial (AB)AB activity against E coli and Enterococcus
and anticoagulation 		[57]
Anticoagulation
Chitosan-chromone derivativeAntibacterial (AB)AB activity against Escherichia coli.
non-toxic to mouse embryonic fibroblast cells.		[58]
Cytotoxicity
Chitosan–thymine conjugateAntibacterial (AB)AB activity against E coli and S aureus and AF activity against Aspergillus niger.
no toxicity on mouse embryonic fibroblast cell line (NIH 3T3) but high toxicity on human liver cancer cell line (HepG2).		[59]
Antifungal (AF)
Cytotoxicity
Chitosan acylation with linoleic and dilinoleic acidAntibacterial (AB)AB assays in vitro exhibited AB effect in direct contact with the material.[60]
p-methoxybenzaldehyde thiosemicarbazone/o-hydroxybenzaldehyde thiosemi-carbazone/p-chlorobenzaldehyde thiosemicarbazone O-Carboxymethyl-chitosanAntibacterial (AB)AB activity against Bacillus subtilis, E coli, and S aureus and AF activity against Aspergillus fumigatus, Candida albicans, and Geotrichum candidum.[61]
Antifungal (AF)
N-(benzyl) chitosan derivatives (C1-C9)
QuaternaryN-(benzyl) chitosan derivatives (QC1-QC9)		Antibacterial (AB)QC derivatives had high AB activity against Agrobacterium tumefaciens and Erwinia carotovora and AF activity against Botrytis cinerea, Botryodiplodia theobromae, Fusarium oxysporum, and Phytophthora infestans.[62]
Antifungal (AF)
O-quaternary ammonium N-acyl thiourea chitosan Antibacterial (AB)AB activity against Bacillus subtilis, E coli, Pseudomonas aeruginosa and Staphylococcus aureus [23]
(Chitosan O-(adamantane) triazolylcarbamate, chitosan O-(benzoyl) triazolylcarbamate, chitosan O-(1-methylbenzene) triazolylcarbamate, chitosan O-(1-methyl phenyl sulphide) triazolylcarbamate, and chitosan O-((R) (1-methyl)-1-Boc-pyrrolidine) triazolylcarbamate) and their nanoparticles (NPs).Antibacterial (AB)AB activity, AF activity and non-toxic to fibroblast cell lines (V79) and human hepatic cell lines (WRL68).[63]
Antifungal (AF)
cytotoxicity
Imine- and amino-chitosan derivativesAntibacterial (AB)AB activity against Gram (+) and Gram (−) bacteria, AF activity against Aspergillus fumigates and highly toxic to MCF-7 (breast cancer cells), HCT-116 (colon cancer cells) and HepG-2 (hepatocellular cancer cells).[64]
Antifungal (AF)
Anticancer
Chitosan-g-poly(acrylamide)/Zn nanocompositeAntibacterial (AB)Inhibited the growth of E coli.
controlled drug delivery. 		[65]
Drug delivery
Nanohybrid films based on chitosan and
biofunctionalized montmorillonite (MMT) with chitosan sulfate chains (SMMT)		Antibacterial (AB)AB activity against E coli and no cytotoxicity to L929 fibroblasts cells.[66]
Cytotoxicity
N-quaternary phosphonium chitosan derivatives (N-QPCS 11, 12, 14 and 21)Antibacterial (AB)AB activity against E coli and S aureus.[67]
Chitosan-aminoacetyl-sulfamethoxydiazine
Chitosan-aminoacetyl-sulfadiazine
Chitosan-aminoacetyl-sulfadimethoxine
Chitosan-aminoacetyl-sulfamethoxazole
Chitosan-aminoacetyl-sulfamerazine
Chitosan-aminoacetyl-sulfisoxazole		Antibacterial (AB)AB activity against Bacillus subtilis, E coli, Sarcina lutea, and S aureus.
AF against Candida albicans, Candida glabrata and Candida sake.
low toxicity, against mouse fibroblasts (L929) cells, except chitosan-aminoacetyl-sulfamerazine.		[68]
Antifungal (AF)
Cytotoxicity
Methylated derivatives, CH30 and CH50Antibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus and CH30 do not affect the viability of human cervical carcinoma cells, whereas CH50 had high toxicity to human cervical carcinoma cells.[69]
Cytotoxicity
Phenolic chitosan Schiff base derivativesAntibacterial (AB)AB effect against Gram (+) bacteria than chitosan with 4-dimethylaminobenzaldehyde and AF activity against Candida albicans and low cytotoxicity against fibroblast cells.[70]
Antifungal (AF)
Cytotoxicity
Methyl acrylate chitosan bearing p-nitrobenzaldehyde Schiff baseAntibacterial (AB)AB effect against Gram (+) bacteria.
anti-biofilm activity against MDR-PA-09 strain, excellent proteinase inhibitory activity (90.3%), antioxidant activity, low cytotoxicity, hemolytic activity 		[71]
Anti-biofilm
Anti-inflammatory
Antioxidant
Cytotoxicity
Hemocompatibility
N-(2-azidoethyl)chitosans
N-(3-azido-2-hydroxypropyl)chitosans		Antibacterial (AB)AB against Escherichia coli and Staphylococcus aureus low cytotoxicity.[72]
cytotoxicity
Schiff bases of chitosan derivatives containing organoselenium and organosulfurAntibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus and AF activity against Candida albicans.[73]
Antifungal (AF)
Chitosan-maltol (CS-maltol) and CS-ethyl maltol derivativesAntibacterial (AB)AB activity against Escherichia coli.[74]
N-guanidinium chitosan acetate/-guanidinium chitosan chloride/N-guanidinium chitosan (N,N′-dicyclohexyl) chloride, N-guanidinium chitosan (N-(3-dimethylaminopropyl)-N’-ethyl hydrochloride) chlorideAntibacterial (AB)AB activity against Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus. AF activity against Candida albicans.[75]
Antifungal (AF)
Chitosan/Tigecycline composite (1–5)Antibacterial (AB)The AB activity of chitosan/tigecycline composite depends on the levels of Tigecycline. Increasing the concentration of Tigecycline increase the AB activity against Staphylococcus aureus.[76]
Chitosan-depolymerization productsAntibacterial (AB)AB activity against both Gram (+) and Gram (−) bacteria.
AF compared to untreated chitosan.
High antioxidant activity		[77]
Antifungal (AF)
Antioxidant
Tetramethyl urea thiosemicarbazone
carboxymethyl chitosan nanofibers		Antibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus.
Strong AC activity against 4T1 breast cancer cells.		[78]
Anticancer (AC)
Heterocyclic (1,2,4-oxadiazoline) chitosan derivatives and their derived nanoparticles (NPs)Antibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus.
Low toxicity against human embryonic kidney 293 cells.		[79]
Cytotoxicity
Betaine chitosan derivatives and nanoparticles (NPs) based on themAntibacterial (AB)AB activity against Escherichia coli and Staphylococcus aureus
low toxicity against human embryonic kidney 293 cells.		[80]
Cytotoxicity
1-phenyl-3-(thiophene-2-yl)-1H-pyrazole-4-carbaldehyde/ 1-phenyl-3-(furan-2-yl)-1H-pyrazole-4-carbaldehyde/1-phenyl-3-(pyridine-3-yl)-1H-pyrazole-4-carbaldehydeAntibacterial (AB)AB activity against Escherichia coli, Klebsiella pneumonia, Staphylococcus, and Streptococcus mutans.
AF activity against Aspergillus fumigatus and Candida albicans.
non-toxic to normal retinal cells.		[81]
Antifungal (AF)
Cytotoxicity
Coupling of chitosan Schiff base derivatives
with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde		Antibacterial (AB)AB activity against Staphylococcus and Streptococcus mutans.
AF activity against Aspergillus fumigates and Candida albicans.
non-toxic to mouse fibroblast cells.		[82]
Antifungal (AF)
Cytotoxicity
Chitosan/poly(vinyl alcohol)/guar gum blendsAntibacterial (AB)AB against Bacillus subtilis, Escherichia coli, Pasteurella multocida and Staphylococcus aureus.[83]
Chitosan-2-imidazolecarboxaldehyde
Chitosan-2-thiophenecarboxaldehyde		Antibacterial (AB)AB activity against Escherichia coli.[84]
Chitosan derivatives inspired heterocyclic anhydride (Chitosan derivative 6, 7 and 8)Antibacterial (AB)AB activity against eight different pathogens
highest enzymatic inhibitory activity.
highest toxicity against the Vero cell line.		[85]
Enzyme inhibitory
Cytotoxicity
2,6-diamino chitosanAntibacterial (AB)AB activity against both Gram-positive and Gram-negative bacteria.[86]
Chitosan oligosaccharide derivativeAntibacterial (AB)AB activity against Aeromonas spp., Pseudomonas spp., and Shewanella putrefaciens [87]
N,O-acyl chitosan (NOAC) derivatives (1–18)Antifungal (AF)The AF activity of NOAC derivatives is higher than that of unmodified chitosan [88]
N-heterocyclic chitosan derivativesAntifungal (AF)N-[(5-methylfuran-2-yl)methyl] chitosan AF against Pyricularia grisea and N-(benzo[d][1,3]dioxol-5-ylmethyl) chitosan and N-(methyl-4H-chromen-4-one) chitosan AF against Fusarium oxysporum and Pythium debaryanum.
significant growth inhibition and antifeedant activity against the larvae of Spodoptera littoralis.		[89]
Insecticidal
4-(5-chloro-2-hydroxybenzylideneamino)-pyridine/4-(5-bromo-2-hydroxybenzylideneamino)-pyridineAntifungal (AF)AF activities against Cladosporium cucumerinum, Colletotrichum lagenarium, Monilinia fructicola, and Fusarium oxysporum[90]
Phenylaldehyde thiosemicarbazone chitosan
o-hydroxyphenylaldehyde thiosemicarbazone chitosan/p-methoxyphenylaldehyde thiosemicarbazone chitosan		Antifungal (AF)AF activity against four phytopathogenic fungi.[91]
1,3,4-thiadiazole/2-methyl-1,3,4-thiadiazole/
2-phenyl-1,3,4-thiadiazole		Antifungal (AF)AF activity against Colletotrichum lagenarium, Monilinia fructicola, and Monilinia fructicola than chitosan and other derivatives.[92]
Diethyl dithiocarbamate chitosanAntifungal (AF)AF activity against Gloeosporium theae sinensis followed by Alternaria porri and Stemphylium solani.[93]
Pyrimethanil grafted chitosan derivatives (1–3)Antifungal (AF)AF activity against Rhizoctonia solani and Gibberella zeae[94]
1,2,3-triazole (TCTS, CTCTS and BTCTS)Antifungal (AF)The AF activity against Colletotrichum lagenarium, Fusarium oxysporum f.sp. niveum and Fusarium oxysporum f.sp. cucumebrium [95]
Tricyclohexylphosphonium acetyl chitosan chloride/Triphenylphosphonium acetyl chitosan chlorideAntifungal (AF)AF activity against Colletotrichum lagenarium, Fusarium oxysporum, and Watermelon fusarium. [96]
Cationic chitosan derivatives/quaternary
ammonium and phosphonium salts		Antifungal (AF)enhanced AF activity than chitosan.[97]
Polyaminoethyl chitosan Schiff base derivatives
Diethoxyphosphoryl polyaminoethyl chitosan Schiff base derivatives		Antifungal (AF)AF activity against Botrytis cinerea, Fusarium solani and Phytophthora capsici.
weak cytotoxicity against HepG2 cells.		[98]
Cytotoxicity
Chitosan derivative bearing 1,2,3-triazole and pyridine/cationic chitosan derivative possessing 1,2,3-triazolium and pyridiniumAntifungal (AF)AF activity against Colletotrichum lagenarium. [99]
Coumarin-functionalized chitosan derivatives (1–4)Antifungal (AF)AF activity against Alternaria solani, Fusarium moniliforme, and Fusarium oxysporum f.sp. vasinfectum.[100]
Chitosan derivatives with triple quaternary ammonium groups using 3-aminopyridine and 3-amino-4-methylpyridine.Antifungal (AF)AF activity against Phytophthora capsica and Rhizoctonia solani.[101]
Quaternary ammonium salt chitosan derivatives Antifungal (AF)AF activity against Botrytis cinerea and Gibberella zeae.
Higher antioxidant activity than chitosan.
good biocompatibility on HaCaT cells.		[102]
Antioxidant
Cytotoxicity
Novel urea-functionalized chitosan derivatives Antifungal (AF)Superior AF activity compared with chitosan.
Five chitosan derivatives displayed higher antioxidant activities than chitosan.
Weak cytotoxicity against L929 cells.		[103]
Antioxidant
Cytotoxicity
Chitosan derivatives bearing Schiff bases and quaternary ammonium salts.Antifungal (AF)AF activity against Botrytis cinerea, Fusarium oxysporum f.sp. cucumerium, and F. oxysporum f.sp. niveum.
Greater antioxidant activity as compared with chitosan.		[104]
Antioxidant
Cationic chitosan derivative bearing triphenylphosphonium saltAntifungal (AF)Stronger antifungal activity against phytopathogens.[105]
Chitosan derivatives bearing urea groupsAntifungal (AF)The derivatives displayed higher AF activity than pristine chitosan.
The derivatives possess enhanced radical (DPPH, hydroxyl, and superoxide) scavenging activity than pristine chitosan.
2,6-(3-(benzylureido)-pyridyl)acetyl chitosan chloride showed low toxicity to L929 cells. 		[106]
Antioxidant
Cytotoxicity
Various carboxymethyl chitosan conjugatesAntifungal (AF)Excellent AF activity against Colletotrichum lagenarium and Phomopsis asparagi.
Enhanced DPPH and superoxide-radical scavenging activity.
Low toxicity to L929 cells.		[107]
Antioxidant
Cytotoxicity
N,N,N-trimethyl-O-(ureidopyridinium)acetyl
chitosan derivatives		Antifungal (AF)AF activity against Botrytis cinerea and Phomopsis asparagus.
Higher radical (DPPH, hydroxyl, and superoxide) scavenging activity than chitosan.		[108]
Antioxidant
Table
Table 2. Antioxidant, cytotoxic, drug delivery applications of various novel chitosan derivatives.
Table 2. Antioxidant, cytotoxic, drug delivery applications of various novel chitosan derivatives.
Novel Chitosan Derivative TypeBiological
Application		Bio-FunctionalityReference
Novel films based on sulfonamide-chitosan derivativesAntioxidantStronger antioxidant properties than chitosan and other film derivatives.
Highest swelling ratio.		[109]
Swelling Ratio
Amino-pyridine functionalized chitosan
quaternary ammonium derivatives		AntioxidantStronger radical (DPPH and hydroxyl) scavenging activity than chitosan.[110]
Double quaternized chitosan derivativesAntioxidantStronger radical (DPPH, hydroxyl, and superoxide) scavenging activity. [111]
Chitosan derivatives with 1,2,3-TriazoliumAntioxidantHigher radical (DPPH, hydroxyl, and superoxide) scavenging activity than chitosan.[112]
Pyridylurea-functionalized chitosan derivativesAntioxidantEnhanced antioxidant activity than N-pyridylurea chitosan derivatives.
Low cytotoxicity to L929 cells.		[113]
Cytotoxicity
Carboxymethyl chitosan derivatives
with thiourea salts		AntioxidantHigher antioxidant activities.
Viability of L929 cells not affected.		[114]
Cytotoxicity
N, O-selenized N-(2-carboxyethyl) chitosan 1, 2 and 3AntioxidantStrong antioxidant properties
Caco-2 cell viability unaffected		[115]
Cytotoxicity
Water-soluble chitosan with 4-fluorescein-carboxaldehyde/N-methyl-carbazole-3-aldehydeBio-imagingUsed to detect of Fe3+ in water and living MCF-7 cells.[116]
Chitosan with phenolic hydroxyl groupsCytotoxicityLow toxicity to L929 cells. [117]
Oligo-chitosan N,O-carboxymethylchitosan
N-carboxymethyl-chitosan		CytotoxicityExcellent cytocompatibility and cell viability.[118]
Water soluble phosphonium chitosan derivativesCytotoxicityLow toxicity to L929 cell lines (mouse fibroblasts).[119]
Norcantharidin-conjugated chitosan conjugate 1
Norcantharidin-conjugated chitosan conjugate 2		CytotoxicityConjugate 1 was more cytotoxic to the human gastric cancer cell line (MGC80-3) than conjugate 2.[120]
Raloxifene–chitosan conjugate (Run 3 and 6)CytotoxicityBoth low toxicity to MCF-7 cells. [121]
Thiolated methylated N-(4-N,N-dimethylaminobenzyl) chitosanCytotoxicityDid not affect the viability of human embryonic kidney 293 cells.[122]
Aminophosphonate-containing chitosan polymer derivativesCytotoxicityFew moderately toxic to human liver cancer cell line (HepG2) while highly toxic to MCF-7 (breast cancer cells).[123]
N-mPEG-N-octyl-O-sulfate chitosan derivativesDrug deliveryThe highest paclitaxel (3.94 mg/mL) was found in N-mPEG-N-octyl-O-sulfate chitosan. [124]
Novel films based on sulfonamide-chitosan derivativesAntioxidantStronger antioxidant properties than chitosan and other film derivatives.
Highest swelling ratio.		[109]
Swelling Ratio
Amino-pyridine functionalized chitosan
quaternary ammonium derivatives		AntioxidantStronger radical (DPPH and hydroxyl) scavenging activity than chitosan.[110]
Double quaternized chitosan derivativesAntioxidantStronger radical (DPPH, hydroxyl, and superoxide) scavenging activity. [111]
Chitosan derivatives with 1,2,3-TriazoliumAntioxidantHigher radical (DPPH, hydroxyl, and superoxide) scavenging activity than chitosan.[112]
Pyridylurea-functionalized chitosan derivativesAntioxidantEnhanced antioxidant activity than N-pyridylurea chitosan derivatives.
Low cytotoxicity to L929 cells.		[113]
Cytotoxicity
Table
Table 3. Summary of the anticancer achievements of ChDs.
Table 3. Summary of the anticancer achievements of ChDs.
Novel ChDsCancer TypeAnticancer ApplicationReferences
Chitosan–thymine conjugateLiver cancerAntiproliferative activity towards HepG2 liver carcinoma cells, no cytotoxic activity on normal mouse fibroblast cells, confirming selective targeting of cancer cells[59]
Polypyrrole–chitosanEhrlich ascites carcinoma, breast cancerActive against Ehrlich ascites carcinoma (EAC) cells and MCF-7 breast cancer cells[129,130]
Sulfated chitosan Breast cancerBlocks cell cycle and FGF-2 mediated phosphorylation ERK[131]
Sulfated benzaldehyde chitosanBreast cancerInduces apoptosis and blocks FGF-2 mediated phosphorylation ERK[131]
Carboxymethyl chitosanLiver cancerAntiangiogenic activity decreasing VEGF and stimulating immune activity [132]
Quaternized amino chitooligosaccharidesCervical cancer, colon cancerInduces necrosis[133]
Sulfated chitooligosaccharides: Cervical cancer, colon cancerInduces necrosis[133]
Chitohexose Cervical cancer, colon cancerDownregulates cyclin D1 and bcl-xl mRNA induction of apoptosis[134]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sivanesan, I.; Hasan, N.; Kashif Ali, S.; Shin, J.; Gopal, J.; Muthu, M.; Oh, J.-W. Novel Chitosan Derivatives and Their Multifaceted Biological Applications. Appl. Sci. 2022, 12, 3267. https://doi.org/10.3390/app12073267

AMA Style

Sivanesan I, Hasan N, Kashif Ali S, Shin J, Gopal J, Muthu M, Oh J-W. Novel Chitosan Derivatives and Their Multifaceted Biological Applications. Applied Sciences. 2022; 12(7):3267. https://doi.org/10.3390/app12073267

Chicago/Turabian Style

Sivanesan, Iyyakkannu, Nazim Hasan, Syed Kashif Ali, Juhyun Shin, Judy Gopal, Manikandan Muthu, and Jae-Wook Oh. 2022. "Novel Chitosan Derivatives and Their Multifaceted Biological Applications" Applied Sciences 12, no. 7: 3267. https://doi.org/10.3390/app12073267

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop