Piperazine based antimicrobial polymers: a review

Abstract

Microbial infections are a life threatening concern in several areas, which include the biomedical sector, healthcare products, water purification systems, and food packaging. Polymers with low molecular weight bioactive agents or disinfectants help the scientific community to reduce the lethality rate caused by pathogenic microbes. Antimicrobial polymeric approach is one of the advanced approaches made by researchers in concern with the problems associated with small molecules that restrict their applications in broad spectrum. History reveals the synthesis of numerous antimicrobial polymers using various antimicrobial agents but lacks the use of piperazine molecule, which is of pharmaceutical importance. This review gives an insight into the current and future perspective for the development of piperazine-based antimicrobial polymers.

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1. Introduction

The piperazine molecule has been classified as a privileged structural motif in drug discovery.¹ It is a six-membered heterocyclic compound with the chemical formula C₄H₁₀N₂ and is also called hexahydropyrazine. Hexahydropyrazine was named as piperazine because of its chemical similarity with piperidine, which is a part of the piperine structure isolated from the black pepper plant (Piper nigrum), and it contains two reactive secondary amine groups at the first and fourth positions.^2,3 Piperazine was first used in the treatment of gout disease in 19th century, and later on molecules obtained by modifying the piperazine moiety were used in the treatment of intestinal infections.^4–6 In the early 20th century, numerous researchers synthesized piperazine and substituted piperazine molecules, which were important pharmacophores found in numerous marketed drugs such as antibiotics, anticancer, antimicrobial, antipsychotics, and antidepressants.⁷ Piperazine was majorly found in the second generation antibiotic drugs and was extended up to sixth generation antibiotics.^8,9 A recent statistical analysis of the substructure has shown that piperazine is the third most frequently used N-heterocycle (ranked right behind piperidine and pyridine) in pharmaceutical small molecule drugs. Several drugs containing the piperazine moiety are amongst the top 100 best-selling pharmaceutical products and are listed in Table 1.^1,8–10

Table 1 List of commercialized drugs containing the piperazine moiety in pharmaceutical applications

S. no.	Drug	Activity	Product name	Company	Ref.
1		Antibiotic	Gatiflo, Tequin and Zymar	Kyorin Pharmaceut-icals, Japan	11–13
2			Noroxin	Merck Co., USA	14–16
3			Floxin, Ocuflox	Daiichi Sankyo, Japan	17–19
4		Antibiotic	Levaquin	Sanofi-Aventis, France	20 and 21
5			Spacin, Zagam	Torrent pharmaceuticals, India	22–24
6			Maxaquin, Okacyn, Uniquin	Wockhardt, India	25 and 26
7		Antibacterial	Cipro, Ciproxifan	Bayer AG, Germany	27–31
8			Pipemidic acid	Yoshindo, Japan	32–34
9			Raxar, Glaxo Wellcome	GlaxoSmithKline, UK	35–37
10		Antifungal	Noxafil	Schering-Plough, USA	38–42
11		Antipsychotic	Seroquel	Biovail Corporation, Canada	43–45
12			Abilify	Otsuka pharmaceuticals, Japan	46–48
13			Geodon	Pfizer, USA	49–51
14		Anticancer	Gleevec	Ciba-Geigy (Navartis), Switzerland	52–54
15			Sprycel	Bristol-Myers Squibb, USA	55–57
16		Antidepressant	Remeron	Adcock Ingram pharmaceuticals, South Africa	58
17			Viibryd	Merck co., USA	59–61
18		Antiretroviral	Crixivan	Merck co., USA	62–64
19		Antidiabetic	Januvia, Tesavel, Xelevia	Merck co., USA	65–67
20		Anxiolytic	Vestipitant	GlaxoSmithKline, UK	68–70
21		To treat insomnia	Lunesta	GlaxoSmithKline, UK	71–73
22		To treat erectile dysfunction	Viagra	Pfizer, USA	74–76

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Small-molecule drugs containing the piperazine moiety have substitutes on either both or single nitrogen atoms and are predominantly used as a linker for different molecules/macromolecules to adjust the physico-chemical properties of a macromolecule. Piperazine, a six-membered heterocyclic ring with two opposing nitrogen atoms, provides a large polar surface area, structural rigidity, and hydrogen-bond acceptors and donors, which often lead to enhanced target affinity, specificity, water solubility, oral bioavailability, and ADME (i.e., absorption, distribution, metabolism, and excretion) properties.^2,77–82 The absence of vinyl groups and multifunctional groups in the piperazine molecule restricts their use in the synthesis of polymers though piperazine and substituted piperazine derivatives are extensively used as antibiotic, anticancer, antimicrobial, antipsychotic, antidepressant drugs and so forth.

Polymeric materials are one among those materials used in combating pathogenic microorganisms to prevent infectious diseases. The growth of pathogenic microorganisms in the surroundings can be inhibited or killed by the macromolecules with the antimicrobial property. The polymer molecules provide promise for escalating the efficacy of some existing low-molecular-weight antimicrobial agents and minimize environmental issues by reducing their residual toxicity. The applications of antimicrobial polymers can be found in water purification systems, fibers, food packaging, surfactants, detergents, surgical, pharmaceutical industries, and so forth.^83–89 Some of the disadvantages of antimicrobial polymers are as follows: (i) macromolecules are very large and thus may not act as fast as small molecule agents, (ii) short half-life, and (iii) degradation issues.^90,91 This review article gives an insight into the recent advancements in the synthesis, applications and development of novel piperazine-based antimicrobial monomers and polymers and is classified into two sub-sections based on their composition, i.e., homo-/co-/tripolymers and grafted polymers.

1.1 Piperazine-based homo-/co-/tripolymers

In 2003, norfloxacin-containing quinolone moieties were converted to monomer (Scheme 1) and polymers and further blended with numerous synthetic polymers and were tested for their antimicrobial activity, thermal stability and mechanical properties by Moon et al. The as-synthesized monomer, polymer and polymer blends exhibited potential activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis) and Micrococcus luteus (M. luteus). Quinolones were chosen for the synthesis of monomer, polymer and polymer blends in food packaging due to their high thermal stability. The moulding of the quinolone polymer was practically impossible because the polymer was brittle and rigid in nature. To reduce the rigidity, the quinolone polymer was blended with numerous synthetic polymers such as low-density polyethylene (LDPE), poly(methyl methacrylate) (PMMA), poly(butylene succinate) (PBS), polycaprolactone (PCL) and maleated polypropylene (PPMA) with varying concentrations of polymer quinolone from 1 wt% to 5 wt%. The quinolone polymer exhibited a potent antimicrobial activity even at the concentration of 1 wt% in the polymer blends. Due to the increase in the concentration of quinolone polymers to the polymer blends, there was a decrease in the tensile property. The decrease in the tensile property was due to the incompatibility between polymer quinolone and synthetic polymers. The decrease in the tensile properties due to compounding with polymer quinolone was less significant in the PCL/PQ blend compared to those in LDPE/PQ, PMMA/PQ, PBS/PQ, and PMMA/PQ blends. This indicated that PQ is more compatible with PCL compared to other polymers. Henceforth, the PCL/PQ blend was expected to have application in food packaging materials due to their antimicrobial activity, high thermal and mechanical properties.⁹²

Scheme 1 Acrylic monomer-containing quinolone moiety.

An efficient non-leaching contact-killing polymer was developed by Supriya et al. in 2006. First, piperazine was reacted with ethylene glycol dimethacrylate (EGDMA), followed by its quaternization using an alkyl iodide (1-iodooctane) to yield a quaternary monomer (Scheme 2). Further, the quaternized monomer was copolymerized with 2-hydroxyethyl methacrylate (HEMA) using redox initiators (ammonium per sulphate (APS) and N,N,N′,N′-tetramethyl ethylenediamine (TEMED)). The copolymers with varying quaternized monomer (QAMA) percentages (0 to 40%) were synthesized. Decline in the thermal properties was observed as the concentration of the monomer increased in the copolymer system, which was due to increase in the hydrocarbon chain length of alkyl iodide. The copolymer with a high monomer ratio exhibited increased activity against E. coli and S. aureus compared to other copolymers with a lower monomer concentration. The copolymer with 40% of the monomer concentration displayed 100% contact-killing activity in a time span of just 10 min.⁹³

Scheme 2 Synthesis of the quaternary amine methacrylate monomer.

Based on their previous study, the same authors in 2007 made an attempt to develop piperazine copolymers with non-leaching, contact-killing properties. Initially the methacrylate monomer, trimethylolpropane trimethacrylate–piperazine–ethyleneglycol dimethacrylate (TMPTMA–PPZ–EGDMA) (Scheme 3), was synthesized by the amination of trimethylolpropane trimethacrylate (TMPTMA) with piperazine (PPZ), followed by its reaction with ethyleneglycol dimethacrylate (EGDMA). The methacrylate monomer (TMPTMA-PPZ-EGDMA) was further copolymerized with 2-hydroxyethyl methacrylate (HEMA) using redox initiators (ammonium persulfate (APS) and N,N,N′,N′-tetramethyl ethylenediamine (TEMED)). The copolymers with varying monomer (TMPTMA–PPZ–EGDMA) percentages (0 to 100%) were synthesized, but after varying monomer (TMPTMA–PPZ–EGDMA) beyond 60% incomplete in the polymerization was observed. Further the obtained copolymers with different monomer ratios were quaternized with 1-iodooctane. Due to increase in the hydrocarbon chain length of the alkyl iodide, depletion in the decomposition temperature was observed as the concentration of the monomer (TMPTMA–PPZ–EGDMA) increased from 0 to 60% in the copolymer system. The quaternized copolymer with variable percentages of TMPTMA–PPZ–EGDMA from 5% to 60% was tested against E. coli and S. aureus. The site of quaternization increases as the monomer ratio increases; hence, the bacterial growth percentage decreases. The contact-killing microbiocidal role of the copolymer can be attributed to the hydrophobic interaction of the alkyl chain with the bilipid layer of the cell wall and the amphiphilic nature of the copolymer, which disrupts the cell membrane and leads to the leakage of K⁺ ions and cytoplasmic fluid. This mechanism was studied via scanning electron microscopy (SEM). The copolymer showed broad spectrum contact-killing antimicrobial properties without releasing any bioactive agents. Hence, the synthesized copolymer is used as contact-killing antimicrobial polymer for numerous biomedical applications.⁹⁴

Scheme 3 Synthesis of the trimethylolpropane trimethacrylate–piperazine–ethyleneglycol dimethacrylate monomer.

In 2012, a well-known second generation antibiotic drug, ciprofloxacin containing piperazine moiety, was converted to a novel methacrylate monomer and cationic tripolymers by Xue et al. The macromonomer (GCM) was synthesized by reacting ciprofloxacin (CPF) with glycidyl methacrylate. Further, the copolymerization of macromonomer (GCM) with acrylamide and diallyl dimethyl ammonium chloride (DADMAC) at different molar ratios was carried out via free radical polymerization using KPS as the initiator, which resulted in the formation of a cationic tripolymer (Scheme 4). The antimicrobial activity of the synthesized cationic tripolymers was screened against E. coli. As the macromonomer (GCM) concentration increased, the antimicrobial activity of the tripolymers also increased. The authors designed these CPF pendant cationic tripolymers for the purpose of antimicrobial paper products (such as tissues, paper towels, kitchen paper, food wrapper and bank notes) and for numerous hygiene products including cellulose based fibres.⁹⁵

Scheme 4 Synthesis of the ciprofloxacin pendant polymer (cationic tripolymer).

In 2018, Ahmed et al. designed cationic poly(guanylurea)s (PGUs) using piperazine and ethylenediamine for the development of biocompatible, specific, and selective antimicrobial polymers. Poly(guanylurea)–piperazine (PGU–P) and poly(guanylurea)–ethylenediamines (PGU–E) (Scheme 5) were synthesized by reacting piperazine and ethylenediamine with a monomer containing tert-butyloxycarbonyl (Boc)-protected guanidine groups at the end of short ethylene oxide side chains. The as-synthesized PGU–P exhibited broader antimicrobial activity compared to PGU–E with high selectivity to target against Mycobacterium smegmatis (M. smegmatis), S. aureus, methicillin resistant Staphylococcus aureus (MRSA), and Shigella flexneri (S. flexneri). The PGU–P polymer has key functional characteristics i.e., piperazine moiety, positive charge, H-bonding, and the lipophilicity, which help kill the bacteria via interacting with the cell membrane, followed by its disruption; the mechanism was studied via transmission electron microscopy (TEM).⁹⁶

Scheme 5 Synthesis of poly(guanylurea)–piperazine (PGU–P) and poly(guanylurea)–ethylenediamines (PGU–E).

In 2019, a novel piperazine–methacrylate monomer and its homopolymer were synthesized by Jalageri et al. Initially, piperazine and epichlorohydrin were used to react with each other to prepare a bifunctional coupler (piperazine-bearing aminochlorohydrin and azetidinium group). To increase the functionalities, the bifunctional coupler was quaternized with bromohexadecane and N,N′-dimethylaminoethyl methacrylate (DMAEMA) to yield a piperazine–methacrylate monomer. Further, the quaternized piperazine–methacrylate monomer was homopolymerized using an azobis(2-methylpropionitrile) (AIBN) initiator (thermal) yielding a multifunctionalized piperazine polymer (Scheme 6). The multifunctionalized piperazine polymer exhibited efficient antimicrobial activity against E. coli, M. smegmatis, S. aureus and Candida albicans (C. albicans) in comparison with standard drugs ciprofloxacin (antibacterial) and fluconazole (antifungal). The mode of action is as follows: the electrostatic interaction occurs between a negatively charged microbial cell wall and positively charged quaternary ammonium group that leads to cell lysis. The authors concluded that the as-synthesized piperazine-based polymer could be applicable in wound dressing, textile industry, biomedical field, water purification system, and so forth.⁷⁴

Scheme 6 Synthesis of the piperazine–methacrylate monomer and its homopolymer.

In 2019, novel biocompatible piperazine polymer (PE) (Scheme 7) for bacterial repellence on biomedical materials was designed and synthesized via green synthetic route by Zhang et al. The piperazine polymer was prepared by the straight-forward reaction of piperazine with ethylenediaminetetraacetic dianhydride (EDTAD). The piperazine polymer exhibited significant antimicrobial activity against E. coli and S. aureus in comparison with standard antibacterial ciprofloxacin. Piperazine targets the cytoplasmic membrane of the bacteria, resulting in the leakage of intercellular components leading to cell death. Based on their antibacterial activity and biocompatibility, the authors reported that the polymer could be applicable in biomedical field.^97,98

Scheme 7 Synthesis of the biocompatible piperazine polymer.

Mechano-growth factor and its 24 amino acid peptide (MGF-Ct24E)-modified piperazine polymer (PEM) for biomedical applications was designed and synthesized by the same author in 2019. First, the piperazine polymer (PE) was synthesized by reacting piperazine with ethylenediaminetetraacetic dianhydride (EDTAD) via the condensation polymerization method. Further, the MGF-Ct24E peptide polymer was grafted to the as-synthesized piperazine polymer (PE) yielding a piperazine-modified polymer (PEM) (Scheme 8). The antimicrobial activity of PE and PEM was tested against E. coli and S. aureus, in which PE showed better antibacterial activity against E. coli compared to PEM. In case of S. aureus, both PE and PEM showed similar activity. After the insertion of MGF-Ct24E to PE, the as-synthesized polymeric material not only maintained the physical and chemical properties but also reduced the biological toxicity of PE and produced the balance between the antibacterial and biological toxicity. Piperazine and amino peptides target the cell wall and cytoplasmic membrane of the bacteria, eventually leading to the leakage of cytoplasmic fluid and cell death; the mechanism was studied via scanning electron microscopy (SEM). The authors stated that the as-synthesized polymer could be applicable in biomedical field for the repair of bone, muscle and neuronal tissues.^97,99 Numerous piperazine-based homo/co/tripolymers are listed in Table 2.

Scheme 8 Synthesis of the MGF-Ct24E-modified piperazine polymer.

Table 2 List of piperazine-based homo/co/tripolymers synthesized by researchers against numerous pathogenic microorganisms

S. no.	Year	Author	Monomer/Polymer	Antimicrobial activity	Applications	Ref.
1	2003	Woong sig moon et al.		E. coli, S. aureus, B. subtilis, and M. luteus	Food packaging	92
2	2006	Supriya et al.		E. coli and S. aureus	Biomedical	93
3	2007	Supriya et al.		E. coli and S. aureus	Biomedical	94
4	2012	Xue et al.		E. coli	Paper products	95
5	2018	Ahmed et al.		M. smegmatis, S. aureus, MRSA, and S. flexneri	Biomedical	96
6	2019	Jalageri et al.		E. coli, S. aureus, M. smegmatis and C. albicans	Biomedical, water purification and textile	74
7	2019	Zhang et al.		E. coli and S. aureus	Biomedical	98
8	2019	Zhang et al.		E. coli and S. aureus	Biomedical	97 and 99

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1.2 Piperazine grafted polymers

In 2014, Subrata et al. developed non-leaching antimicrobial surfaces in a solution by synthesizing azetidinium-functionalized polytetrahydrofurans. Initially, they prepared a bifunctional coupler (piperazine-bearing amino chlorohydrin and azetidinium group) using piperazine and epichlorohydrin. The as-synthesized bifunctional coupler was further post-polymerized with synthetic polymer aminotelechelic polytetrahydrofuran (PTHF) [XTJ-548], resulting in the formation of azetidinium-functionalized polytetrahydrofuran polymers (Scheme 9). The authors concluded that the as-synthesized functional polymer could be applicable to solve the problems associated with hospital environment because of its excellent activity exhibited (>9.99–100%) in both solution and on the surfaces of textiles against E. coli and S. aureus. Azetidinium-functionalized polymers possess cationic nature, ionic interaction and covalent linkage, which helps to inhibit the bacterial growth via interacting with cell wall, followed by its death.^100,101

Scheme 9 Synthesis of functionalized polytetrahydrofurans.

The same author in 2014 fabricated antimicrobial fabrics by coating synthesized multifunctional polymers induced with piperazine on to cotton fibre. A one pot synthesis method was adopted to synthesize multifunctional polymers. Piperazine was reacted with epichlorohydrin to produce a bifunctional coupler, which helped in producing polymers. Further to induce hydrophobicity, the bifunctional coupler was reacted with decylamine (C-10 amine) and hexylamine (C-6 amine) to produce two different hydrophobic couplers. Hydrophobic couplers and bifunctional couplers were introduced to the side chain of Poly(vinyl amine)s (PVAms) using the post-polymerization method to produce multifunctional azetidinium-functionalized Poly(vinyl amine)s (PVAms) (Scheme 10), which mimic the natural antimicrobial peptides. Further, these polymers were coated onto cotton fabrics and tested for their antimicrobial activity against E. coli and S. aureus. Due to the presence of alkyl chains and cationic moieties (hydrophobic and hydrophilic modifications), the polymers exhibited efficient activity against tested microbes.¹⁰²

Scheme 10 Step-wise synthesis of multifunctional azetidinium-functionalized Poly(vinyl amine) by reacting PVAm with the functionalized coupler and the bifunctional coupler.

Jalageri et al. in 2019 synthesized an eco-friendly functionalized Jeffamine polymer having the piperazine moiety for surface coating applications. The functionalized Jeffamine polymer (Scheme 11) was synthesized by the post-polymerization of Jeffamine ED-2003 (having molecular weight of 2000) with a bifunctional coupler (piperazine-bearing aminochlorohydrin and azetidinium group) via a one-pot synthesis method. Because of the presence of the piperazine moiety, counter ions (Cl⁻), hydroxyl (–OH), and quaternary ammonium groups, the functionalized Jeffamine polymer exhibited antimicrobial activity against E. coli, M. smegmatis, S. aureus and C. albicans. The antimicrobial action of the functionalized Jeffamine polymer is ascribed to the quaternary ammonium group, which leads to cell lysis where electrostatic interaction takes place between the positively charged Jeffamine polymer and negatively charged microbial cell wall. In addition, it also contains –OH groups associated with azetidinium and amino-chlorohydrin, which are known for targeting the cytoplasmic membrane of microorganisms. This leads to leakage in intercellular components, followed by the death of microbes; the mechanism was studied via scanning electron microscopy (SEM). The author conveyed that the as-synthesized functionalized Jeffamine polymer having the piperazine moiety could be applicable in antimicrobial coatings, biomedical applications, textile industries, water purification system, and so forth.² Numerous piperazine-grafted polymers are listed in Table 3.

Scheme 11 Synthesis of the functionalized Jeffamine polymer.

Table 3 List of piperazine grafted polymers synthesized by researchers against numerous pathogenic microorganisms

S. no.	Year	Author	Polymer	Antimicrobial activity	Applications	Ref.
1	2012	Subrata et al.		E. coli and S. aureus	Textile	100 and 101
2	2013	Subrata et al.		E. coli and S. aureus	Textile	102
3	2019	Jalageri et al.		E. coli, S. aureus, M. smegmatis and C. albicans	Biomedical, coatings, and textile	2

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2. Conclusion

In summary, this review highlights the use of piperazine in the synthesis of antimicrobial polymers due to their wide range of pharmacological activities, which lead to the development of new therapeutic agents. In this aspect, piperazine-based antimicrobial polymers have gained interest from both academic and industrial researchers. The probable drawbacks and challenges encountered in the synthesis of piperazine polymers are (i) difficultly in handling due to its hygroscopic nature that liquidifies by absorbing moisture from air, therefore interrupting in the polymerization process, (ii) it contains only two reactive sites: secondary amines that restrict the adaptability of conversion to monomer or limits itself in incorporating into polymer structures, (iii) synthesized polymers may encounter difficulty in maintaining physical stability due to the hygroscopic nature of piperazine, (iv) polymer synthesis involves a multi-step synthetic procedure, which makes the purification of the polymer laborious. By considering the future perspectives of piperazine, a highly potential pharmacological interest can be used for the synthesis of antimicrobial polymers, which may have significant importance in sectors such as biomedical, food packaging and storage, textile, drug carriers, wound dressing, water purification system, and health care products.

Conflicts of interest

There are no conflicts to declare.

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