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Medicinal Chemistry
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Review Exploring Biological Potentials of Piperazines

Shweta Verma* and Sushil Kumar

Faculty of Pharmacy, IFTM University, Moradabad-244001, India

*Corresponding Author:
Shweta Verma
Faculty of Pharmacy, IFTM University
Moradabad-244001, India
Tel: +918393843909
E-mail: [email protected]

Received Date: December 19, 2016; Accepted Date: January 20, 2017; Published Date: January 24, 2017

Citation: Verma S, Kumar S (2017) Review Exploring Biological Potentials of Piperazines. Med Chem (Los Angeles) 7:012-019. doi: 10.4212/2161-0444.1000425

Copyright: © 2017 Verma S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

In modernization nitrogen containing heterocyclic compounds and their derivatives has attracted great interest due to their efficacious biological and pharmacological properties. The moiety of piperazines and substituted aryl piperazines were found to present in compounds aim at evaluating new entities that possess anti-microbial, anti-tubercular, anticonvulsant, anti-depressant, anti-malarial and anti-inflammatory activities. Piperazines show a broad range of activities and are found in many potent biologically active compounds such as thiothixene and pimozide (anti-psychotics), Loxapine (schizophrenia), Clozapine (Atypical anti-psychotics). The modifications in the moiety of piperazine ring shows high efficacy with better potency and lesser toxicity. This review focused on multifarious biological activities related to piperazines and its derivatives.

Keywords

Loxapine; Pharmacological activity; Piperazines

Introduction

Pharmaceutical chemistry deals with the discovery, development, interpretation and identification of mechanism of action of biologically active compounds at the molecular level. It was revealed that many potentially active synthetic compounds contain six membered two nitrogen heterocyclic compounds in their structure and one such compound was found to be piperazine and its derivatives. Piperazine consist of six membered heterocyclic rings containing two nitrogen at two opposite positions in the ring exist as small alkaline deliquescent crystals with a saline taste. Piperazines moiety containing polar nitrogen atoms confers bioactivity to molecule and increases the favorable interactions with macromolecules [1]. The utmost property of piperazine is their ability to cross the blood brain barrier due to its small size and lipophilic nature which promote its activity upon central nervous system (CNS) and make it favorable to treat various mental disorders including anxiety disorders, Alzheimer’s disease, psychosis and depression [2]. Many potent marketed drugs like flunarizine, cinnarizine, lomerizine, fluphenazine, ciprofloxacin, Merck HIV protease, crixivan, etc. have a piperazine nucleus. Some examples of bioactive piperazines derivatives are shown in Figures 1-12 [3]. In this review, our aim is to focus on various biological activities related to piperazines and its derivatives. They too have been found potent in treatment of various ailments such as anti-hypertensive [4], antiinflammatory [5], anti-allergenic [6], anti-tussive [7], anti-bacterial [8], anti-serotonic [9], anti-psychotic [10], anti-influenza [11], anticancer [12], anti-schizophernia [13]. Piperazine derived compounds like N-benzylpiperazine (BZP),1-(3,4- methylenedioxybenzyl) piperazine (MDBP), 1-(4-methoxyphenyl) piperazine(MeOPP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), and 1-(3-chlorophenyl)- piperazine (mCPP) belong to one of the newer groups of designer drugs that are mentioned as psychoactive chemicals in “scene books”, seizures of these drugs have been made throughout the world [14] (Figures 1-12).

medicinal-chemistry-bioactive-piperazine

Figure 1: Represent some bioactive piperazine derivatives.

medicinal-chemistry-piperazine-moiety

Figure 2: CNS agents containing piperazine moiety.

medicinal-chemistry-Cardiovascular-agents

Figure 3: Cardiovascular agents containing piperazine moiety.

medicinal-chemistry-Anti-oxidative

Figure 4: Anti-oxidative agents containing piperazine moiety.

medicinal-chemistry-Calcium-channel

Figure 5: Calcium channel blocker agents containing piperazine moiety.

medicinal-chemistry-Anti-malarial

Figure 6: Anti-malarial agents containing piperazine moiety.

medicinal-chemistry-respiratory-insufficiency

Figure 7: Piperazine containing agent used for respiratory insufficiency.

medicinal-chemistry-anti-microbial-agents

Figure 8: Piperazine moiety containing agents used as anti-microbial agents.

medicinal-chemistry-Anti-helmintic

Figure 9: Anti-helmintic agents containing piperazine moiety.

medicinal-chemistry-piperazine-hydro-bromide

Figure 10: N1-[1-(4-bromobenzyl)-3-piperidinocarbonyl] - N4-(2-chlorophenyl)- piperazine hydro bromide.

medicinal-chemistry-Anti-Alzheimer

Figure 11: Anti-Alzheimer agent containing piperazine moieties.

medicinal-chemistry-Anti-histaminic

Figure 12: Anti-histaminic agent containing piperazine moiety.

Synthesis Methods of Piperazine and its Derivatives

The diversity in biological potency of piperazine and its derivatives has induced extensive attention. It has been revealed that an rigorous research and method has been conducted and developed for the synthesis of the piperazine core. A different research has evoked the different methods for the synthesis of piperazine and its derivatives due to its different and potential biological activities. Some of them are listed below.

Kitchen et al. [15] has synthesized piperazine by heating diethylene triamine in the presence of raney nickel under high temperature, the reaction involves the liberation of ammonia to yield ammonia (Scheme 1).

medicinal-chemistry-synthesis-piperazine

Scheme 1: Representing synthesis of piperazine.

Aspinall et al. [16] synthesized 2-phenyl piperazine by allowing reaction of bromo-phenyl-acetic acid ethyl ester with to obtain 3-phenyl-piperazin-2-one. The obtained compound was further reduced with lithium aluminum hydride to give 2-phenylpiperazine (Scheme 2).

medicinal-chemistry-synthesis-piperazine

Scheme 2: Representing synthesis of 2-phenylpiperazine.

Synthesis of 2-phenylpiperazine was also reported by Pollard et al. [17] involving the formation of intermediate 2-(2-aminoethylamino)- 1-phenyl-ethanol from 2-phenyl-oxirane and ethylenediamine in methanol, followed by reduction of 2-(2-withraney nickel (Scheme 3).

medicinal-chemistry-synthesis-piperazine

Scheme 3: Representing synthesis of 2-phenylpiperazine.

Nenajdenko et al. [18] has developed a novel and effective approach to synthesize chiral substituted pyrrolo ketopiperazines via a threecomponent Ugi reaction from chiral 2-(2-formyl-1H-pyrrol-1-yl) acetic acids, isocyanides and primary amines (Scheme 4). The method was found to be efficient with good %yield.

medicinal-chemistry-synthesis-piperazine

Scheme 4: Representing synthesis of piperazine derivative.

Haass et al. [19] carried out a palladium catalyzed carboamination reaction to achieve piperazines in high yield. The distereoselective carboamination reaction of N1-allyl-N2-aryl-N1-vinyl-propane-1,3- diamine in the presence of palladium catalysts and aryl bromide yield cis-piperazine (Scheme 5).

medicinal-chemistry-synthesis-piperazine

Scheme 5: Representing synthesis of cis-piperazine.

Patino-Molina et al. [20] developed an intramolecular reductive amination of 4-(2-benzyloxycarbonylaminopropionylamino)-3-oxobutyric acid methyl ester to give (6-methyl-5-oxo-piperazin-2-ylidene)- acetic acid methyl ester. The desired piperazinones were obtained in good yields using Palladium catalyst (Scheme 6).

medicinal-chemistry-synthesis-piperazine

Scheme 6: Representing synthesis of (6-methyl-5-oxo-piperazin-2-ylidene)- acetic acid methyl ester.

Multifarious biological activities

Central nervous system (CNS) activity: Various psychological and neurological disorders were generated due to CNS disease which ultimately affects the brain and spinal cord. Researchers continued their effort in synthesizing piperazines and their derivatives because of their potency to treat the CNS disorder. Bali et al. [21] carried out synthesis of a new series of acetophenone based 1-(aryloxypropy)-4- (chloroaryl) piperazines (4) as potential atypical anti-psychotics. The physicochemical similarity of the new analogs with respect to standard drugs clozapine, ketanserin, ziprasidone and risperidone was assessed by calculating from a set of 10 physicochemical properties using software programs and revealed that compounds bearing hydrogen bond acceptor substituent showed higher efficacy with potential apsychotic profile. Dash et al. [22] synthesized 6[3-(4-substituted phenylpiperazin-1-yl) propoxy] benzo[d] [1,3] oxathiol-2-ones (5) to treat mental disorders such as schizophrenia and evaluated them invivo to predict ability of inhibiting apomorphine induced climbing behavior and inhibition of 5-HTP induced head twitches. QSAR studies were also generated for anti-psychotic activity. The researchers continued their work and synthesized a series of 6-(4-(4-substituted phenylpiperazin-1-yl) butoxy) benzo[d] [1, 3] oxathiol-2-one (6) as potential anti-psychotic agents [23]. 2-[4-(Aryl substituted) piperazin- 1-yl]-N-phenylacetamides (7), developed by Kumar et al. [24] and the compounds were evaluated for its anti-psychotic activity. Quinazoline containing piperazines (8) were synthesized by Mukherjee et al. [25] and screened for anti-convulsant activity by Pentylenetetrazole induced seizure tests. The screening reveals that the compounds synthesized were found to be effective against petit mal epilepsy. Brito et al. [26] design and synthesized new piperazine 4-(1-phenyl-1h-Pyrazol-4- ylmethyl)-Piperazine-1-Carboxylic Acid Ethyl ester (9) (LQFM008), and evaluated for its anxiolytic-like profile in Swiss mice using Rota rod, sodium-pentobarbital induced sleep, open-field, elevated plus maze and light-dark box tests. Aytemir et al. [27] synthesized 3-hydroxy-6- methyl-2-substiuted 4H-pyran-4-one derivatives (10) and evaluated for its anti-convulsant activity. Aytemir et al. [28] also synthesized new Kojic acid derivatives containing piperazine ring and evaluated for its anti-convulsant activity. He reported that 3-hydroxy-6-hydroxyethyl-2- [4-(2-methylphenyl) piperazine-1-yl methyl]-4-pyran-4-one (11) was found to be highly active. Moller et al. [29] synthesized 1, 4-disubstituted piperazines comprising a pyrazolo [1, 5-a] pyridine ring linked with 1, 2, 3-triazole and investigated its QSAR, docking and its serotonin, dopamine receptor selectivity. In search of potent anti-psychotic agent Srinivas et al. [30] synthesized 1-(1, 2-dihydro-2-acenaphthylenyl) piperazine (12) derivatives and evaluated them as potent anti-psychotic agents in mice

Kumar et al. [31] reported synthesis of long chain aryl piperazines linked with salicylamide linker and evaluated them for atypical antipsychotic activity by different models such as apomorphine induced climbing behavior and 5-HTP-induced twitches. The researchers further new arylpiperazine (13) derivatives and demonstrated them for atypical anti-psychotic activity and investigated their computational studies [32].

Cardiovascular activity: Various new drugs have been explored for the treatment of various cardiovascular diseases like hypertension, Congestive heart failure, diabetic nephropathy, left ventricular systolic dysfunction, chronic renal failure, systemic sclerosis and acute myocardial infarction. Santoshi et al. [33] synthesized 1-benzhydrl piperazine derivatives and evaluated for in-vitro ACE inhibition and antimicrobial activity. Compound (14) showed moderate ACE inhibition activity as compared to standard ACE enzyme inhibitor. (RS)-N-(2, 6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] piperazin-1-yl] acetamide (15) was synthesized by Hale et al. [34] and reported for its anti-anginal activity. Fragasso et al. [35] reported the synthesis of 1-(2, 3, 4-trimethoxybenzyl) piperazine (16) a partial free fatty oxidation inhibitor and found that it was efficacious for the patient with heart failure. Hajos et al. [36] reported the synthesis of substituted benzhydril-2-hydroxypropyl piperazine derivatives (17) and revealed that compound is a potent cardiotonic agent. Kaneko et al. [37] synthesized a new series of benzhydrilpiperazine (18) derivatives and screened their inhibiting effect over contraction and overextension of the myocardium. This compound was obtained as a myocardial necrosis inhibitor which protect against myocardial necrosis.

Anti-oxidative activity: An anti-oxidant inhibits the oxidation of molecules. Oxidation is the production of free radicals that can damage any cell. Many of the researchers continued their work to synthesize potent anti-oxidant drugs. It was discovered that phenypiperazine containing moiety show potent anti-oxidative property. Kawasaki et al. [38] synthesized new series of benzhydril piperazine trimethylhydroquinone derivatives and screened for their antioxidative and anti-allergic effects. Compound 4-[4-(4-diphenylmethyl- 1-piperazinyl)- butoxy]-2, 3, 6- trimethyl phenol (19) showed potent anti-oxidative and anti-allergic activities. Shanklin et al. [39] reported Flunarizine bearing benzhydril piperazine (20) as calcium antagonist and anti-oxidants. Pietrzycka et al. [40] synthesized 1-(phenoxyethyl)- piperazine (21) derivatives and evaluated for their anti-oxidant activity and the anti-oxidant property profile were compared to Trolox and Resveratrol. The compound possessing methyl group was found to be highly potent. A new series of diphenyl alkyl piperazine derivatives (22) was synthesized by Kimura et al. [41] and they showed anti-oxidant activity along with high affinities for the dopamine transporter.

Calcium channel blockers: Calcium channel blockers block the movement of calcium ions and are used as anti-hypertensive drugs. But Miyake et al. [42] reported Tamolarizine (23) as Ca2+ channel blocker for its reversing effect on tumor cells which are multidrug resistant. It potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells. Ito et al. [43] synthesized Lifarizine (24) containing benzhydril piperazine and imidazole skeleton as a calcium antagonist.

Anti-malarial activity: Various piperazine and its derivatives has proved its efficacy against malarial. Researchers synthesized and designed piperazine derivatives with improved efficacy. Flipo et al. [44] synthesized a new class of piperazine incorporating chloroquine moiety (25) and found it as an inhibitor of PfA-M1, a neutral zinc aminopeptidase of P. falciparum. Ryckebusch et al. [45] reported N’- (7-chloro-4-quinolyl)-1, 4-bis (3-aminopropyl) piperazine derivatives (26) as anti-mialarial against a CQR strain of P. falciparum. Musonda et al. [46] carried out a synthesis of 4-aminoquinoline containing 2,4,5-trisubstituted aminoxazoles and piperazine/morpholine (27) and screened in-vitro against two strains of the P. falciparum parasite and revealed that many of the synthesized compounds exhibited significantly more potent activity than standard drug chloroquine.

Respiratory insufficiency: Labrid et al. [47] have synthesized almitrine (28) which is a triazinylpiperazine derivative and currently using for respiratory insufficiency.

Anti-microbial activity: The budding bacterial resistance has been escalating now days and has become a new task for researcher to synthesize potent compounds against it. In search of the bioactive molecules Chaudhary et al. [48] synthesized a series of substituted N-alkyl (29) and N-aryl piperazine (30) derivatives and evaluated for their anti-bacterial and anti-fungal activity. Azole containing piperazine derivatives (31) have been synthesized by Gan et al. [49] and were investigated in-vitro for their anti-bacterial activity, anti-fungal and cytotoxic activities. Thriveni et al. [50] synthesized pyrimidine incorporated piperazine (32) derivatives and evaluated them for their anti-bacterial and anti-fungal activity. The compounds showed significant anti-fungal activity at 40μg/ml concentration when compared with standard drugs. Fluorine containing piperazine derivatives were also found potent for anti-bacterial activity. Choudhary et al. [51] synthesized piperazine (33) and morpholine derivatives (34) containing fluorine and evaluated for their anti-bacterial activity against two gram positive bacteria Staphylococcus aureus, and Bacillus subtilis and two gram negative bacteria Escherichia coli, and Pseudomonas aeruginosa showing potent activity. Jain et al. [52] synthesized 4-substituted- 1-(4-substituted phenyl) piperazine (35) derivatives and evaluated for their anti-microbial properties using Ampicillin as standard drug respectively against four strains i.e. S. aureus, S. epidermidis, P. aeruginosa and E. coli. Almost all compounds show activity but compound containing chloro group show excellent activity against S. aureus and methyl group shows excellent activity against P. aeruginosa. Patil et al. [53] synthesized a novel series of substituted phenylacetamide by condensing 1-4(aminophenyl)-2-{4(S)-(4-chlorophenyl) (phenyl) methyl-1-piperazinyl} ethanone (36) in presence of acid catalyst under reflux conditions and synthesized compounds were than evaluated for anti-bacterial activity against Staphylococcus aureus, Streptococcus pyogenses, Escherichia coli, Pseudomonas aeruginosa anti-fungal activity against Candida albicans, Aspergillus niger.

Anti-helmintic agents: Panchal et al. synthesized some new piperazine derivatives and evaluated for its in-vitro anthelmintic activity against Eisenia fetida. This reaction involves the formation of mannich bases derivatives and all the structure were elucidated from the different spectral analysis and activity results revealed that N-03, 04 and 05 (37), (38), (39) exhibited highly significant action for time taken to paralysis and death which is equivalent to standard drug.

As an anti-platelet aggression activity: Youssef et al. designed and synthesized new carbamoyl pyridine and carbamoyl piperidine analogues containing nipecotic acid scaffold and evaluated the derivatives for their platelet aggregation inhibitory activity. The impact of lipophilicity and molecular modeling was performed and Structure activity relationship of the series was generated. N1-[1- (4-bromobenzyl)-3-piperidinocarbonyl] - N4-(2-chlorophenyl)- piperazine hydro bromide (40) was found to be most active anti-platelet aggregating compounds in this study.

Anti-Alzheimer activity: Anti-alzheimer activity in piperazines was studied by Ranagppa et al. He synthesized 1-[bis (4- flurophenyl) methyl] piperazine (41) derivatives and evaluated its efficacy for acetylcholinestrase inhibition which acts as a stimulant of central cholinergic neurotransmission in Alzheimer disease.

Anti-histamine activity: The drugs that riled the action of histamine at H1 receptors instead of H2 receptors are known as antihistamine. Piperoxan discovered in ancient times has the ability to treat asthma induced by histamine which leads to research of antihistamine drugs. Meclozine discovered by Dahl et al. demonstrated the piperazine moiety also possess anti-histamine activity. Nicholson et al. reported the synthesis of Cinnarizine containing piperazine as antihistaminic drug. Synthesis of hydroxyzine was reported by Simons et al. possessing piperazine as anti-histaminic drug. Levocitrizine, cetrizine, Niaprazine synthesized by Grant et al. Anderson et al. and Bodiou et al. all were demonstrated as anti-histaminic drugs enclosing piperazine ring in their structure. However, Bucle et al. designed and synthesized a new series of N-benzylpiperazino derivatives and evaluated its antihistamine activity on guinea pig ileum and compared with standard drug mepyramine. The compound (42) showed efficient anti-histamine activity when compared to standard.

Conclusion

This review article has compiled significant information about various biological activities of piperazine based compounds along with some synthetic methods for the preparation of piperazines. It may be concluded that piperazine motif is a versatile and medicinally important heterocyclic nucleus containing various biological activity like anti-psychotic and anti-convulsant. Therefore, it was accomplished that piperazine nuclei is an important pharmacophore for the designing and development of various drugs for the CNS activity along with many other potential biological activities.

Conflict of Interest

None declared.

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