Subscribe to RSS
DOI: 10.1055/a-1323-2813
Piperazine: A Promising Scaffold with Analgesic and Anti-inflammatory Potential
Abstract
Piperazine, a nitrogen-containing heterocyclic has acquired an inimitable position in medicinal chemistry because of its versatile structure, which has fascinated researchers to design novel piperazine based molecules having various biological actions. The subsistence of various compounds possessing diverse pharmacological activities in the literature further confirms this fact. Currently available analgesics and anti-inflammatory drugs are associated with side effects that limit their use. Moreover, the literature reveals the incredible anti-inflammatory and analgesic potential of piperazine derivatives along with their method of synthesis, therefore; the present review has been designed to collate the development made in this area that will surely be advantageous in designing novel piperazine based candidates with enhanced efficacy and less toxicity. An extensive literature survey was carried by scrutinizing peer reviewed articles from worldwide scientific databases available on GOOGLE, SCOPUS, PUBMED, and only relevant studies published in English were considered.
Publication History
Received: 10 September 2020
Accepted: 16 November 2020
Article published online:
17 December 2020
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Furst R, Zundorf I. Plant-Derived anti-inflammatory compounds: Hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediat Inflamm (Spcl issue Herbal Medicines for Inflammatory Diseases) 2014; 1-9
- 2 Bardalai D, Panneerselvam P.. Pyrazole and 2-Pyrazoline derivatives: Potential anti-inflammatory and analgesic agents. Int Res J Pharm App Sci 2012; 2: 1-8
- 3 Magee DJ, Jhanji S, Poulogiannis G. et al. Nonsteroidal anti-inflammatory drugs and pain in cancer patients: a systematic review and reappraisal of the evidence. Br J Anaesth 2019; 123: e412-e423
- 4 Kashfi K. Anti-inflammatory agents as cancer therapeutics. Adv Pharmacol 2009; 57: 31-89
- 5 Olszanecka A, Reczek L, Schonborn M. et al. Analgesic drug use in patients with hypertension and coronary artery disease. J Hypertens 2018; 36: e165
- 6 Schjerning AN, McGettigan P, Gislason G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol 2020; 1-11
- 7 Cronstein BN, Terkeltaub R. The inflammatory process of gout and its treatment. Arthritis Res Ther 2006; 8: S3
- 8 Pelletier JR, Pelletier JM, Rannou F. et al. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheu 2016; 45: S22-S27
- 9 Brandt KD. The role of analgesics in the management of osteoarthritis pain. Am J Ther 2000; 7: 75-90
- 10 Moore AH, Bigbee MJ, Boynton GE. et al. Non-steroidal anti-inflammatory drugs in alzheimer's disease and parkinson's disease: Reconsidering the role of neuroinflammation. Pharmaceuticals (Basel) 2010; 3: 1812-1841
- 11 Ali MM, Ghouri RG, Ans AH. et al. Recommendations for anti-inflammatory treatments in alzheimer’s disease: A comprehensive review of the literature. Cureus 2019; 11: e4620
- 12 Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 2013; 16: 821-847
- 13 Thankarajan S, Thangaraj P. Analgesic, Anti-inflammatory, and GC-MS studies on Castanospermum australe A. Cunn. & C. Fraser ex Hook. Sci World J 2014; 1-9
- 14 Fokunang C, Fokunang ET, Frederick K. et al. Overview of non-steroidal anti-inflammatory drugs (nsaids) in resource limited countries. MOJ Toxicol 2018; 4: 5-13
- 15 Shukla S, Mehta A, Mehta P. et al. Studies on anti-inflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models. Food Chem Toxicol 2010; 48: 61-64
- 16 Narnaware PH, Shende PN. An overview on heterocyclic compounds and their versatile applications. IJCESR 2018; 5: 159-162
- 17 Arora P, Arora V, Lamba HS. et al. Importance of heterocyclic chemistry: a review. Int J Pharm Sci Res 2012; 3: 2947-2954
- 18 Al-Ghorbani M, Bushra BA, Zabiulla MSV. et al. Piperazine and morpholine: Synthetic preview and pharmaceutical applications. J Chem Pharm Res 2015; 7: 281-301
- 19 Sourav D, Niranjan BM, Suneel BT. et al. A review article on importance of heterocyclic compounds. MJPMS 2016; 5: 18-27
- 20 Gupta M. Heterocyclic compounds and their biological significance: A review. Int J Phys Chem Math Sci 2015; 4: 21-24
- 21 Dua R, Shrivastava S, Sonwane SK. et al. Pharmacological significance of synthetic heterocycles scaffold: A review. Adv Biol Res 2011; 5: 120-144
- 22 Irannejad H. Nitrogen rich heterocycles as a privileged fragment in lead discovery. Med Analy Chem Int J 2018; 2: 1-6
- 23 Saini MS, Kumar A, Dwivedi J. et al. A review: Biological significances of heterocyclic compounds. IJPSR 2013; 4: 66-77
- 24 Nagaraju K, Gummidi L, Maddila S. et al. A review on recent advances in nitrogen-containing molecules and their biological applications. Molecules 2020; 25: 1-42
- 25 Gandhi D, Kalal P, Agarwal S. Synthetic aspects and biological studies of some heterocycles. Chemistry and Biology Interface 2017; 7: 79-101
- 26 Shaikh AR, Farooqui M, Satpute RH. et al. Overview on nitrogen containing compounds and their assessment based on ‘International Regulatory Standards. J Drug Deliv Ther 2018; 8: 424-428
- 27 Jampilek J. Heterocycles in medicinal chemistry. Molecules 2019; 24: 3839
- 28 Dhingra AK, Chopra B, Dua JS. et al. Therapeutic potential of N-heterocyclic analogs as anti-inflammatory agents. Antiinflamm Antiallergy Agents Med Chem 2017; 16: 136-152
- 29 Muralidharan V, Asha DC, Raja S. A review on anti-inflammatory potential of substituted pyrazoline derivatives synthesised from chalcones. Int J Pharm Pharm Sci 2018; 10: 9-14
- 30 Bekhit AA, Hymete A, Bekhit AEA. et al. Pyrazoles as promising scaffold for the synthesis of anti-inflammatory and/or antimicrobial agent: A review. Mini Rev Med Chem 2010; 10: 1014-1033
- 31 Ganguly S, Jacob SK. Therapeutic outlook of pyrazole analogs: A mini review. Mini Rev Med Chem 2017; 17: 959-983
- 32 Tiwary BK, Pradhan K, Nanda AK. et al. Implication of Quinazoline-4(3H)-ones in medicinal chemistry: A brief review. J Chem Biol Ther 2015; 1: 104
- 33 Amir M, Javed SA, Kumar H. Pyrimidine as antiinflammatory agent: A review. Indian J Pharm Sci 2007; 69: 337-343
- 34 Sharma V, Chitranshi N, Agarwal AK. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem 2014; 1-31
- 35 Singh J, Sharma D, Bansal R. Pyridazinone: an attractive lead for anti-inflammatory and analgesic drug discovery. Future Med Chem 2016; 9: 1-8
- 36 Ostrowska K. Coumarin-piperazine derivatives as biologically active compounds. Saudi Pharm J 2020; 28: 220-232
- 37 James T, MacLellan P, Burslem GM. et al. A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds. Org Biomol Chem 2014; 12: 2584-2591
- 38 Kumar RA, Anburaj DB. Growth, nucleation kinetics and structural studies on L-valine piperazinium single crystals. Asian J Chem 2019; 31: 1966-1970
- 39 Singh K, Siddiqui HH, Shakya P. et al. Piperazine – a biologically active scaffold. IJPSR 2015; 6: 4145-4158
- 40 Henry DW. A facile synthesis of piperazines from primary amines. J Heterocycl Chem 1966; 3: 503-511
- 41 Reilly SW, Mach RH. Pd-Catalyzed synthesis of piperazine scaffolds under aerobic and solvent-free conditions. Org Lett 2016; 18: 5272-5275
- 42 Jida M, Ballet S. Efficient one-pot synthesis of enantiomerically pure N- protected- α- substituted piperazines from readily available α-amino acids. New J Chem 2018; 42: 1595-1599
- 43 Halimehjani AZ, Badali E. DABCO bond cleavage for the synthesis of piperazine derivatives. RSC Adv 2019; 9: 36386-36409
- 44 Liu KG, Robichaud AJ. A general and convenient synthesis of N-aryl piperazines. Tetrahedron Lett 2005; 46: 7921-7922
- 45 Asif M. Piperazine and pyrazine containing molecules and their diverse pharmacological activities. IJASRE 2015; 1: 05-11
- 46 Rajashree A, Markandewar MABaseer. Exploring pharmacological significance of piperazine scaffold. World J Pharm Res 2016; 5: 1409-1420
- 47 Shaquiquzzaman M, Verma G, Marella A. et al. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents. Eur J Med Chem 2015; 102: 487-529
- 48 Mallesha L, Mohana KL. Synthesis, antimicrobial and antioxidant activities of 1–4x(1,4–benzodioxane–2–carbonyl) piperazine derivatives. Eur J Chem 2011; 2: 193-199
- 49 Patel RV, Park SW. An evolving role of piperazine moieties in drug design and discovery. Mini Rev Med Chem 2013; 13: 1579-1601
- 50 Rathi AK, Riyaz S, Shin HA. et al. Piperazine derivatives for therapeutic use: a patent review (2010-present). Expert Opin Ther Pat 2016; 26: 777-797
- 51 Verma S, Kumar S. Review exploring biological potentials of piperazines. Med Chem 2017; 07: 1-8
- 52 Tomar A, Mall M, Verma M. Piperazine: the molecule of diverse pharmacological importance. Int J Res Ayurveda Pharm 2011; 2: 1547-1548
- 53 Swartzwelder C, Miller JH, Sappenfield RW. The effective use of piperazine for the treatment of human helminthiases. Gastroenterology 1957; 33: 87-96
- 54 Orjales A, Gil-Sanchez JC, Cires LA. et al. Synthesis and histamine H1-receptor antagonist activity of 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment. Eur J Med Chem 1996; 31: 813-818
- 55 Mendoza A, Silanes SP, Quiliano M. et al. Aryl piperazine and pyrrolidine as antimalarial agents. Synthesis and investigation of structure-activity relationships. Exp Parasitol 2011; 128: 97-103
- 56 Ibezim E, Duchowicz PR, Erlinda V. et al. SAR on aryl-piperazine derivatives with activity on malaria. Chemometr Intell Lab 2012; 110: 81-88
- 57 Silva GNS, Schuck DC, Cruz LN. et al. Investigation of antimalarial activity, cytotoxicity and action mechanism of piperazine derivatives of betulinic acid. Trop Med Int Health 2015; 20: 29-39
- 58 Chaudhary P, Kumar R, Verma AK. et al. Synthesis, characterization and in vitro biological studies of novel cyano derivatives of N-alkyl and N-aryl piperazine. Eur J Med Chem 2007; 42: 471-476
- 59 Somashekhar M, Mahesh AR. Synthesis and antimicrobial activity of piperazine derivatives. AJPTR 2013; 3: 640-645
- 60 Patil M, Poyil AN, Joshi SN. et al. Design, synthesis, and molecular docking study of new piperazine derivative as potential antimicrobial agents. Bioorg Chem 2019; 92: 103217
- 61 Qigui X, Tianyu L, Tian R. et al. Synthesis and antiemetic activity of 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives. Front Chem China 2009; 4: 63
- 62 Bali A, Bhalla A, Bala S. et al. Synthesis and computational studies on aryloxypropyl piperazine derivatives as potential atypical antipsychotic agents. Lett Drug Des Discov 2012; 9: 218-224
- 63 Walayat K, Mohsin NA, Sana AS. et al. An insight into the therapeutic potential of piperazine-based anticancer agents. Turk J Chem 2019; 43: 1-23
- 64 Gurdal EE, Buclulgan E, Durmaz I. et al. Synthesis and anticancer activity evaluation of some benzothiazole-piperazine derivatives. Anticancer Agents Med Chem 2015; 15: 382-389
- 65 McNair MDTJ, Wibin MDFA, Hoppe ET. et al. Antitumor action of several new piperazine derivatives compared to certain standard anticancer agents. J Surg Res 1963; 3: 130-136
- 66 Varadaraju KR, Kumar JR, Mallesha L. et al. Virtual screening and biological evaluation of piperazine derivatives as human acetylcholinesterase inhibitors. Int J Alzheimers Dis 2013; 1-13
- 67 Kaya B, Ozkay Y, Temel HE. et al. Synthesis and biological evaluation of novel piperazine containing hydrazone derivatives. J Chem 2016; 1-7
- 68 Panchal NB, Captain AD. Synthesis and screening of some new piperazine derivatives as potential anthelmintic agents. IJPRS 2015; 4: 26-37
- 69 Alonso RMS, Santana ERL, Sanmartin GMM. et al. Piperazine derivatives of benzimidazole as potential anthelmintics. Part 1: Synthesis and activity of methyl-5-(4-substituted piperazin-1-yl)benzimidazole-2-carbamates. Pharmazie 1989; 44: 606-607
- 70 Brito AF, Moreira LKS, Menegatti R. et al. Piperazine derivatives with central pharmacological activity used as therapeutic tools. Fundam Clin Pharmacol 2019; 33: 13-24
- 71 Jingfen L, Yong Y, Lisheng W. et al. Synthesis, characterization, and anti-inflammatory activities of methyl salicylate derivatives bearing piperazine moiety. Molecules 2016; 21: 1-11
- 72 Kumar CSA, Veeresh B, Ramesha KC. et al. Synthesis and anti inflammatory activity of 1-Benzhydryl-piperazine urea derivatives bearing piperazine moiety. J Appl Chem 2017; 6: 282-290
- 73 Srivastava S, Pandeya SN, Yadav MK. et al. Synthesis and analgesic activity of novel derivatives of 1,2-substituted benzimidazoles. J Chem 2013; 1-6
- 74 Patel N, Karkhanis V, Patel P. Synthesis and biological evaluation of some piperazine derivatives as anti-inflammatory agents. J Drug Deliv Ther 2019; 9: 353-358
- 75 Shakya AK, Kaur A, Al-Najjar BO. et al. Molecular modeling, synthesis, characterization and pharmacological evaluation of benzo[d]oxazole derivatives as non-steroidal anti-inflammatory agents. Saudi Pharm J 2016; 24: 616-624
- 76 Liu ZP, Gong CD, Xie LY. et al. Synthesis and in vivo anti-inflammatory evaluation of piperazine derivatives containing 1,4-benzodixon moiety. Acta Chim Slov 2019; 66: 421-426
- 77 Ganji LV, Agrawal PN. Design, synthesis and antiinflammatory evaluation of 5(6)-(un)-substituted-1H-benzimidazol-2-ylthioacetylpiperazine derivatives. Indian J Pharm Sci 2019; 82: 21-31
- 78 Mulazim Y, Berber C, Erdogan H. et al. Synthesis and analgesic activities of some new 5-chloro-2(3H)-benzoxazolone derivatives. EuroBiotech J 2017; 1: 235-240
- 79 Erden B, Murat S, Burcu CE. et al. Synthesis of the amide derivatives of 3-[1-(3-Pyridazinyl)-5-phenyl-1H-pyrazole-3-yl]propanoic acids as potential analgesic compounds. Turk J Chem 2007; 31: 677-687
- 80 Alam T, Abida MAsif. A review on analgesic and anti-inflammatory activities of various piperazinyl containing pyridazine derivatives. Prog Chem Biochem Res 2020; 3: 81-92
- 81 Channigarayappa AH, Swamy S, Nadigar MR. et al. Synthesis, characterization and pharmacological assessment of alkylated sulfonyl piperazines. Asian J Pharm Pharmacol 2017; 3: 177-185
- 82 Yulu M, Xi Z, Hui G. et al. Design, synthesis, and biological evaluation of novel benzofuran derivatives bearing N-aryl piperazine moiety. Molecules 2016; 21: 1-11
- 83 Mishra P, Middha A, Saxena V. et al. Synthesis, biological evaluation and comparative study of some cinnoline derivatives. UK J Pharm Biosci 2016; 4: 74-80
- 84 Abdel-Rahman HM, Sheha MM. Synthesis, analgesic and anti-inflammatory activities of 4-oxo-4-(4-(pyrimidin-2-yl) piperazin-1-yl) butanoic acid derivatives. MCAIJ 2005; 1: 7-13
- 85 Hayun H, Maggadani BP, Kurnia A. et al. Anti-inflammatory and antioxidant activity of synthesized mannich base derivatives of (2E,6E)-2-[(4-hydroxy-3-methoxyphenyl)methylidene]-6-(phenylmethylidene) cyclohexan-1-one. Int J App Pharm 2019; 11: 246-250
- 86 Ahmadi A, Khalili M, Nafarie A. et al. Synthesis and anti-inflammatory effects of new piperazine and ethanolamine derivatives of H1-antihistaminic drugs. Mini-Rev Med Chem 2012; 12: 1282-1292
- 87 Kopardea S, Hosamania KH, Kulkarnia V. et al. Synthesis of coumarin-piperazine derivatives as potent anti-microbial and anti-inflammatory agents, and molecular docking studies. Chem Data Coll 2018; 15-16: 197-206
- 88 Altuntas TG, Baydar A, Kurt ZK. et al. Novel piperazine substituted indole derivatives: Synthesis, anti-inflammatory and antioxidant activities and molecular docking. J Res Pharm 2020; 24: 350-360