Mini-review Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents Mohammad Shaquiquzzaman, Garima Verma, Akranth Marella, Mymoona Akhter, Wasim Akhtar, Mohemmed Faraz Khan, Sharba Tasneem, Mohammad Mumtaz Alam * Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India article info Article history: Received 5 January 2015 Received in revised form 13 July 2015 Accepted 15 July 2015 Available online 18 July 2015 Keywords: Heterocyclic Piperazine Pharmacological activity abstract Piperazine is one of the most sought heterocyclics for the development of new drug candidates. This ring can be traced in a number of well established, commercially available drugs. Wide array of pharmaco- logical activities exhibited by piperazine derivatives have made them indispensable anchors for the development of novel therapeutic agents. The review herein highlights the therapeutic significance of piperazine derivatives. Various therapeutically active piperazine derivatives developed by several chemists are reported here. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction Heterocycles, characterized by the presence of one or more rings with at least one atom other than carbon represent an important class of biological and pharmacological significance [1e3]. These are indispensable for fulfillment of a number of physiological functions in plants and animals [4,5]. A large number of commer- cially available drugs contain heterocycles as their structural scaf- folds [6,7]. Nitrogen bearing heterocycles are of immense significance and therefore have gained extensive attention from the researchers [8,9]. Piperazine, (Fig. 1) a noteworthy six membered, nitrogen containing heterocyclic is of significant importance in medicinal chemistry [10,11]. Piperazine derivatives are reported to elicit a broad spectrum of pharmacological activities viz. antidepressant [12], anticancer [13], anthelmentic [14], antibacterial [15], antifungal [16], anti- mycobacterial [17], antimalarial [18], anticonvulsant [19] etc. The presence of this heterocyclic can be witnessed in numerous well known drugs, belonging to diverse pharmacological classes [20]. These drugs are tabulated in Table 1 . Several patents have also been filed on piperazine. Overview of these patents has been included in Supplementary Material. Based on the diverse activities of piperazine, numerous derivatives have been developed by several researchers with sun- dry pharmacological properties, which have been presented in the subsequent sections. 1.1. Analgesic and anti-inflammatory activity Pain is a disagreeable and subjective sensation due to a stimu- lation which alerts the body about the current injury to its tissues or organs [60]. Inflammation is a non-specific immune response to infection, irritation or some other sort of injury. The characteristic features of inflammation are redness, warmth, swelling and pain [61]. Non steroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to combat the conditions of pain and inflammation [62,63]. Prolonged use of NSAIDs usually leads to the disruption of mucosal layer of the gastrointestinal tract. Hence, the hunt for development of newer analgesic and anti-inflammatory agents is unrelenting [64,65]. Piperazine derivatives with analgesic and anti- inflammatory activity developed by various researchers are shown in Fig. 2. Amongst the piperazine derivatives developed by Boido et al., Compound 1 displayed highest analgesic activity with IC 50 of 580 nM [66]. Piperazine analogs were synthesized and evaluated for analgesic activity by Sladowska et al. All the compounds dis- played potent analgesic activity in comparison to acetylsalicylic acid. However, compound 2a was found to be most active in ‘writhing test’ and compound 2b was most active in ‘hot-plate’ test * Corresponding author. E-mail address: drmmalam@gmail.com (M.M. Alam). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.07.026 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 102 (2015) 487e529