Among all of the synthesized compounds, compound 7a has shown the most significant protection against the damaging effect of the hypotonic solution compared to the control

Among all of the synthesized compounds, compound 7a has shown the most significant protection against the damaging effect of the hypotonic solution compared to the control. Inflammation is a body’s defense response against injury, infectious agents and autoimmune reactions.1 However, the outcome of chronic inflammation involves tissue destruction and fibrosis, which may lead to rheumatoid arthritis,2 cancer,3,4 neurodegenerative disorder5 and cardiovascular diseases.6,7 Several markers play an important role in inflammation including cytokine receptors, nuclear factor kappa-B (NF-B), nitric oxide synthase (NOS), tumor necrosis factor alpha (TNF-), interferons, chemokines and pro-inflammatory enzymes COX-2 and LOX (lipoxygenase).8C10 Among them, cyclooxygenase and lipoxygenase are the real culprits, and thus, are the primary targets of anti-inflammatory agents.11 Cyclooxygenases causes inflammation arachidonic acid metabolism by catalyzing the formation of prostaglandin H2, a precursor for the biosynthesis of prostacyclins, prostaglandins, and thromboxane that affects diverse biological processes such as regulation of immune function, and maintenance of renal blood flow, reproductive biology, and gastrointestinal integrity.12 Studies have demonstrated that COX exists in multiple isoforms, each with its own physiological expression and function.13 Two main isoforms are COX-1, designated as the housekeeping enzyme present in almost all cells and tissues, which regulates homeostasis and blood clotting, and COX-2 which is an inducible enzyme expressed in cells that mediate inflammation such as synoviocytes, macrophages, and monocytes leading to the synthesis of the prostanoids involved in acute and chronic inflammatory conditions. In this context, nonsteroidal anti-inflammatory drugs (NSAIDs) are well TW-37 recognized drugs for the treatment of inflammatory diseases which exert their therapeutic effects by preventing the metabolism of arachidonic acid inhibition of COX enzymes.14 However, conventional NSAIDs, including non-selective COX-1/2 inhibitors such as aspirin, ibuprofen, indomethacin and diclofenac, are associated with gastric side effects, whereas selective COX-2 inhibitors (COXIBs) such as celecoxib 1 prevent these side effects of non-selective NSAIDs.15C18 The severe side effects of clinically used NSAIDS include gastrointestinal lesions,19 cardiovascular diseases20,21 and renal injury,22 which necessitated the development of new chemical entities with higher efficacy and low/no side effects. Coumarins have attracted intense interest due to their wide range of applications in pharmacological chemistry such as anticancer,23 anti HIV,24 antimicrobial,25 anticoagulant, antioxidant,25,26 antiulcer,27 dyslipidemic,28 antitumor,29 and anti-inflammatory applications.30 Literature reports revealed variedly substituted coumarins, pyrazoles, isoxazoles/isoxazolidines, oxadiazoles as potential anti-inflammatory and analgesic agents inhibition of cyclooxygenase/pro-inflammatory TW-37 cytokines (Fig. 1).31C38 Open in a separate window Fig. 1 Variedly substituted molecules as potential anti-inflammatory/analgesic agents. It is well established that a common structural feature of selective COX-2 inhibitors is the presence of two vicinal aryl rings or 1,3-aryl groups attached with a central five or six-membered heterocyclic or carbocyclic motif. On the other hand, various marketed COX-2 inhibitors comprise a sulfone moiety which was found to be responsible for their pro-oxidant activity. This pro-oxidant effect could be related to the adverse effects observed with rofecoxib and etoricoxib due to which these drugs have not been approved by the FDA for TW-37 the U.S. market.39On the basis of these considerations, the present work describes the rational design and synthesis of coumarinCpyrazoline in which the coumarin nucleus was envisaged as a probable replacement for one of the aryl rings in a selective COX-2 inhibitor (celecoxib 1), and 3-acetyl pyrazoline as a central five membered carbocyclic ring with the underlying anticipation that the designed compounds would have a selective COX-2 inhibitory effect with low/no side-effects. Further, the however, to the best of our knowledge, their anti-inflammatory activity IKBA has not been reported yet, therefore, keeping in mind their pharmacological potential and their structural resemblance to selective COX-2 inhibitors such as celecoxib, herein, we have re-synthesized coumarinCpyrazoline derivatives 7a and 7e along with some novel derivatives 7b, 7c, 7d, 7f and 7g and evaluated them for detailed anti-inflammatory and analgesic activities. 2.?Results and discussion 2.1. Chemistry The synthetic methodology employed for the synthesis of target compounds is illustrated in Scheme 1. The reaction of salicylaldehyde 2 with ethyl acetoacetate 3 in the presence of piperidine at RT yielded 3-acetyl coumarin 4.40 The literature reports both acid- and base- catalyzed methods for the preparation of coumarinCchalcone derivatives, for instance, in the presence of piperidine (at 80 C),41,42 10% NaOH43 and 40% NaOH.44 Herein, we have reported the synthesis of coumarinCchalcones by the reaction of 3-acetyl coumarin 4 with substituted benzaldehydes 5 using a few drops of conc. H2SO4 in glacial acetic acid in excellent yields. Subsequently, chalcone 6 was cyclized in the presence of hydrazine hydrate in.