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  • Further studies are needed as continuation of this

    2020-02-11

    Further studies are needed as continuation of this work to explore the effects of type and position of substituents of pyridazinone ring on anti-inflammatory activity profile. Taking into consideration that the phenyl moiety at position 2 wasn\'t a favorable substituent, even certain studies may be required to explore the effect of different substitution pattern of phenyl group at postion-2 of pyridazinone ring on in vitro COX-2 inhibitory, in vivo anti-inflammatory activity and gastric safety. Regarding postion-6, an important contribution is to synthesize novel pyridazin-3(2H)-ones with different heterocyclic moieties at postion-6 and study their effect on COX-2 inhibitory, anti-inflammatory activity and gastric safety profile. Compound 2f may be used as a starting point for further derivatives\' synthesis owing to its COX-2 selectivity and gastric safety. Further optimizations for vorapaxar 2d are still required to improve its GI safety. As a continuation of this work, we will study the effect of replacing the carbonyl of pyridazinone derivatives with other isosteric groups such as thione on the binding to COX-2 enzyme and in vitro COX-2 inhibition. Last but not least, progressive development of the attractive pyridazinone scaffold is still needed for the design and synthesis of selective COX-2 inhibitors, useful and safe anti-inflammatory agents as the pyridazinone skeleton still offers various options to medicinal chemists for further structural exploration.
    Experimental
    Acknowledgments The authors are grateful to Dr. Amany Ameen Sleem, Professor of Pharmacology, Pharmacology Department, National Research Center, Dokki, Giza, Egypt for carrying out the in vivo anti-inflammatory assay and gastric ulcerogenic activity. The authors thank Dr. Esam Rashwan, Head of the confirmatory diagnostic unit VACSERA-EGYPT, for carrying out the in vitro COX-1 and COX-2 inhibitory assay. The authors would like to acknowledge Dr. Amr Sayed Motawi, Lecturer of Pharmaceutical Organic Chemistry, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University for helping in Molecular Docking.
    Introduction Most of the currently used non-steroidal anti-inflammatory drugs (NSAIDs) show severe side effects and majority of these drugs showing gastrointestinal and renal toxicity [1], [2]. There has been a continuous interest among researchers in discovering newer NSAIDs which are selective to cyclooxygenase-2 (COX-2) enzyme. Unrelated and non-specific side effects exerted by the classical NSAIDs is due to inhibition of physiologically important cyclooxygenase-1 (COX-1) enzyme [3]. Isozyme COX-2 is more responsible for the release of prostaglandins as inflammatory mediators [4], [5]. The heterocyclic class of compounds have been studied widely as a new class of NSAIDs with lesser gastric side effects, a new series of compounds were synthesized with a focus to develop safer drugs [6]. Pyrazole derivatives are well established heterocyclic systems with established biological significance, safe and effective drugs used therapeutically. Feasible synthetic routes and conjugation with diverse aromatic and heterocyclic rings are subjected in many research investigations of varied pharmacological profiles such as anti-inflammatory, antipyretic, antimicrobial, antiviral, antitumor, anticonvulsant, antihistaminic, and antidepressant activities [6], [7], [8]. The pyrazole scaffold is a well-known and widely explored for anti-inflammatory activity by many research groups [9], [10], [11], [12], [13], [14]. Most commonly prescribed NSAIDs which are pyrazole based derivatives like celecoxib, deracoxib, etc., are selective and potent COX-2 inhibitors [15], [16]. In view of above mentioned findings, authors have utilized the strength of pharmacophore modelling to investigate the structural features of pyrazole derivatives required to selectively inhibit COX-2 enzyme. In addition to that, we have used pyrazole derivatives celecoxib, SC-558 and antipyrine (2,3-dimethyl-1-pheny-3-pyrazolin-5-one) one of the first identified pyrazolone derivative prescribed and suggested in the management of pain and inflammation. The drug Antipyrine was withdrawn because of its toxicity, but due to its potential activity their derivatives have enticed the attention of researchers across the globe [17], [18], [19]. Further, we employed the most advanced Auto Quantitative Structure Activity Relationship (AutoQSAR) tool to build a model of experimentally reported pyrazoles which are selective COX-2 inhibitors to quantify the therapeutic potential of synthesized pyrazoles. In continuation of our previous study and to explore the potential of new candidates which are selective and less toxic anti-inflammatory agents, we are reporting the ligand based design and synthesis, evaluation by in vitro and in vivo methods for anti-inflammatory activity of novel pyrazole derivatives [20]. Also the ulcerogenic activity has been carried out to check the gastric related side effects of these drugs.