Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Full length article Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents Jignasa K. Savjani a, ⁎ , Suja Mulamkattil b , Bhavesh Variya a,c , Snehal Patel a a Institute of Pharmacy, Nirma University, S.G.Highway, Ahmedabad, Gujarat 382481, India b Beiersdorf. Nivea India, plot no: SM-9/1, Sanand-2, Industrial Estate, Ahmedabad, Gujarat 382110, India c Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India ARTICLE INFO Keywords: Acute toxicity study Anti-inflammatory agents COX-2 inhibitors Gastro intestinal safety study GUSAR Molecular modelling ABSTRACT Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Cyclooxygenase-2 (COX-2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti-inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID-4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4-Dimethylaminopyridine (DCC/ DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure-Activity Relationships) software. The study indicated most of the compounds under safe category. In- vitro pharmacological assessment of heterocyclic compounds was done for COX-1 and COX-2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti-inflammatory activity and ED 50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX-2 enzyme. The pharmacological screening uncovered that compound substituted with p- bromophenyl indicated maximum potency. 1. Introduction Anti-inflammatory drugs are used to treat pain and inflammation associated with musculoskeletal muscle and joints. Inflammation is a result of an increase in the level of prostanoids which are also responsible for the protection of the gastric mucosal membrane (Kalgutkar et al., 2002). Cyclooxygenase (COX) enzyme is involved in the rate-limiting step for the synthesis of different prostaglandins and thromboxanes from arachidonic acid (Marnett et al., 1999). The COX-1 enzyme is responsible for the cytoprotection and the COX-2 enzyme is inducible and responsible for the biosynthesis of Prostaglandins in inflammatory tissues (Dogné et al., 2006; Kalgutkar et al., 2002; Marnett et al., 1999). Unfortunately, anti-inflammatory agents dis- covered till now suffer from major side-effects. Classical NSAIDs are associated with adverse effects like gastric ulceration, hepatotoxicity, anemia etc. In order to overcome these side effects various selective COX-2 inhibitors were discovered. As a result, celecoxib (Celebrex®) (Penning et al., 1997), rofecoxib (Vioxx®), (Prasit et al., 1999) valdecoxib (Kalgutkar et al., 2000) and etoricoxib (Riendeau et al., 2001) were marketed as selective COX-2 inhibitors for the treatment of inflammation (Bansal et al., 2014). However, in the year 2004, Merck & Co., voluntarily withdrawn rofecoxib from the market due to severe cardiovascular adverse events. The adverse cardiovascular toxicity related to selective COX-2 inhibitors is due to the increased level of TXA 2 in platelet (Patrono and Baigent, 2014). Kalgutkar et al. synthe- sized various derivatives of classical NSAIDs (Aljadhey et al., 2010). They have synthesized various amide and ester derivatives of meclo- fenamic acid and indomethacin, which showed selectivity for the COX- 2 enzyme. There are several reports which revealed that derivative preparation of well-known NSAIDs showed better results (Kalgutkar et al., 2000; Talley et al., 2000; Woods et al., 2001). Moreover, the gastric irritation associated with NSAIDs and COX-2 inhibitors is free of the route of the administration totally, mitigating any rationalization that removing the carboxylic acid moiety would bring about less gastro- http://dx.doi.org/10.1016/j.ejphar.2017.02.051 Received 8 February 2017; Received in revised form 27 February 2017; Accepted 28 February 2017 ⁎ Corresponding author. E-mail address: Jignasasavjani@gmail.com (J.K. Savjani). European Journal of Pharmacology xxx (xxxx) xxx–xxx 0014-2999/ © 2017 Elsevier B.V. All rights reserved. Please cite this article as: Savjani, J.K., European Journal of Pharmacology (2017), http://dx.doi.org/10.1016/j.ejphar.2017.02.051