title: Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents.
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 ED50value 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.
authors.affiliation: Institute of Pharmacy, Nirma University, S.G.Highway, Ahmedabad, Gujarat 382481, India. Electronic address: Jignasasavjani@gmail.com.
authors.forename: Jignasa K
authors.initials: JK
authors.lastname: Savjani
authors.affiliation: Beiersdorf. Nivea India, plot no: SM-9/1, Sanand-2, Industrial Estate, Ahmedabad, Gujarat 382110, India.
authors.forename: Suja
authors.initials: S
authors.lastname: Mulamkattil
authors.affiliation: Institute of Pharmacy, Nirma University, S.G.Highway, Ahmedabad, Gujarat 382481, India; Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India.
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Variya
authors.affiliation: Institute of Pharmacy, Nirma University, S.G.Highway, Ahmedabad, Gujarat 382481, India.
authors.forename: Snehal
authors.initials: S
authors.lastname: Patel
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D008528:Mefenamic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008528:Mefenamic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: Acute toxicity study; Anti-inflammatory agents; COX-2 inhibitors; GUSAR; Gastro intestinal safety study; Molecular modelling