title: Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents.
abstract: A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a-k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a-k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4thh, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC50 values.
authors.affiliation: Department of Pharmaceutical Chemistry, K.L.E.U's College of Pharmacy, Vidyanagar, Hubli 580 031, Karnataka, India; Department of Pharmaceutical Chemistry, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa. Electronic address: palkarmahesh4u@rediffmail.com.
authors.forename: Mahesh B
authors.initials: MB
authors.lastname: Palkar
authors.affiliation: Department of Pharmaceutical Chemistry, K.L.E.U's College of Pharmacy, Vidyanagar, Hubli 580 031, Karnataka, India.
authors.forename: Anuj S
authors.initials: AS
authors.lastname: Singhai
authors.affiliation: Department of Pharmaceutical Chemistry, K.L.E.U's College of Pharmacy, Vidyanagar, Hubli 580 031, Karnataka, India.
authors.forename: Pradeepkumar M
authors.initials: PM
authors.lastname: Ronad
authors.affiliation: Department of Pharmacology, K.L.E.U's College of Pharmacy, Vidyanagar, Hubli 580 031, Karnataka, India.
authors.forename: A H M
authors.initials: AH
authors.lastname: Vishwanathswamy
authors.affiliation: Department of Pharmacology, Shri Siddaganga College of Pharmacy, Tumkur 572 102, Karnataka, India.
authors.forename: Thippeswamy S
authors.initials: TS
authors.lastname: Boreddy
authors.affiliation: Department of Pharmacology, Shri Siddaganga College of Pharmacy, Tumkur 572 102, Karnataka, India.
authors.forename: Veeresh P
authors.initials: VP
authors.lastname: Veerapur
authors.affiliation: Department of Pharmaceutical Chemistry, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa.
authors.forename: Mahamadhanif S
authors.initials: MS
authors.lastname: Shaikh
authors.affiliation: Department of Pharmaceutical Chemistry, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Rane
authors.affiliation: Department of Pharmaceutical Chemistry, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa. Electronic address: karpoormath@ukzn.ac.za.
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Karpoormath
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: 1,3,4-Oxadiazole; Analgesic; Anti-inflammatory; Cyclooxygenase (COX); Diclofenac; Docking; Mannich base; NSAIDs; Ulcerogenic