title: Design, synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach.
abstract: A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC500.60-1.11μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
authors.forename: Anupam G
authors.initials: AG
authors.lastname: Banerjee
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India; Department of Pharmaceutical Sciences, Assam University, Silchar 788 011, India.
authors.forename: Nirupam
authors.initials: N
authors.lastname: Das
authors.affiliation: National Toxicology Centre, Vadgaon Khurd, Sinhagad Road, Pune 411 041, India.
authors.forename: Sushant A
authors.initials: SA
authors.lastname: Shengule
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
authors.forename: Piyoosh A
authors.initials: PA
authors.lastname: Sharma
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
authors.forename: Radhey Shyam
authors.initials: RS
authors.lastname: Srivastava
authors.affiliation: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India. Electronic address: skshrivastava.phe@iitbhu.ac.in.
authors.forename: Sushant Kumar
authors.initials: SK
authors.lastname: Shrivastava
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014456:Ulcer / Q000139:chemically induced / Q000188:drug therapy
chemical_list: C000620934:5,6-diphenyl-1,2,4-triazin-3(2H)-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D014227:Triazines; D002351:Carrageenan; D051546:Cyclooxygenase 2
keywords: 1,2,4-triazine; 1,3,4-oxadiazole; 1,3,4-thiadiazole; COX-2; Cardiotoxicity; Molecular hybridisation