Format

Send to

Choose Destination
Bioorg Chem. 2016 Dec;69:102-120. doi: 10.1016/j.bioorg.2016.10.003. Epub 2016 Oct 11.

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.

Author information

1
Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India.
2
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.
3
National Toxicology Centre, Vadgaon Khurd, Sinhagad Road, Pune 411 041, India.
4
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.

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 (IC50 0.60-1.11μM) 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.

KEYWORDS:

1,2,4-triazine; 1,3,4-oxadiazole; 1,3,4-thiadiazole; COX-2; Cardiotoxicity; Molecular hybridisation

PMID:
27750057
DOI:
10.1016/j.bioorg.2016.10.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center