SYNTHESIS AND DOCKING STUDIES OF 2-(NITROOXY) ETHYL-4-(2-(SUBSTITUTED PHENYL)-4-(SUBSTITUTE DPHENYL)-1H-IMIDAZOL-1-YL) BENZOATE AS ANTI-INFLAMMATORY, ANALGESIC AND NITRIC OXIDE RELEASING AGENTS
Objective: The objective of the present study was to develop potent and non toxic Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) by using heterocyclic nuclei and having Nitric Oxide releasing group.
Methods: The compounds were designed with the help of docking studies. In the synthetic study, the target compounds were obtained by reacting substituted diphenyl imidazole benzoic acid (2a-2x) with nitro-oxy alkyl bromide in the presence of dimethyl formamide and potassium carbonate to give substituted 2,4-diphenyl nitric oxide releasing imidazole derivatives (3a-3x). The synthesized compounds were characterized with the help of different analytical studies and further evaluated for anti-inflammatory, analgesic and nitric oxide releasing activity.
Results: In the docking study compounds 3a, 3b, 3c, 3e, 3r and 3s showed significant G-score. In the anti-inflammatory and analgesic study compounds 3a, 3b, 3c, 3e, 3r and 3s exhibited promising activity. All the synthesized compounds exhibited significant nitric oxide releasing properties both in-vitro and in-vivo.
Conclusion: Compounds 3a, 3b, 3c, 3e, 3r and 3s exhibited prominent anti-inflammatory and analgesic activity.
2. Bias P, Buchner A, Klesser B, Laufer S. The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from a randomized, controlled trial. Am J Gastroenterol 2004;99:611-8.
3. Doggrell SA. The safety of lumiracoxib when used in the treatment of arthritis. Expert Opin Pharmacother 2005;6:347-50.
4. Velazquez C, Rao PNP, McDonald R, Knaus EE. Synthesis and biological evaluation of 3,4-diphenyl-1,2,5-oxadiazole-2-oxidesand 3,4-diphenyl-1,2,5-oxadiazolesas potential hybrid COX-2inhibitor/nitric oxide donor agents. Bioorg Med Chem 2005;13:2749-57.
5. Lombardino JG, Wiseman EH. Preparation and anti-inflammatory activity of some non acidic trisubstituted imidazoles. J Med Chem 1974;17:1182-8.
6. Sharpe TR, Cherkofsky SC, Hewes WE, Smith DH, Gregory WA, Haber SB, et al. Preparation and antiarthritic and analgesic activity of 4,5-diaryl-2-(substituted thio)-1 H-imidazoles and their sulfoxides and sulfones. J Med Chem 1985;28:1188-94.
7. Khanna IK, Weier RM, Yu Y, Xu XD, Koszyk FJ, Collins PW, et al. 1, 2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents. J Med Chem 1997;40:1634-47.
8. Baumann M, Baxendale IR, Ley SV, Nikbin N. An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J Org Chem 2011;7:442-95.
9. Adib M, Ansari S, Feizi S, Damavandi JA, Mirzaei P. A one-pot, four-component synthesis of N-substituted 2,4-diarylimidazoles. Synlett 2009;20:3263-6.
10. Shan R, Velazquez C, Knaus EE. Syntheses, calcium channel agonist-antagonist modulation activities, and nitric oxide release studies of nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate racemates, enantiomers, and diastereomers. J Med Chem 2004;47:254-61.
11. Kaur J, Bhardwaj A, Huang Z, Narang D, Chen TY, Plane F, et al. Synthesis and biological investigations of nitric oxide releasing nateglinide and meglitinide type II antidiabetic prodrugs: in-vivo antihyperglycemic activities and blood pressure lowering studies. J Med Chem 2012;55:7883-91.
12. Winter CA, Risley EA, Nuss GN. Carrageenan induced edema in hind paw of the rats as an assay for anti-inflammatory drugs. Proc Soc Exp Biol 1962;111:544-7.
13. Koster R, Anderson M, de Beer EJ. Acetic acid for analgesic screening. Fed Proc 1959;18:412-6.
14. Calderone V, Martinotti E, Scatizzi R, Pellegrini A, Breschi MC. A modified aortic multiple-ring preparation for functional studies. J Pharmacol Toxicol Methods 1996;35:131-8.
15. Abadi AH, Hegazy GH, El-Zaher AA. Synthesis of novel 4-substituted-7-trifluoromethylquinoline derivatives with nitric oxide releasing properties and their evaluation as analgesic and anti-inflammatory agents. Bioorg Med Chem 2005;13:5759-65.
16. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.