Synthesis, biological evaluation, molecular docking and theoretical evaluation of ADMET properties of nepodin and chrysophanol derivatives as potential cyclooxygenase (COX-1, COX-2) inhibitors

• Published in: European journal of medicinal chemistry Vol. 80; pp. 47 - 56
• Main Authors: Grover, Jagdeep, Kumar, Vivek, Singh, Vikram, Bairwa, Khemraj, Sobhia, M. Elizabeth, Jachak, Sanjay M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 10-06-2014
• Subjects: Absorption, Physicochemical; Animals; Anthraquinones - chemical synthesis; Anthraquinones - chemistry; Anthraquinones - metabolism; Anthraquinones - pharmacology; Anti-inflammatory; Catalytic Domain; Chemistry Techniques, Synthetic; Chrysophanol; COX inhibitors; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - metabolism; Female; Inhibitory Concentration 50; Molecular docking; Molecular Docking Simulation; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - metabolism; Naphthalenes - pharmacology; Nepodin; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Anti-inflammatory; Nepodin; Chrysophanol; Molecular docking; COX inhibitors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.04.033

Nepodin and chrysophanol, isolated from Rumex nepalensis roots, showed significant cyclooxygenase (COX) inhibitory activity. To further optimize these lead molecules and study structure activity relationship (SAR), eighteen derivatives of nepodin and nine derivatives of chrysophanol were synthesized and evaluated for COX-1 and COX-2 inhibitory potential. Among the synthesized compounds, four nepodin (1f, 1g, 1h and 1i) and three chrysophanol (2e, 2f and 2h) derivatives displayed more pronounced COX-2 inhibition than their respective lead molecule. Further, compounds 1f, 1g, 2e and 2h exhibited better anti-inflammatory activity than ibuprofen in carrageenan-induced rat paw edema assay. Taking into account the in vitro and in vivo results, molecular docking and in silico prediction of ADMET properties of compounds were carried out respectively.
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•Compounds 1f–i, 2e, 2f and 2i were found to be most potent in in vitro assay.•Compounds 1f, 1g and 2e displayed better anti-inflammatory activity than ibuprofen in vivo.•Compounds 1f displayed good ADMET profile, similar to naproxen.