Discovery of novel Methylsulfonyl phenyl derivatives as potent human Cyclooxygenase-2 inhibitors with effective anticonvulsant action: Design, synthesis, in-silico, in-vitro and in-vivo evaluation

• Published in: European journal of medicinal chemistry 2018-05, Vol.151, p.520-532
• Main Authors: Mishra, Chandra Bhushan, Kumari, Shikha, Prakash, Amresh, Yadav, Rajesh, Tiwari, Ankit Kumar, Pandey, Preeti, Tiwari, Manisha
• Format: Article
• Language: English
• Subjects: Anti-convulsant; COX-2 Inhibitor; Epilepsy; Kindling; Sc-PTZ; Toxicity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.007

A novel series of methylsulfonyl phenyl derivatives has been designed and synthesized to evaluate their COX-2 inhibitory activity along with anti-convulsant potential. In-vitro evaluation revealed that two compounds MTL-1 and MTL-2 appeared as most potent and selective COX-2 inhibitors in the entire series. Anti-convulsant activity of both potent COX-2 inhibitors was assessed in sc-PTZ induced seizure test and MTL-1 excellently protected animals against PTZ induced seizure at the dose of 30 mg/kg. MTL-1 also indicates long duration of action in time course study and displayed significant seizure protection up to 6 h of drug administration. Further, the anti-epileptogenic effect of MTL-1 has been examined in PTZ induced chronic model of epilepsy. The results indicated that MTL-1 had a significant anti-epileptogenic effect in PTZ kindled rats as compared to Etoricoxib (ETX) and PTZ alone treated group. Additionally, MTL-1 successfully improved cognition deficit in PTZ kindled rats, which was confirmed by social recognition, novel object recognition and light-dark chamber tests. Moreover, molecular docking and molecular simulation (MD simulation) studies were also performed to elucidate the interaction of MTL-1 with the active site of COX-2 and results showed that MTL-1 suitably binds within active site of COX-2. To investigate the safety profile of MTL-1, a sub-acute toxicity study was also performed and MTL-1 emerged as a new non-toxic chemical entity. Thus, the present investigation discovered a potent and safe COX-2 inhibitor, which is endowed with an effective anti-epileptic action. [Display omitted] •MTL-1 has appeared as selective and potent COX-2 inhibitor in the entire series.•MTL-1 successfully protected animals from sc-PTZ induced seizure.•In chronic model of epilepsy, MTL-1 also showed excellent anti-epileptic activity.•MTL-1 nicely interacted with the active site of COX-2 which was confirmed by molecular docking and MD simulation studies.•It also improved cognition impairment in kindled rats and appeared non toxic in sub-acute toxicity study.