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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.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 May 10; Vol. 151, pp. 520-532. Date of Electronic Publication: 2018 Apr 04. - Publication Year :
- 2018
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Abstract
- 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.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Anticonvulsants pharmacology
Cyclooxygenase 2 metabolism
Cyclooxygenase 2 Inhibitors pharmacology
Drug Design
Epilepsy chemically induced
Epilepsy drug therapy
Epilepsy enzymology
Humans
Male
Methylation
Molecular Docking Simulation
Pentylenetetrazole
Rats
Rats, Wistar
Seizures chemically induced
Seizures enzymology
Sulfinic Acids chemistry
Sulfinic Acids pharmacology
Sulfinic Acids therapeutic use
Anticonvulsants chemistry
Anticonvulsants therapeutic use
Cyclooxygenase 2 Inhibitors chemistry
Cyclooxygenase 2 Inhibitors therapeutic use
Seizures drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 151
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29655084
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.04.007