title: Design, synthesis and pharmacological evaluation of N-[4-(4-(alkyl/aryl/heteroaryl)-piperazin-1-yl)-phenyl]-carbamic acid ethyl ester derivatives as novel anticonvulsant agents.
abstract: A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30mg/kg (0.5h) and 100mg/kg (4h) and also delivered excellent protection in sc-PTZ test (100mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule.
authors.affiliation: Bio-Organic Chemistry Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi 110007, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Bio-Organic Chemistry Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi 110007, India.
authors.forename: Chandra Bhushan
authors.initials: CB
authors.lastname: Mishra
authors.affiliation: Bio-Organic Chemistry Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D010433:Pentylenetetrazole; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010879:Piperazines; D000077489:Piperazine; C070766:carbamic acid; D010433:Pentylenetetrazole
keywords: Anticonvulsant; Epilepsy; Kindling; Oxidative stress; Piperazine