title: Design, synthesis and biological evaluation of some novel benzimidazole derivatives for their potential anticonvulsant activity.
abstract: Selective GABA(A) receptor ligands are widely used clinically to reduce the occurrence of convulsions. Hence there is an intense interest in developing new benzimidazole derivatives demonstrating high selectivity and high affinity for GABA(A) receptors. With the purpose of designing new chemical entities with an enhanced binding affinity for GABA(A)/BZd receptor complex, we carried out a QSAR study on benzotriazine derivatives. We studied 28 potent GABA(A) receptor ligands; derivatives of benzotriazines, using a combination of various tested physicochemical, steric, electronic and thermodynamic descriptors to determine the quantitative correlation between binding affinity and structural features. The developed and validated final model showed a good correlative and predictive ability expressed by a squared correlation co-efficient (r(2)) of 0.954. The equation indicated that the binding affinity is strongly dependent upon the thermodynamic properties (CDE, DDE and PC). Correlation between these properties and anticonvulsant activity was used to synthesize compounds possessing potent anticonvulsant activity. Most of the compounds showed an ability to inhibit the maximum electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Compound 1A, i.e. 2-(4-Chloro-phenyl)-5-nitro-1H-benzimidazole exhibited maximum activity in both the convulsion models.
authors.affiliation: Department of Pharmaceutical Chemistry, VNS Institute of Pharmacy, Bhopal, MP, India.
authors.forename: Priyal
authors.initials: P
authors.lastname: Jain
authors.forename: Prakash Kumar
authors.initials: PK
authors.lastname: Sharma
authors.forename: Harish
authors.initials: H
authors.lastname: Rajak
authors.forename: Rajesh Singh
authors.initials: RS
authors.lastname: Pawar
authors.forename: Umesh Kumar
authors.initials: UK
authors.lastname: Patil
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Singour
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000627:therapeutic use*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004597:Electroshock / Q000379:methods; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D001562:Benzimidazoles; C031000:benzimidazole