Acta Pharm. 66 (2016) 353-372
Original research paper
Design, synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant
agent
ASHOK K. SHAKYA, MEHNAZ KAMAL, VISHAL M.
BALARAMNAVAR, SANNA K. BARDAWEEL, RAJASHRI R. NAIK, ANIL K. SAXENA and H. H.
SIDDIQUI
ashokshakya@hotmail.com;
ak_shakya@ammanu.edu.jo
1 Faculty of
Pharmacy and Medical Sciences, Al-Ahliyya Amman
University, Amman, 19328, Jordan
2 Faculty of
Pharmacy, Integral University, Kursi Road, Lucknow 226026 (U. P.), India
3 Department of Pharmaceutical Chemistry, College of
Pharmacy (Female Section), Prince Sattam Bin Abdulaziz University, Al-Kharj
11942, Kingdom of Saudi Arabia
4 Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow-226001 (U. P.), India
5 Dept. of
Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and
Research, Kashipur, Uttarakhand
244713 India
6 Faculty of Pharmacy, The University of Jordan, Amman,
Jordan
Accepted February 5, 2016
Published online May 6,
2016
A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran-3-yl)-2-(substituted) acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All the synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg–1 body mass during 0.5–4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, compounds 5i [N-(2-(4-chlorobenzoyl)-benzofuran-3-yl)-2-(cyclohexyl(methyl)amino)-acetamide] and 5c [N-(2-(4-chlorobenzoyl)-benzofuran-3-yl)-2-(4-methylpiperidin-1-yl)acetamide] demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas compound 5f [(N-(2-(4-chlorobenzoyl)-benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl) acetamide] exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg–1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg–1 (~23.4 to 127.6 mg kg–1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.
Keywords: benzofuran, anticonvulsant,
neurotoxicity, GABA-AT, pharmacophore modeling, docking, Molegro Virtual Docker 4.0