A quantitative structure-activity relationship study for α-substituted acetamido-N-benzylacetamide derivatives — A novel anticonvulsant drug class

Abstract

A library of 35 benzylacetamide derivatives was evaluated for anticonvulsant activity as reflected in the ED50 (mg/kg) required to suppress seizure activity in the maximal electroshock seizure (MES) test. Using the method of partial least-squares regression in conjunction with cross-validation, the influence of 31 topological, electronic, physico chemical, and structural properties on anticonvulsant activity was investigated. A QSAR model of the logED50 in the MES test was established (R2adj = 0.77) as a function of the following seven properties: the Wiener index on distance code (Wmean), the mean information index on atomic composition (rIac), the partial charge at the C-terminal carbonyl carbon (qCC), the sum of partial charges in the α substituent (qαtotal), the number of hydrogen bond donors and acceptors in the α substituent (Hdα and Haα), and the calculated value of the squared n-octanol/water partition coefficient. Based on this model, two new amido ketone compounds — (R,S)-2-acetamido-5-phenyl-3-pentanone and cis/trans-(R,S)-2-acetamido-5-phenyl-4-penten-3-one — were synthesized and shown to have significant anticonvulsant activity in the MES test.Key words: QSAR, anticonvulsant, benzylacetamide, functionalized amino acid, amido ketones.