Nicotinic acid hydrazones: a novel anticonvulsant pharmacophore

A series of aryl acid hydrazones of substituted aromatic acid hydrazides (D (1) to D (20)) were synthesised and evaluated for anticonvulsant activity. Aryl acid hydrazones of Nicotinic acid hydrazide (D (8), D (9), and D (10)) have displayed excellent protection in maximal electroshock screen. These compounds have also exhibited excellent binding properties with Lys 329 residue of gamma amino butyrate amino transferase (GABA-AT) in Lamarckian genetic algorithm based flexible docking studies. Compound D (8), N (1)-(4-chlorobenzylidene) nicotinohydrazide was found to be the most potent analog with ED50 value of 16.1 mg/kg and protective index (PI = TD50/ED50) value of > 20, which was much greater than that of the prototype drug phenytoin (PI = 6.9). It has shown free binding energy value of -10.20 kcal/mol and inhibition constant (Ki) value of 33.30 nM for GABA-AT, indicating that aryl acid hydrazones of nicotinic acid hydrazide could be considered as a new pharmacophore in the design of novel anticonvulsant drugs.