DESIGN, SYNTHESIS AND ANTICONVULSANT PROFILE OF 5-(BENZO [D][1,3]DIOXOL-5-YL)-3-TERT-BUTYL-4, 5-DIHYDROPYRAZOLE DERIVATIVES

摘要

Objective: Utilisation of the ligand-based design and molecular hybridization to design promising candidates with prospective efficacy and safety. Synthesis of the designed candidates using different synthetic methods. Biological evaluation of the newly synthesised candidates as anticonvulsant agents. Methods: Three novel series of 5-(benzo[d][1,3]dioxol-5-yl)-3- tert -butyl-4,5-dihydropyrazoles have been designed via ligand-based drug discovery and molecular hybridization. Proper synthetic routes have been followed in the preparation of compounds (2-23) which have been characterised by different spectral techniques. Antiepileptic potential was assessed by biological evaluation using ‘classical’ animal models of epilepsy, in addition to rotarod test for toxicity. Results : 4-Nitrophenyl derivatives (5, 13, and19) displayed the highest potency. Compound 5was the most active substituent in series A (N'-aroyl-3- tert -butyl-4,5-dihydro-1 H -pyrazole-1-carbohydrazide). It was 2.7 and 1.3 times more active than reference drug Stiripentol (I) and lead compound III, respectively. Compound13 was the best candidate in series B (N'-arylidene-3- tert -butyl-4,5-dihydro-1 H -pyrazole-1-carbohydrazide). It was 3.3, 1.5, and 1.2 times more potent than Stiripentol, lead compound III and new compound 5, respectively. Two members (19 and 21) of series C (1,3,4-oxadiazole derivatives) achieved 100 % protection at lower doses than I and III, being 2.6 and 2.4 times more active than Stiripentol. In sc PTZ screen, the most active congeners (5, 13, 19) exhibited ED 50 values of 45, 48, and 81 mg/kg, respectively, which are highly superior as compared to that of reference drug Stiripentol(I) and lead compound III (ED 50 115 and 110 mg/kg, respectively). Conclusion : Ligand-based design together with molecular hybridization in drug design succeeded to produce potent and wide spectrum candidates.