Design, Synthesis and Anticonvulsant Profile of 5-(Benzo [D][1,3]dioxol-5-Yl)-3-Tert-Butyl-4, 5-Dihydropyrazole Derivatives

Abstract

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-1H-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-1H-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 scPTZ screen, the most active congeners (5,13,19) exhibited ED50 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 (ED50 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.

Enantioselective Separation of Chiral N1-Substituted-1H-pyrazoles: Greenness Profile Assessment and Chiral Recognition Analysis

“…Compounds from 1–18 have been synthesized according to the reported procedures by El-Behairy et al HPLC-grade solvents ( n -hexane, methanol, ethanol, and acetonitrile) were purchased from Sigma-Aldrich (St. Louis, MO, USA). HPLC enantioseparation was performed using the commercially available Lux amylose-2 [amylose tris­(5-chloro-2-methylphenylcarbamate)] and Lux cellulose-2 [cellulose tris­(3-chloro-4-methylphenylcarbamate)] (250 mm × 4.6 mm, 3 μm) columns (Phenomenex, Le Pecq, France).…”

“…An integrated understanding of the molecular bases in chiral recognition will be achieved via further investigations on diverse sets of compounds and chiral selectors. Thus, recent investigations on HPLC enantioseparation of chiral compounds on polysaccharide-based CSPs under versatile mobile phase composition were conducted and resulted in a better understanding of chiral recognition. − Compounds 1–18 have been synthesized in our group and showed promising biological activity . However, they have been tested in the racemic form; thus, it was of interest to estimate the biological activity of each enantiomer separately to study the impact of chirality on biological activity.…”

“…In the same vein, the potential of polysaccharide-based chiral columns (Lux amylose-2 and cellulose-2, Figure ) and different mobile-phase modes (normal and polar organic modes) in selectivity and recognition of enantiomers was investigated via the development of stereoselective HPLC separations of the anticonvulsant 4,5-dihydro-1 H -pyrazole derivatives ( 1–18 ) . Moreover, the developed stereoselective analytical HPLC techniques of 1–18 will be applied in the stereospecific pharmacological, pharmacokinetic, pharmacodynamic, and toxicological studies of the bioactive compounds ( 1–18 ).…”