Abstract
A series of novel N-(2-(benzylamino)-1-substituted-2-oxoethyl)-4-(1,3-dioxoisoindolin-2-yl)butanamide derivatives were synthesized unifying the functionalized amino acid unit and GABA–phthalimide moiety with essential amino acid substituted on it with a view to explore prospective anticonvulsant candidates. The initial screening was performed using the intraperitoneal (i.p) maximal electroshock test and sub-cutaneous Pentylenetetrazole (scPTZ) test in mice. The neurotoxicity was determined by the minimal motor impairment based on rotarod test. The outcomes established the ability of the compounds to suppress the convulsions generated by electrical seizures. The scPTZ test provided insignificant activity profile. The leads of initial screening (4a, 4e and 4g) were subjected to the quantification studies in mice (i.p) and rats (p.o). The quantitative study in mice depicted an increase of 1.7-, 2.3- and 4-fold over phenytoin in the protective index, the keystone in the drug discovery for the anticonvulsant activity. The PI values in rat oral administration were 13.33, >145 and >100 for these compounds, respectively. The gamma-amino butyric acid level in the different brain regions also increased on administration of the active compounds with 4g providing the maximum increment. These results encourage our future investigation on the rational modification of this basic framework for better potency.
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Acknowledgments
The authors extend their gratitude Jamia Hamdard, New Delhi, India for providing research facilities and Shrenik Pharma Ltd., Mumbai for providing gift sample of Pentylenetetrazole.
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Ahuja, P., Husain, A. & Siddiqui, N. Essential aminoacid incorporated GABA–phthalimide derivatives: synthesis and anticonvulsant evaluation. Med Chem Res 23, 4085–4098 (2014). https://doi.org/10.1007/s00044-014-0949-5
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DOI: https://doi.org/10.1007/s00044-014-0949-5