| In this research project, a library of uracil-based molecules was devised to target epilepsy therapy via a novel approach aiming at both ictogenesis and epileptogenesis. On the assumption that uracil analogs may be metabolized in vivo to potentially neuroprotective and antiepileptogenic beta-amino acid derivatives, multiple uracil analogs were synthesized and tested for biological activity in various animal models of inducedseizures. Although the results of 3-D QSAR studies by CoMFA and CoMSIA supported the hypothesis of metabolism activation, it was not possible to predict the biological activity of uracil derivatives from structures as the observed therapeutic effects were induced by the uracil derivative and/or metabolites.; Established literature procedures were adapted to the synthesis of various C6-, C5- and N-substituted uracil derivatives. Moreover, the development of two novel synthetic procedures allowed a convenient access to uncommon 5,5'-methylene-bis-uracil derivatives from acid-catalyzed reactions of C5-unsubstituted uracils with sulfoxides; and DBU-catalyzed reactions of these uracils and aldehydes.; The results of biological tests in various animal models indicate that several uracil derivatives outperform established anticonvulsant drugs in providing protection against chemically and electrically induced seizures. While carbamazepine and phenytoin offered 68.9% and 73.6% protective effects in the pilocarpine-induced seizure model, 1-benzyl-5-bromouracil (3a ), 6-butyl-2-thiouracil (5c), 5-bromo-1-para-nitrobenzyluracil (7e), and 3-benzoyl-1-benzyl-5-iodouracil (13b) provided 80.5%, 77.8%, 82.8% and 78.9% protective effects, respectively. In maximum electroshock- and pentylenetetrazole-induced seizure tests performed by the anticonvulsant screening project of the National Institute of Health where the ED50 and TD50 values were estimated and compared to data of established anticonvulsants, 1-benzyl-5-bromouracil (3a), 5-bromo-1-isopropyl (3b), and 1-benzyl-5-iodouracil (7d) presented overall better drug profiles.; Preliminary biological test results in animal models are very encouraging and suggest that uracil-based molecules have great potential as antiepileptic drug candidates that could become a life-saving alternative to current anticonvulsants that are associated with many side-effects and fail to offer relief to about one third of the patient population. Uracil-based drugs may therefore become the arsenal of choice in epilepsy management and therapy if the high therapeutic index observed in animal models could be repeated in clinical applications to humans. |
