Background: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy had been almost the exclusive strategy for identifying the marketed compounds. However, the actual structural and functional information about the molecular targets of the anticonvulsant drugs, and the increasing knowledge of the molecular alterations that generate epileptic seizures, allow a more rational identification of active compounds. Objective: This review compiles target-based strategies used for the discovery of new anticonvulsant candidates and is divided into two main topics. The first one provides an overview of the computational approaches (docking-based virtual screening and molecular dynamics) to find anticonvulsant structures that interact with the voltage-gated ion channels and the enzyme carbonic anhydrase. The second one includes the analysis of active compounds synthesized to act simultaneously on different molecular targets by a combination of pharmacophores of anticonvulsant drugs. Conclusion: Current knowledge of the architectures of anticonvulsant targets makes computational simulations attractive methods for the discovery and optimization of active compounds. Combining the results achieved by virtual screening on different targets could lead to multitarget compounds as an alternative to the design of structures that merge scaffolds of known drugs.

The study of tautomerism has gained relevance in the scientific community because several cellular processes occur through different tautomeric forms of certain compounds. The percentage of each tautomer in compounds with tautomerism capability depends on numerous factors, such as temperature and solvent polarity, among others; and, by changing the external conditions, equilibrium displacement can be established very quickly. This manuscript deals with nitrile-ketenimine tautomerism in some unsaturated malononitriles. This kind of compounds with two nitrile groups conjugated to a double bound is able to rearrange accessible hydrogens and provide new and complex structures of different functionalities. The authors' motivation for investigating these compounds lies in understanding their tautomeric behavior in solution and gas phases and to predict reaction deportment to then account for the final products obtained. Four unsaturated malononitriles were synthesized to study the substituent effect on equilibrium displacement. Characterization was performed using nuclear magnetic resonance (NMR) and tautomeric equilibrium in gas phase was evaluated by mass spectrometry. Correlation with theoretical calculations was carried out in order to comprehend the system behavior.