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Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, <b>KA-11</b>, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely <b>KA-228</b> and <b>KA-232</b>, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), <i>sc</i>PTZ and <i>iv</i>PTZ. Among these compounds, <b>KA-232</b>, which was designed as a water-soluble salt, was distinctly more effective than <b>KA-228</b> and assured similar antiseizure protection as its chemical prototype <b>KA-11</b>. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, <b>KA-232</b> was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of <b>KA-11</b> enabled the identification of new pharmacologically active chemotypes, particularly water-soluble <b>KA-232</b>, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.