Exploration of the Isosteric Concept Applied to 1,2,4-Benzothiadiazine 1,1-Dioxides in the Discovery of Novel AMPA Receptor Positive Allosteric Modulators

The present study aims to highlight the impact on biological activity of the application of the isosteric concept to 1,2,4-benzothiadiazine 1,1-dioxides (BTDs) reported as AMPA receptor positive allosteric modulators (AMPAR PAMs). In a previous work, thiochroman 1,1-dioxides were designed as AMPAR PAMs by removing the two nitrogen atoms of the thiadiazine ring, a first pharmacomodulation process that led to encouraging results. In this study, another pharmacomodulation approach was employed to assess the impact of removing only one of the two nitrogen atoms of the thiadiazine ring providing two new series of candidates: 1,2-benzothiazine 1,1-dioxides and 1,4-benzothiazine 1,1-dioxides. Moreover, the isosteric concept between the carboxamide and the sulfonamide function was also explored leading to quinazolinone analogues of BTDs. The biological data revealed that 1,4-benzothiazine 1,1-dioxides appeared to be the most promising isosteres of BTDs since a significant AMPAR potentiation activity was observed with representative compounds. Among them, the chloro-substituted compound 25b demonstrated the highest activity, being the closest structural analogue of the well-known BTD AMPAR potentiator BPAM121. On the other hand, none of the 1,2-benzothiazine 1,1-dioxides and the quinazolinones studied were found to exert a significant AMPAR potentiation activity. In conclusion, activity on AMPARs can be retained with compounds where the nitrogen atoms at the 2-position (1,4-benzothiazine 1,1-dioxides) or at the 2,4-positions (thiochroman 1,1-dioxides) of BTDs was replaced by one or two carbon atoms. Further investigations are required to explore additional structural modifications that could improve biological activity.