Synthesis of new sulfoximines and sulfonimidamides derivatives as NKCC1 inhibitors

The Na-K-2Cl cotransporter isoform 1 (NKCC1) regulates cell volume and ionic distribution, thereby also controlling the efficacy of neuronal GABAergic inhibition. enhanced activity of the NKCC1 chloride importer and high Cl. levels has been reported in a long list of disorders, including epilepsies, brain trauma, peripheral and central cancers, spinal cord injury or chronic pain, and cerebrovascular infarcts, indicating that NKCC1 inhibitors might constitute promising therapeutic avenues. Synthetized four decades ago, bumetanide constitutes the only agent that is widely used in animal models and human trials, limiting the possibility to assign some NKCC1 inhibitors specifically to treat some disorders.

Here, we have synthetized many novel NKCC1 inhibitors to augment the range of molecules that can be tested in animal models and pre-IND tests. We used modifications of the bumetanide parent molecule by modifying two sites with alterations that have not been envisaged before. Specifically, we incorporated carboxylic acid bioisosteres and sulfonimidamides or sulfoximines moieties. Their efficacy was evaluated against NKCC1, NKCC2, and KCC2 using human cell lines.

The synthesis of the new inhibitors and the structure-activity relationship (SAR) are described. Some molecules are superior to bumetanide as NKCC1 inhibitors, which widens the family of NKCC1 inhibitors and paves the way for more efficient agents. Our aims here are solely chemical, namely, describing the possible targets of the bumetanide molecule that can be changed using novel approaches. In the future, we and others will test these molecules in animal models and clinical trials to validate the use of some of them in treating a variety of disorders.