Synthesis of 3-Carboxy-6-sulfamoylquinolones and Mefloquine-Based Compounds as Panx1 Blockers: Molecular Docking, Electrophysiological and Cell Culture Studies

The membrane channel protein Panx1 is a promising therapeutic target since its involvement was demonstrated in a variety of pathologies such as neuropathic pain, ischemic stroke and cancer. As a continuation of our previous work in this field, we report here the synthesis and biological evaluation of two classes of compounds as Panx1 blockers: 3-carboxy-6-sulphonamidoquinolone derivatives and new Mefloquine analogs. The series of 3-carboxy-6-sulphonamidoquinolones gave interesting results, affording powerful Panx1 channel blockers with 73.2 < I% < 100 at 50 µM. In particular, <b>12f</b> was a more potent Panx1 blocker than the reference compound CBX (IC₅₀ = 2.7 µM versus IC₅₀ = 7.1 µM), and its profile was further investigated in a cell culture model of polycystic kidney disease. Finally, interesting results have been highlighted by new molecular modeling studies.