First-in-Class Dual Targeting Compounds for the Management of Seizures in Glucose Transporter Type 1 Deficiency Syndrome

Thegenetic disorder glucose transporter type 1 deficiency syndrome(GLUT1-DS) heavily affects the main intake of energy in tissues anddetermines the most relevant outcomes at the central nervous system(CNS) district, which is highly dependent on glucose. Herein, we reportthe design and development of a set of compounds bearing the glucosyland galactosyl moieties. We assessed their ability to enhance theGLUT1 mediated glucose intake in non-small-cell lung cancer (NSCLC)cells and to inhibit the carbonic anhydrase (CA; EC 4.2.1.1) isoformsimplicated in the physiopathology of uncontrolled seizures associatedto epilepsy (i.e., I, II, IV, VA, VB, and XII). The binding mode of 8 in adduct with hCA II was determined by X-ray crystallography.Among the selected derivatives, compound 4b proved effectivein suppressing the occurrence of uncontrolled seizures on the in vivo induced maximal electroshock (MES) model and thusgives sustainment of an unprecedently reported pharmacological approachfor the management of GLUT1-DS associated diseases.