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

The
genetic disorder glucose transporter type 1 deficiency syndrome
(GLUT1-DS) heavily affects the main intake of energy in tissues and
determines the most relevant outcomes at the central nervous system
(CNS) district, which is highly dependent on glucose. Herein, we report
the design and development of a set of compounds bearing the glucosyl
and galactosyl moieties. We assessed their ability to enhance the
GLUT1 mediated glucose intake in non-small-cell lung cancer (NSCLC)
cells and to inhibit the carbonic anhydrase (CA; EC 4.2.1.1) isoforms
implicated in the physiopathology of uncontrolled seizures associated
to 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 effective
in suppressing the occurrence of uncontrolled seizures on the in vivo induced maximal electroshock (MES) model and thus
gives sustainment of an unprecedently reported pharmacological approach
for the management of GLUT1-DS associated diseases.