(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities

The (R)‐α‐lipoyl‐glycyl‐L‐prolyl‐L‐glutamyl dimethyl ester codrug (LA‐GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA‐GPE to penetrate the blood–brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA‐GPE against the cytotoxicity induced by 6‐hydroxydopamine (6‐OHDA) and H2O2 on the human neuroblastoma cell line SH‐SY5Y by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH‐dependent permeability profile. Furthermore, LA‐GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells. Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi‐target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties.