Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies

Mihaela-Liliana Tîntas (1) , Vincent Gembus (2) , F. Alix (2) , A. Barré (3) , Gaël Coadou (1) , Lina Truong (1) , Muriel Sebban (1) , Cyril Papamicaël (1) , Hassan Oulyadi (1) , Vincent Levacher (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 VFP Therapies Drugs : Highway to the Brain
3 inconnu

Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.

Mots clés: Dual-binding site inhibitor; Alzheimer; Acetylcholine esterase inhibitors

Domaines: Chimie

Mihaela-Liliana Tîntas, Vincent Gembus, F. Alix, A. Barré, Gaël Coadou, et al.. Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies. European Journal of Medicinal Chemistry, 2018, 155, pp.171-182. ⟨10.1016/j.ejmech.2018.05.057⟩. ⟨hal-02024536⟩