Molecular docking-based design of novel tricyclic tetrahydropyridothienopyrimidinone derivatives as AChE/MAO-B dual inhibitors.

The present study describes the design, synthesis, and evaluation of novel tricyclic tetrahydropyridothienopyrimidinone (THPTP) derivatives as dual AChE/MAO-B inhibitors. Building on our previous hit A03, an additional benzyl substituent was added to improve interactions with the peripheral anionic site of AChE and enhance MAO-B binding. The derivatives showed increased inhibitory activities, with compound A03-12 exhibiting significant potency (huAChE: IC₅₀ = 0.14 µM, huMAO-B: IC₅₀ = 0.52 µM). Kinetic studies and molecular simulations revealed distinct binding interactions, supporting its mixed-type AChE inhibition and competitive MAO-B inhibition. Compound A03-12 also demonstrated high metabolic stability, better pharmacokinetic parameters, favorable blood-brain barrier permeability, and low cytotoxicity (CC₅₀ > 100 µM). These results offer a promising chemical template, especially compound A03-12, as a potential lead for designing new anti-AD drugs.