Thymol carbamates bearing cyclic amines as potent and selective BuChE inhibitors alleviate memory impairments for Alzheimer’s disease therapy

Thymol, an isomer of carvacrol, exhibits anti-Aβ activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, TC-4, TC-6, H4 and H5 bearing cyclic amines exhibited nanomolar inhibitory activity with IC50 values of 13, 3.6, 47, and 12 nM. TC-6 bearing a piperidinyl moiety demonstrated nanomolar hBuChE inhibition (IC50 = 3.6 nM), >2,500-fold selectivity over hAChE, and pseudo-irreversible kinetics (Kd = 0.25 μM, k2 = 0.98 min−1). TC-6 exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H2O2-induced damage. In Aβ1-42-induced AD mice, TC-6 (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain Aβ levels, and restored hippocampal neuron density. These results highlight TC-6 as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.