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-A<i>β</i> activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, <b>TC-4</b>, <b>TC-6</b>, <b>H4</b> and <b>H5</b> bearing cyclic amines exhibited nanomolar inhibitory activity with IC₅₀ values of 13, 3.6, 47, and 12 nM. <b>TC-6</b> bearing a piperidinyl moiety demonstrated nanomolar <i>h</i>BuChE inhibition (IC₅₀ = 3.6 nM), >2,500-fold selectivity over <i>h</i>AChE, and pseudo-irreversible kinetics (<i>K</i>_d = 0.25 μM, <i>k</i>₂ = 0.98 min^-1). <b>TC-6</b> exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H₂O₂-induced damage. In A<i>β</i>_1-42-induced AD mice, <b>TC-6</b> (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain A<i>β</i> levels, and restored hippocampal neuron density. These results highlight <b>TC-6</b> as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.