Wu_2026_J.Enzyme.Inhib.Med.Chem_41_2623314

Thymol, an isomer of carvacrol, exhibits anti-Abeta 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 IC(50) values of 13, 3.6, 47, and 12 nM. TC-6 bearing a piperidinyl moiety demonstrated nanomolar hBuChE inhibition (IC(50) = 3.6 nM), >2,500-fold selectivity over hAChE, and pseudo-irreversible kinetics (K(d) = 0.25 microM, k(2) = 0.98 min(-1)). TC-6 exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H(2)O(2)-induced damage. In Abeta(1-42)-induced AD mice, TC-6 (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain Abeta levels, and restored hippocampal neuron density. These results highlight TC-6 as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.