Design-led synthesis and multidimensional evaluation of novel thiadiazoles as multitarget anti-Alzheimer agents: kinetics, DFT and in silico mapping.

A novel series of thiadiazole-based Schiff base derivatives (1-16) was synthesized via an efficient multi-step route and characterized using 1H NMR, 13C NMR, and HREI-MS. These compounds were evaluated for their anti-Alzheimer's and anti-urease potential. Among them, compounds 8 and 9 exhibited the most potent inhibition with IC₅₀ values of 6.60 ± 0.40 and 8.10 ± 0.10 μM for AChE, 7.40 ± 0.20 and 8.80 ± 0.40 μM for BChE, and 9.75 ± 1.60 and 10.15 ± 0.50 μM for urease, respectively. Donepezil and thiourea were used as standard inhibitors for comparative evaluation. Molecular docking and pharmacophore modeling supported the inhibitory potential of these compounds. ADMET profiling confirmed favorable drug-likeness and pharmacokinetic properties, while DFT and molecular dynamics simulations validated their stability and reactivity. These results highlight compounds 8 and 9 as promising leads for further development as multifunctional therapeutic agents against Alzheimer's disease and urease-related pathologies.