A series of Z/E isomeric β-cycloalkoxyphosphonated hydrazones [R1R2C(CH2O)2P(=O)CH2-C{=Nsingle bondN(H)R5}C(H)R3R4] 3 bearing a six-membered dioxaphosphorinane ring was prepared, structurally analysed, and subjected to in silico studies to assess their Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) inhibition activity. Furthermore, their ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties were determined. Hydrazones 3 were prepared from their corresponding allenylphosphonates [R1R2C(CH2O)2P(=O)C(H)=C=CR3R4] 2 by addition of various hydrazines NH2single bondNHR5. Since NMR studies indicated the occurrence of several isomeric species in solution, conformational and configurational studies, based on mechanistic elucidation and energy stability using Density functional theory (DFT) calculation at the B3LYP/6-311 G++ (d,p) level of theory, were performed to determine their relative predominance. The hydrazone 1-(2-oxo-1,3,2-dioxaphosphoranyl)-3-phenylpropanone 3c was crystallographically analysed by single-crystal X-ray diffraction (SCXRD), revealing the occurrence of strong intra- and intermolecular Nsingle bondH···O hydrogen bonding. These secondary interactions were further examined by a Hirshfeld surface analysis. The experimental SCXRD parameters are compared with the theoretical calculated ones and the preferred configuration of product 3c was determined. Furthermore, the crystal structure of the symmetric azine 2,2′-((2E,2′E)-hydrazine-1,2-diylidenebis(3-phenylpropan-1-yl-2-ylidene))bis(5-methyl-5-propyl-1,3,2-dioxaphosphinane 2-oxide) 4, resulting from the reaction between hydrazone 3a and allene 2a, has been determined. To predict whether hydrazones 3 are appropriate as anticholinesterase agents exhibiting a potential activity for treatment of the Alzheimer disease, in silico molecular docking simulations were employed to investigate the interaction modes between hydrazones 3 and the active sites of the BuChE and AChE enzymes. Additionally, an ADMET-properties prediction was carried out for selected hydrazones to determine their pharmacokinetics and drug-likeness properties.