New 1,3-Benzoxazol-2(3H)-one Aroylhydrazone and Acetamide Hybrids as Promising Acetylcholinesterase Inhibitors: Microwave Synthesis, Structure–Activity Relationship, and Drug-Likeness Evaluation

Abstract Objective: A new series of benzoxazole-based aroylhydrazone and acetamide hybrids was designed, synthesized, and evaluated for acetylcholinesterase (AChE) inhibitory activity. In addition, a structure–activity relationship (SAR) study was performed, and absorption, distribution, metabolism, and excretion (ADME) properties were calculated using the SwissADME web tool. Methods: The synthesis of the hybrids was carried out using conventional techniques, a household microwave oven, and a monomode microwave reactor. Results and Discussion: The outcomes of the different synthetic approaches were compared. Most of the synthesized hybrids exhibited high inhibitory activity, with IC50 values ranging from 12.00 ± 0.15 to 18.50 ± 0.25 µg/mL, exceeding that of the reference drug galantamine (20.75 ± 0.25 µg/mL). SAR analysis revealed that the introduction of the aroylhydrazone moiety into the benzoxazole scaffold enhanced AChE inhibitory activity. In particular, the presence of chlorine-containing substituents on the benzoxazole ring positively influenced the activity. Conclusions: Furthermore, ADMET profiling indicated that all active compounds exhibited drug-likeness and complied with ADME rules, with no violations detected. Collectively, the newly synthesized hybrid compounds represent promising lead scaffolds for the treatment of Alzheimer’s disease.