A series of alpha,beta-unsaturated carbonyl based piperidinone derivatives were synthesized and evaluated for their abilities to inhibit AChE and BuChE. All compounds exhibited AChE and BuChE inhibitory activity in different ratios. Among the series, compound 1d, (1-benzyl-3,5-bis(4-nitrobenzylidene)piperidine-4-one), was found to be the most potent derivative against AChE (IC50 = 12.55 mu M) and compound 1g, (1-benzyl-3,5-bis(4-chlorobenzylidene)piperidine-4-one) showed the best anti-BuChE activity (IC50 = 17.28 mu M). The derivatives exhibited selectivity on AChE enzyme with respect to BuChE. Only compound 1g, bearing chlorine substituents, demonstrated as a dual inhibitor of cholinesterases. Taken together, these results indicated that alpha,beta-unsaturated carbonyl based piperidinone scaffold might be a promising drug candidate for further anti-AD drug development.