Alzheimer's disease is the common cause of dementia characterized by the accumulation of amyloid-β produced by breakage of amyloid-β precursor protein (APP). The present study was designed to synthesize and investigate the effect of chloroquine derivatives on the expression of presenilin. Among the five chloroquine derivatives (D1, D2, D3, D4 and D5) synthesized, D5 with diisopropyl substitution was found to be most effect. The results from western blot analysis showed the inhibition of presenilin 1 protein expression on treatment with chloroquine derivative D5 in Daudi cells. The results were also confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). It was observed that chloroquine derivative D5 downregulates presenilin expression via the inhibition of ubiquilin 1 expression. Thus our study demonstrates that chloroquine derivative D5 treatment can have preventive against Alzheimer's disease.