Design, synthesis, and anti-plasmodial profiling of oxalamide-linked 4-aminoquinoline-phthalimide hybrids

Abstract

A series of hydrazinyl-oxoacetamide linked 4-aminoquinoline-phthalimides were synthesized and assayed for their anti-plasmodial activities against the chloroquine-resistant W2 strain of P. falciparum. The synthesized compounds exhibited activity in the low nanomolar range with eight compounds being more active than the standard drug, chloroquine (CQ). Structure–activity relationship studies indicated the dependence of anti-plasmodial activity on the length of the alkyl chain used as a spacer with two of the most promising compounds of the series exhibiting an IC₅₀ value of 0.037 μM. Inhibition of hemozoin formation proved to be the primary mechanism of action of the most promising compound of the series with superior binding affinity toward heme compared to CQ.