Abstract: A series of new piperaquine analogues with three piperazinyl groups in side chain was synthesized. Primary screening test on mice-infected with blood form parasites of Plasmodium berghei showed that all of these compounds were active. Compounds Ⅳ_c,g,h were shown to completely suppress the parasitemia of infected mice at the dose of 3 mg/kg for 3 consecutive days. In protection test on the same screening system, two compounds appeared to have a marked long-lasting protective effect against the blood infection of P. berghei in mice. Compound Ⅳ_a is the same compound reported as M 1020 in reference number 8. Compound Ⅳ_d protected mice against intervening challenge with P. berghei for 45 days following a single oral dose of 600 mg/kg. It also exhibited long-lasting protective effect of about 20 to 25 days against P. cynomolgi in monkeys.