Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

Abstract

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

Keywords: Amodiaquine; Chloroquine; Drug resistance; Malaria.

Figure 1

Life cycle of the malaria parasite: Humans and female Anopheles mosquitoes are two hosts of malaria parasites. In humans, the parasites grow and multiply in the liver cells (liver stage) and then in the red blood cells (blood stage). In mosquitoes, gametocytes are picked up during a blood meal and started sexual cycle.

Figure 2

Chemical structure of antimalarial drugs containing the quinoline ring.

Figure 3

CQ is transferred to the food vacuole (FV) of the parasite and trapped in its acidic form. Then, Plasmodium parasite is killed by inhibiting haemozoin formation.

Figure 4

Mutations in transporter proteins (PfCRT and PfMDR1) decrease CQ accumulation in the parasite’s Food Vacuole.

Figure 5

CQ is metabolized to active metabolite DCQ. AQ is metabolized to DEAQ as its major active metabolite and toxic metabolite (AQQI).

Figure 6

Important parts of CQ containing the quinoline ring, the pentamidine chain and amino alkyl head.

Figure 7

The synthetic analogues of CQ containing modified side chain with antimalarial activity.

Figure 8

The synthetic analogues of AQ containing modified side chain with antimalarial activity.