Chloroquine Aralen

Ball-and-Stick Model

Space-filling Model

Space-filling Model

Year of discovery: 1934 (Germany) and during 1940s (USA); Year of introduction: 1945; Drug category: Quinoline antimalarial agent; Main uses: For the prophylaxis and treatment of malaria attacks by Plasmodium vivax, P. ovale, and P. malariae. Also against chloroquine-sensitive strains of P. falciparum; Related drugs: Quinine, Quinidine, Mefloquine (Lariam), Primaquine.

Chloroquine, a synthetic quinoline derivative first prepared in 1934, is still an important agent for the prevention and treatment of malaria either as monotherapy or in combination with other antimalarial drugs. (The quinoline ring is shown in blue in the structures herein.)

Quinine, a naturally occurring quinoline alkaloid (see below) produced by the cinchona tree, has been used as an oral medicine for the prevention of malaria for almost 400 years. Quinine and its stereoisomer quinidine are administered intravenously when used for acute malarial infection. During an intense program of research to eradicate malaria in the mid 20th century, thousands of compounds were synthesized and tested for efficacy in animal models. Pamaquine, an 8-amino substituted quinoline derivative, was identified as a potent antimalarial agent.


Quinine affects the malaria parasite at the stage of its life cycle when it dwells in the bloodstream, whereas pamaquine acts on the parasite in the liver. Consequently, the combination of pamaquine with quinine effectively clears an infection from both the liver and the blood. Pamaquine was followed by the second generation antimalarial agents sontoquine and chloroquine. Chloroquine was found to be more potent and less toxic than sontoquine and became the most important antimalarial treatment during the 20th century (Aralen™, Sanofi Aventis). It is now a generic drug and is formulated as the phosphate salt, which can be administered both orally and intravenously.

While in the circulation, malaria parasites attack, infect and destroy red blood cells (erythrocytes) and use the proteins and other components therefrom to reproduce.1 The removal of protein from the oxygen-carrying hemoglobin of erythrocytes leaves behind the oxygen-binding subunit, a heme-iron complex, which is toxic to the parasites. In the absence of chloroquine, this toxin precipitates and is rendered nontoxic to the parasite. Chloroquine interferes with this vital detoxification process.2 As a consequence, the heme-iron complex remains in solution where it combines with oxygen to form reactive oxygen species that are deadly to the parasite, which is unusually sensitive to oxidative damage. Chloroquine may also act by interfering with enzymes other than the parasite heme polymerase, or even directly by binding to DNA.3

Although chloroquine-resistant strains have emerged, chloroquine is still active against the eythrocytic forms of Plasmodium vivax, Plasmodium malariae and some strains of Plasmodium falciparum. Despite its reduced efficacy, chloroquine is widely used in African countries because of its lower cost. Several new antimalarial drugs are in development.4

1. Tropical Medicine 2004, 4, 97-128; 2. Coord. Chem. Rev. 1999, 190-192, 493-517; 3. Mini-Rev. Med. Chem. 2006. 6, 177-202; 4. Med. Res. Rev. 2007, 27, 65-107; Refs. p. 179

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