QUALAQUIN (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. It’s an alkaloid derived from the bark of the cinchona tree and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented. Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of quinine sulfate is not completely understood. It is thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. As a schizonticidal drug, it is less effective and more toxic than chloroquine. Quinine is FDA-approved. It is not considered safe and effective for the treatment or prevention of leg cramps-- an "off-label" (non-FDA-approved) use. Quinine is associated with serious and life-threatening adverse events, including: thrombocytopenia, hypersensitivity reactions, and QT prolongation. Thrombocytopenia associated with the use of quinine for the treatment or prevention of leg cramps includes: immune thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic thrombocytepenic purpura with associated renal insufficiency.

Artefenomel, a novel trioxolane, is a lead candidate for inclusion in a new antimalarial combination, specifically formulated for children. Artefenomel has been demonstrated curative in as little as one dose.

AQ-13 is a drug candidate in development for the treatment of Plasmodium falciparum infections. The chemical structure is similar to chloroquine, a 4-aminoquinoline, with a shorter diaminoalkane side chain. The outstanding attribute of AQ-13 is its retrieval of activity against chloroquine-resistant P.falciparum. The most likely future indication of AQ-13 could be case management of uncomplicated falciparum malaria - as a partner drug in a combination therapy.

Pafuramidine or DB289, [2,5-bis-(4-amidinophenyl)furan bis-O-methylamidoxime] is a pro-drug of DB75, [2,5-bis(4-amidinophenyl)furan] also known as furamidine. The biotransformation process of DB289 to DB75 in the human liver consists of three O-demethylation reactions catalyzed by the Cyp4F enzyme subfamily and three N-dehydroxylation reactions catalyzed by cytrochrome b5 and NADH-cytochrome b5 reductase. DB289 was studied for therapeutic treatment against human African trypanosomiasis, Pneumocystis pneumonia and malaria. In November 2006, Immtech Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) had granted orphan drug designation for pafuramidine (DB289) to treat Pneumocystis jiroveci pneumonia (PCP), a common life-threatening opportunistic infection in HIV/AIDS and other immunosuppressed patients. Despite the high efficacy of DB289 in patients, the mechanism of action of DB75 is unknown. The mechanism of antimicrobial activity of diamidine compounds is incompletely understood. They undergo active uptake by purine transporter systems in trypanosomes and their mechanism of action may involve interference with DNA-associated enzymes inhibition of heme crystallization11 or/and collapse of the transmitochondrial membrane potential.

Pyronaridine was developed in China and has been registered in that country since the 1980s. Outside China, none of the existing formulations is registered because of the failure to meet international regulatory standards. Pyronaridine is generally active against chloroquine-resistant parasites. Pyronaridine has been investigated for the treatment of Malaria. Pyronaridine targets hematin. Combination of pyronaridine with artesunate was indicated for the blood-stage treatment of both strains of malaria:  P. falciparum and P. vivax.  WHO currently recommends artesunate-pyronaridine in areas where other artemisinin-based combination therapies are failing.