Category:Antimalarials

An antimalarial is a medicine used to treat or prevent infection by Plasmodium, the protozoan parasite responsible for malaria. The category is the most consequential sub-set of the antiprotozoals both by the number of people it has affected (malaria has been, by some estimates, the largest single cause of human death in history) and by the contemporary public-health investment in its control. The medicines act at different stages of the parasite life cycle: the blood schizonticides on the asexual erythrocytic forms responsible for symptomatic disease, the tissue schizonticides on the hepatic forms, the hypnozoiticides on the dormant liver-stage hypnozoites of P. vivax and P. ovale that cause relapse, the gametocytocides on the sexual forms that infect the mosquito and so on transmission, and the sporontocides on the parasite within the mosquito itself.

The pharmacological history is among the oldest documented in medicine. The bark of the cinchona tree, an evergreen of the eastern slopes of the Andes, was used by the Quechua of what is now Peru to treat shivering fevers; Jesuit missionaries observed the practice in the 1630s and brought the bark to Europe under the name "Jesuit's powder". A celebrated 1638 case in which the Countess of Chinchón, wife of the Spanish viceroy of Peru, was reportedly cured of malaria by the bark gave the tree its modern Latin name (the Countess's name was Latinised as Chinchona, then changed by a typographic error to Cinchona by Linnaeus in 1742, and the misspelling has stood ever since). The active principle, quinine, was isolated in 1820 by Pierre Joseph Pelletier and Joseph Bienaimé Caventou at the École de Pharmacie in Paris;^[1] the same two chemists, working in the same laboratory in the same year, also isolated colchicine, brucine, strychnine, veratrine, and caffeine, an output without parallel in pharmacognosy. Quinine became the standard antimalarial for the next century, manufactured from cinchona bark cultivated in Dutch and British colonial plantations in Java and India.

The synthetic era began at IG Farben in the 1930s. The 8-aminoquinoline pamaquine was the first synthetic antimalarial, introduced in 1925 as Plasmochin. The 4-aminoquinoline chloroquine, synthesised by Hans Andersag at IG Farben in 1934 as Resochin and (after wartime disruption) re-developed by the U.S. Army research programme during the Second World War as the successor to atabrine (quinacrine), became the standard antimalarial of the post-war decades.^[2] Primaquine, the 8-aminoquinoline that finally provided eradication of P. vivax liver-stage hypnozoites, came from the same wartime programme. Chloroquine resistance in P. falciparum was first reported in Cambodia and in Colombia in the 1950s and 1960s; it spread westward across south-east Asia, jumped to East Africa in the 1970s, and by the 1990s had reached most of sub-Saharan Africa, with substantial increases in malaria mortality in regions that lost the medicine.

The antifolate combination sulfadoxine-pyrimethamine (Fansidar, Roche 1971) filled the post-chloroquine gap for a brief period before resistance emerged within five years of its widespread deployment. Mefloquine (the U.S. Walter Reed antimalarial discovery programme, approved 1989) gave a once-weekly prophylactic option but produced a neuropsychiatric adverse-effect profile (vivid dreams, anxiety, depression, in rare cases psychosis) that has largely retired it from current use. Atovaquone (Wellcome) combined with the antimalarial proguanil as Malarone (1997) provided well-tolerated travel prophylaxis and is now the most commonly prescribed prophylactic regimen for short-term travel to malarial regions, alongside doxycycline.

The transformative event of contemporary antimalarial pharmacology was the discovery of artemisinin by Tu Youyou of the Chinese Academy of Traditional Chinese Medicine in 1972. Tu's work was conducted under Project 523, the classified Chinese antimalarial-research programme established at the request of Ho Chi Minh for the antimalarial supply of the North Vietnamese army during the Vietnam War; the project screened thousands of compounds from traditional Chinese medicine, and Tu identified artemisinin (qinghaosu) in extracts of Artemisia annua (sweet wormwood), used in traditional medicine for fever for over a thousand years and described in Ge Hong's fourth-century Zhouhou Beiji Fang.^[3] The compound's structure (a sesquiterpene lactone with an endoperoxide bridge essential for antiplasmodial activity) was unprecedented; its mechanism of action involves iron-mediated cleavage of the endoperoxide and the resulting generation of carbon-centred radicals that alkylate parasite proteins. Tu received the Nobel Prize in 2015. The semi-synthetic derivatives artesunate (water-soluble, for intravenous use in severe malaria), artemether (lipid-soluble, oral), and dihydroartemisinin are short-acting (terminal half-life one to two hours); they are combined in modern practice with a longer-acting partner agent to reduce the selection pressure for resistance.

The contemporary first-line treatment of uncomplicated P. falciparum malaria is therefore an artemisinin-based combination therapy (ACT). The WHO-recommended combinations include artemether-lumefantrine (Coartem/Riamet), artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, and the recent artesunate-pyronaridine. Each combination delivers a rapid parasite-killing pulse from the artemisinin component and a longer-lasting clearance from the partner. The intravenous formulation of artesunate is the standard treatment for severe malaria worldwide; the SEAQUAMAT and AQUAMAT trials demonstrated its superiority over intravenous quinine in adults and in African children respectively. The unfortunate counterpart of the ACT story is the emergence of artemisinin partial resistance in southeast Asia, first reported in 2008 in western Cambodia and now confirmed in the Greater Mekong subregion, in eastern India, and (most recently and most concerningly) in Eritrea, Rwanda, and Uganda;^[4] the molecular marker is the K13 propeller gene, and the clinical phenotype is delayed parasite clearance rather than overt treatment failure, although partner-medicine failure compounds the picture.

The contemporary public-health pharmacopoeia of malaria extends beyond the treatment medicines to prevention. Insecticide-treated bed nets, indoor residual spraying, intermittent preventive therapy in pregnancy (sulfadoxine-pyrimethamine in regions of preserved sensitivity), seasonal malaria chemoprevention in children of the Sahel (sulfadoxine-pyrimethamine plus amodiaquine), and the recent licensing of the RTS,S vaccine (Mosquirix, 2021) and the more efficacious R21 vaccine (2023) have together produced substantial reductions in malaria incidence and mortality in the African continent; child mortality from malaria has approximately halved between 2000 and 2020 across the WHO African region. The post-2020 plateau in progress, attributed to the COVID-19 disruption of malaria programmes and to the accumulating resistance challenges, is a current focus of WHO and partner attention.

By chemistry and life-cycle target:

• Quinoline-based blood schizonticides:
  • Cinchona alkaloids: quinine (oral and intravenous; severe malaria second-line where artesunate unavailable), quinidine (now rarely used)
  • 4-aminoquinolines: chloroquine (used for sensitive P. vivax, P. ovale, P. malariae, P. knowlesi), hydroxychloroquine (less malaria use, more autoimmune use; described under DMARDs and immunomodulators), amodiaquine
  • Aryl-amino alcohols: mefloquine (limited current use), lumefantrine (paired with artemether), halofantrine (largely retired for QT)
  • Bisquinolines: piperaquine (paired with dihydroartemisinin), pyronaridine (paired with artesunate)
• 8-aminoquinoline hypnozoiticides (for P. vivax and P. ovale relapse prevention; G6PD testing required):
  • Primaquine (multi-day regimen)
  • Tafenoquine (single-dose, approved 2018)
• Antifolate combinations:
  • Sulfadoxine-pyrimethamine (Fansidar) for intermittent preventive therapy in pregnancy
  • Atovaquone-proguanil (Malarone) for travel prophylaxis and treatment in chloroquine-resistant areas
• Artemisinin derivatives and ACT combinations:
  • Monotherapy artemisinins (intravenous severe malaria): artesunate (intravenous), artemether (intramuscular/oral), dihydroartemisinin (oral)
  • Artemisinin-based combination therapies (first-line treatment of uncomplicated falciparum malaria): artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, artesunate-pyronaridine
• Antibacterials with antimalarial activity:
  • Doxycycline (travel prophylaxis; standard for chloroquine-resistant regions)
  • Clindamycin (paediatric, pregnancy; combined with quinine for severe malaria when artesunate unavailable)
• Vaccines (not antimalarials in the strict pharmacological sense; mentioned for completeness):
  • RTS,S/AS01 (Mosquirix), approved 2021 for African children
  • R21/Matrix-M, approved 2023; higher efficacy than RTS,S

The boundary of this category is "medicine used to treat or prevent infection by Plasmodium species." The antiprotozoals for other species (Toxoplasma, the trypanosomatids, the amoebic parasites) are collected separately; the antimalarial-trained medicines used in those indications (hydroxychloroquine in autoimmune disease, quinacrine, atovaquone in toxoplasmosis prophylaxis) are cross-indexed where appropriate. Insecticides and vector-control medicines used in mosquito eradication (DDT in historical use, pyrethroids in current bed-net impregnation, ivermectin in mass administration trials) are not antimalarials in the conventional sense and are listed under public-health pharmacology. The malaria vaccines (RTS,S and R21) are biologics rather than antimalarials in the small-molecule sense and are listed under biologics in their primary classification; they are mentioned here for the public-health context.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.