Chloroquin

The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

Malaria affects an estimated 270 million people and causes 2—3 million deaths annually, approximately one million of which occur in children under the age of five. While primarily an affliction of the tropics and subtropics, it has occurred as far north as the Arctic Circle. The disease essentially has been eradicated in most temperate-zone countries, but some 1100 cases of malaria in U.S. citizens returning from abroad were reported to the Centers for Disease Control during 1990. Malaria is seen today in Southeast Asia, Africa, and Central and South America. It is on the increase in Afghanistan, Brazil, China, India, Mexico, the Philippines, Sri Lanka, Thailand, and Vietnam. Escalation of the disease is because of the discontinued use of the insecticide DDT which effectively kills mosquito larvae, but has been found to be toxic to Hvestock and wildlife. Also, chloroquine (6), a reUable dmg for the prophylaxis and treatment of falcipamm malaria, is ineffective in many parts of the world because of the spread of dmg-resistant strains. 

Plasmodium vivax, responsible for the most prevalent form of malaria (benign tertian), has an incubation period of 8—27 days (14 average). A variety seen in northern and northeastern Europe has an incubation period as long as 8—10 months. The disease can cause splenic mpture and anemia. Relapses (renewed manifestations of erythrocytic infection) can occur with this type of malaria. Overall, P. vivax is stiU susceptible to chloroquine however, resistant strains have been reported from Papua New Guinea and parts of Indonesia. Plasmodium malariae the cause of quartan malaria, has an incubation period of 15—30 days and its asexual cycle is 72 hours. This mildest form of malaria can cause nephritis in addition to the usual symptoms. It is a nonrelapsing type of malaria but the ted blood ceU infection can last for many years. No resistance to chloroquine by this plasmodium has been reported. Plasmodium ovale responsible for ovale tertian malaria, has an incubation period of 9—17 days (15 average). Relapses can occur in people infected with this plasmodium. No chloroquine resistance has been reported for this parasite. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

The best example of the class of phenanthrene-methanols is halofantrine (66, Halfan [36167-63-2]) a dmg that is effective against chloroquine-resistant malaria and is now being evaluated in Africa. It produces temporary gastrointestinal disturbances. 

Quinones and naphthoquinones were explored during the World War 11 Antimalarial Dmg Program. Now that chloroquine resistance is a serious problem, compounds of this group such as menoctone (76) are being reinvestigated. 

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

Woodward s synthesis, 4, 416-419 Chlorophyll b, 4, 382 Chlorophyll c, 4, 382 Chlorophyll d, 4, 382 Chlorophylls, 4, 378 biosynthesis reviews, 1, 99 structure, 4, 370 substituents reactions, 4, 402 Chloroporphyrin e, 4, 404 Chloroprothixene pharmacology, 3, 942 Chloropyramine as antihistamine, 1, 177 Chloropyrifos synthesis, 2, 201 Chloropyrifos-ethyl as insecticide, 2, 516 Chloropyrifos-methyl as insecticide, 2, 516 Chloroquine, 1, 145 adsorption on nucleic acids, 1, 179 as antimalarial, 1, 173, 2, 517 Chloroquine, hydroxy-as antimalarial, 2, 517 Chlorosulfonyl isocyanate cycloaddition reactions... 

The hydroxyl group is then replaced by chlorine by means of phosphorus oxychloride (70). Displacement of the reactive halogen at the 4 position by means of the aliphatic diamine, 71, yields the synthetic antimalarial agent chloroquine (72). ... 

Diethylamino-4-aminopentane Chloroquine phosphate 4-Diethylamino-2-butynyl acetate Oxybutynin chloride 2-Diethylamino-1 -chloroethane Bietaserpine Fenoxedil... 

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