Proguanil base

Condensation of/>-chlorophenyl guanidine with iso-propyl eyanamide gives the proguanil base which on treatment with one mole of hydroehloric acid yields proguanil hydrochloride. 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

During World War II, chemists at ICI, then a newcomer in pharmaceutical research, discovered antimalarials based on biguanidines, including proguanil (89) (Paludrine, 1944), prepared from 3-chloroaniline (Scheme 28), and its metabolite dihydrodiazine (90). In 1950, George Hitchings developed the diaminotriazine into what became known as pyrimethamine (Diaprim) (91) (Scheme 29)98. 

Another alternative regimen for chemoprophylaxis is the combination of atovaquone and proguanil (Malarone) 1 tablet daily beginning 1 to 2 days prior to travel and continuing for the duration of stay and 1 week after leaving the area. Daily primaquine 15 mg (base) also has been recommended for prophylaxis for both P. vivax and P falciparum malaria. ... 

If quinine-based therapy cannot be used, mefloquine currently is the preferred alternative (except for Southeast Asia) but could be supplanted in this role by atovaquone-proguanil once more experience is obtained. 

In lactating mothers, atovaquone-proguanil is not recommended. Also, the infant must be shown to have a normal G6PD level before using primaquine. For prophylaxis in long-term travelers, chloroquine is safe at the doses used, but may necessitate yearly retinal examinations. Mefloquine and doxycycline are well tolerated. Atovaquone-proguanil has been studied for up to 20 weeks but probably is acceptable for years based on experience with the individual components. 

Following the observation that mouth ulcers appeared to be common in those taking prophylactic antimalarials, an extensive study was undertaken in 628 servicemen in Belize. Of those taking proguanil 200 mg daily, 24% developed mouth ulcers, and in those also taking chloroquine base 150 to 300 mg weekly, 37% developed mouth ulcers. The incidence of diarrhoea was also increased from 63% among those who did not develop ulcers to 83% in those that did develop ulcers (any treatment). The reasons are not understood. The authors of the study suggested that these two... 

The assay of proguanil hydrochloride depends on the precipitation of a copper complex of the base and the official method is as follows ... 

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