| Description | Amodiaquine is a prodrug form of the antimalarial compound N-desethyl amodiaquine . It is active against several strains of P. falciparum in vitro (EC50s = 0.23-0.52 nM) and exhibits a synergistic effect when used in combination with N-desethyl amodiaquine. Amodiaquine dose-dependently inhibits development of parasitemia in a mouse model of P. berghei infection. |
| Chemical Properties | Cyrstalline Solid |
| Originator | Camoquin HCl,Parke Davis,US,1950 |
| Uses | An antimalarial |
| Definition | ChEBI: A quinoline having a chloro group at the 7-position and an aryl amino group at the 4-position. |
| Indications | Amodiaquine (Camoquin) is another 4-aminoquinolinederivative whose antimalarial spectrum and adverse reactionsare similar to those of chloroquine, althoughchloroquine-resistant parasites may not be amodiaquine-resistant to the same degree. Prolonged treatmentwith amodiaquine may result in pigmentation ofthe palate, nail beds, and skin. There is a 1:2000 risk ofagranulocytosis and hepatocellular dysfunction whenthe drug is used prophylactically. |
| Manufacturing Process | 72.8 g (0.5 mol) of p-aminophenol hydrochloride is dissolved in 500 cc ofwater and added to 99 g (0.5 mol) of 4,7-dichloroquinoline. After a fewminutes of warming in a steam bath, 4-(4'-hydroxyanilino)-7-chloroquinolinehydrochloride, of sufficient purity for use in further experiments, precipitatesas a yellow crystalline solid. Recrystallized from methanol, the MP is over300°C.
A mixture consisting of 13.5 g of 4-(4'-hydroxyanilino)-7-chloroquinolinehydrochloride dissolved in absolute ethanol is treated with a solution of 4.38 g of diethylamine and 1.8 g of paraformaldehyde in 20 cc of absolute ethanol.The reaction mixture is heated under reflux for 16 hours, evaporated to onehalfvolume and the warm solution treated with an excess of hydrogenchloride dissolved in absolute ethanol. Acetone is added to the warm solutionuntil it becomes turbid and then the solution is cooled. The crudedihydrochloride which separates is collected and purified by recrystallizationfrom methanol; MP 240-242°C.
By using an equivalent amount of 4-(4'-hydroxyanilino)-7-bromoquinoline inthe above procedure, 4-(3'-diethylaminomethyl-4'-hydroxyanilino)-7-bromoquinoline dihydrochloride is obtained; MP (base) 206-208°C dec. |
| Brand name | Camoquin (Parke-Davis);Amodoquin tablets;Basoquin;Caniquin. |
| Therapeutic Function | Antimalarial |
| World Health Organization (WHO) | Amodiaquine, an antimalarial agent related to chloroquine, wasintroduced over 40 years ago for the treatment and prophylaxis of malaria. Thedrug was voluntarily withdrawn in the United Kingdom in 1975 for commercialreasons but was subsequently reintroduced in 1985 to meet the medical demandfor an antimalarial drug to deal with the rapid spread of chloroquine-resistantfalciparum malaria in Asia and Africa. By 1986 a significant number of cases ofagranulocytosis associated with prophylactic use, some of which were fatal, hadbeen reported there and it has been estimated that the frequency of this risk is ofthe order of 1:2,000. Although most cases occurred when amodiaquine had beenused in combination with other antimalarials, the major manufacturer decided towithdraw the prophylactic indication worldwide following discussions with experts.Preparations remain available for the treatment of acute attacks of malaria whichinvolves only a short period of exposure to the drug.(Reference: (WHODI) WHO Drug Information, 1, 5, 1987) |
| Pharmaceutical Applications | A mono-Mannich-base 4-aminoquinoline, formulatedas the dihydrochloride dihydrate or free base for oraladministration.It is active against P. falciparum and P. vivax and is moreactive than chloroquine for the treatment of uncomplicated P.falciparum malaria. Chloroquine-resistant strains may remainsusceptible, but resistance to amodiaquine is also spreadingin some regions of Africa. The pharmacological properties aresimilar to those of chloroquine. The terminal elimination halflifeis 1–3 weeks. It is rapidly and extensively metabolized to thedesethyl derivative which has reduced antiplasmodial activity.Prophylactic use has been abandoned because of agranulocytosisand hepatotoxicity due to formation of a quinoneiminemetabolite.A fixed dose combination with artesunate and derivatives(for example, isoquine) with altered metabolism and reducedtoxicity is in development. |
| Clinical Use | Treatment of falciparum malaria |
| Clinical Use | Mechanistically, it is very similar to chloroquine and does nothave any advantages over the other 4-aminoquinoline drugs.When used for prophylaxis of malaria, it had a higher incidenceof hepatitis and agranulocytosis than that was chloroquine.There is evidence that the hydroquinone (phenol)amine system readily oxidizes to a quinone imine either autoxidatively and/or metabolically, and this productmay contribute to amodiaquine’s toxicity. |
| Synthesis | Amodiaquin, 4-[(7-chloro-4-quinilyl)amino]-|á-diethylmaino-o-cresol(37.1.1.21), is made by reacting 4,7-dichloroquineoline (37.1.1.1) with 4-aminophenol to make 7-chloro-4-(4-hydroxyphenylamino)-quiniline (37.1.1.20), which then undergoes anaminomethylation reaction using formaldehyde and diethylamine, giving amodiaquin. |
| Purification Methods | Amodiaquin crystallises from 2-ethoxyethanol or EtOH. [Burckhalter et al. J Am Chem Soc 70 1363 1948, Beilstein 22 III/IV 4647.] |
