Quinolines antimalarials

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

Malaria parasite has developed resistance to many of these so-called quinoline antimalarials rendering them completely obsolete. This situation has forced the use of combination regimens that consists of a mixture of two or more antimalarial active ingredients this approach has proven to work better than monotherapies, but often is only a temporary soulu-tion. Nevertheless, quinine remains a very effective drug, with only few treatment failures or resistance reported around the globe. 

Egan TJ, Ncokazi KK. (2005) Quinoline antimalarials decrease the rate of p-hematin formation. J Inorg Biochem 99 1532-1539. 

M. Foley, L. Tilley (1998). Quinoline antimalarials Mechanisms of action. Pharmacol. Then 79 55. 

The first synthetic quinoline antimalarial agent interestingly carried the basic side chains at the 8 rather than the 4 position, as in quinine, lending further credence to the... 

Chemical/Pharmaceutical/Other Class Amino-quinoline antimalarial/antirheumatic Chemical Formula C18H26CIN3 Chemical Structure ... 

OR Idowu, JO Peggins, TG Brewer, C Kelley. Metabolism of a candidate 8-amino-quinoline antimalarial agent, WR 238605, by rat liver microsomes. Drug Metab Dispos 23 1, 1995. 

Loria, P., Miller, S., Foley, M., and Tilley, L. (1999). Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials. Biochem. ]. 339(Pt 2), 363-370. 

Quinoline antimalarials such as hydroxychloroquine (Fig. 5-6) and chloroquine have been found to have antiarthritic properties however, the onset of clinical improvement, as with penicillamine and gold, takes months. Irreversible retinopathy, including retinal opacity, can be encountered. Lesser toxicities include skin pigmentation and alopecia. Proposals to possible mechanisms of action are speculative at best. It should be emphasized that none of the slow-action antiarthritic agents discussed earlier should be considered as initial therapy in RA. The salicylates and other NSAIDs deserve this distinction. If results are unsatisfactory gold may be considered as the subsequent therapeutic step. Penicillamine would be a logical alternate, as would short-term steroids or cytotoxic agents. 

Interaction of marine isonitriles derivatives with heme was shown to inhibit the transformation of heme into / -hematin and then hemozoin, a polymer produced by Plasmodium in order to neutralize the toxic (detergent-like) free heme produced in the food vacuole. In addition, isonitriles were shown to prevent both the peroxidative and glutathione-mediated destruction of heme under conditions that mimic the environment within the malaria parasite. In summary, isonitriles, similarly to quinoline antimalarials [38], exert their antiplasmodial activity by preventing heme detoxification. 

Mefloquine hydrochloride (lariam) is available for oral administration only. Tablets marketed in the U.S. contain 250 mg mefloquine hydrochloride, equivalent to 228 mg mefloquine base (this may vary in Canada and elsewhere). The dosing below is expressed in mg salt. Adults and children >45 kg body weight take 250 mg weekly starting 1-2 weeks before entering an endemic area and ending 4 weeks after leaving. Pediatric doses, taken by the same schedule, are 5 mg/kg for children up to 15 kg (may have to be prepared by a pharmacist) 62.5 mg (1/4 tablet) for 15-19 kg 125 mg (V2 tablet) for 20-30 kg 187.5 mg /k tablet) for 31 5 kg. Note Mefloquine is not recommended for children weighing <5 kg or individuals with a history of seizures, severe neuropsychiatric disturbances, sensitivity to quinoline antimalarials, or cardiac conduction abnormalities. 

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