Quinoline-based antimalarials

There are two reasons for the great interest being shown in artemisinin and its derivatives. First, there is little cross resistance with Plasmodium falciparum between the members of this series and the quinoline-based antimalarials like chloroquine (203). On the contrary, significant potentiation of effect is observed in combination with chloroquine analogs such as mefloquine (204). Second, the high lipid solubility of, for example, arte-mether ensures rapid penetration into the CNS, so these sesquiterpene lactones are first-... 

Any perturbation of this heme-detoxification process that is unique to Plasmodium is expected to have drastic consequences for the parasite survival. The inhibition of heme aggregation is the targeted action of conventional quinoline based antimalarial drugs such as quinine, chlmnquine and mefloquine. 

It has been underlined that the antimalarial activity of quinoline-based drugs (quinine, chloroquine, mefloquine) also depend on their interactions with heme, thus preventing aggregation of toxic heme released during proteolysis of hemoglobin by die parasite. In vitro, efficient quinolines block the aggregation... 

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. 

SAR of Pamaquine. It is indeed strueturally related to the einehona alkaloids essentially having a 6-methoxy group like quinine, but the various substituents on the quinoline nucleus are strategically positioned at C-8 rather than C-4 as found on the cinchona alkaloids. It has a four-carbon alkyl linkage or bridge between the two N-atoms. It has only one chiral centre. Though it has been eritieally observed that there exists certain differenees in the metabolism of each stereoisomer and type of adverse response, there is hardly any differenee in the antimalarial aetion based on the pamaquin s stereochemistry. 

Synthetic pharmaceuticals based on the quinoline ring are numerous. During World War II when supplies of the highly important antimalarial quinine became scarce, research was conducted in many laboratories to find a synthetic substitute. From this research came the dmg chloro-quine (9.103) and many related highly active compounds. Chloroquine is still in use today in the treatment of malarial infections. It is synthesized by a modification of the Conrad-Limpach synthesis as shown in Scheme 9.52. 

Among the many biological molecules that contain polycyclic aromatic rings, the amino acid tryptophan contains an indole ring and the antimalarial dmg quinine contains a quinoline ring. Adenine and guanine, two of the five heterocyclic amine bases found in nucleic acids, have rings based on purine. 

---