Quinolines mefloquine

VI.a.2.1. AminoquinoUnes. The aminoquinolines currently used as antimalarials include the 4-amino-quinolines chloroquine and mefloquine and the 8-aminoquinoline primaquine. 

Quinoline derivatives chloroquine phosphate hydroxychloroquine sulfate mefloquine hydrochloride primaquine phosphate... 

III. Quinoline-methanol derivatives Mefloquine (MEFLOC) 15 mg/kg single dose (for treatment, maximum 1 g) 5 mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance)... 

Mefloquine Quinoline methanol Chemoprophylaxis and treatment of infections with P falciparum... 

Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-... 

Quinolines represent an important class of heterocycles, and the quinoline skeleton is present in various natural products, especially in alkaloids. Among them quinine is an active ingredient for the treatment of malaria [286]. Despite its relatively low efficacy and tolerability, quinine still plays an important role in the treatment of multiresistant malaria, one of the world s most devastating infectious diseases [287]. Therefore, the design of many drugs and affordable chemotherapies are based upon synthetic quinoline derivatives, such as chloroquine, mefloquine or quinacrine [288-292]. In addition, chimanine alkaloids, are also effective against parasitic diseases such as leishmaniasis and trypanosomiasis [293-295]. Besides,... 

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-... 

Over decades of sublethal exposure the resistance of all types of malaria has increased to a point where chloroquine no longer offers certain protection (217). With the partial exception of quinine and dihydroquinine (218), resistance to antimalarials had reached the stage at the time of the Vietnam war where more research was required. The development of mefloquine (164) was a continuation of the World War II effort, with a gap of about 20 years. Resistance to chloroquine had developed widely during that period, but surprisingly less so to quinine, given the obvious similarities in structure. This observation stimulated a reappraisal of quinolines, known as quinoline methanols, which bear a hydroxy group on the a-carbon of a substituent at-... 

Mefloquine, a fluorinated derivative of 4-quinoline methanol, is a product of the US Army s antimalarial research program. It is active against chloroquine-resistant Plasmodium falciparum, and has an excellent schizonti-cidal effect in the blood in experimentally induced Plasmodium vivax infections in volunteers. It is not gametocidal. P. vivax infections can persist after successful treatment of the falciparum infection with other drugs the fact that mefloquine is effective against both organisms is thus of practical importance (SEDA-13, 808). 

Expanded studies in this direction revealed that chlorination of the quinoline and phenyl rings in 2-aryl-4-quinolinyl-2 -piperidinyl methanols may diminish phototoxicity [49]. Further molecular modifications in 2-substituted quinine derivatives showed that replacement of the 2-phenyl group by trifluoromethyl groups could further reduce phototoxicity with retention of antimalarial activity [50]. This observation was systematically exploited at the Walter Reed Army Research Institute culminating in the discovery of mefloquine (23a) [51]. The other effective anhmalarials,... 

Quinine (1) is the oldest example of this class which has been used as a "lead molecule" to design quinoline-4-methanols with improved antimaiarial activity. The most successful outcome of this effort had been the discovery of mefloquine (71) as an antimaiarial. A discussion on the development of mefloquine and related quino-line-4-methanols is given in chapter 14 (sec. 2.1.1.1). 

Quinoline compounds and the plants that contain them have historically anchored the antimalarial arsenal, and they remain principal drugs today. Quinine and its diastereomer, quinidine, are quinoline alkaloids which were isolated in 1820 from the bark of the Cinchona tree, by virtue of the traditional South American use of this bark to treat intermittent fevers. Quinine is an effective schizonticide (i.e., it kills the form of the parasite in peripheral blood), but because it also affects mammalian lysosomes, the drug has been associated with significant adverse toxicity (48,50). The development of synthetic derivatives of quinine has resulted in improvement in potency and selectivity over the parent compound. Chloroquine and mefloquine are more potent and less toxic than quinine (49,51), thus, chloroquine had largely replaced quinine in clinical use however, resistance of P. falciparum to chloroquine has been reported... 

Up to the middle of this century quinine (1) was used for the treatment of malaria, and with the widespread development of chloroquine-resistant strains of Plasmodium falciparum it has become important again. Quinine has been used for the treatment of malaria for more than 350 years and has its origin in Peru in the early 17th century. Quinine was the lead structure in the discovery of new synthetic derivatives like mefloquine that have higher antimalarial activity. This section will focus on other new quinoline alkaloids. The mechanism of antiplasmodial action and resistance of quinolines is well described elsewhere [116]. 

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. 

The mechanism of action of mefloquine is unknown but may be similar to that of chloroquine. Certain isolates of P. falciparum exhibit resistance to mefloquine via unknown mechanisms. Chloroquine-resistant alleles of the crt gene actually confer increased sensitivity to mefloquine and some other quinolines. Amplification of the pfmdrl gene is associated with resistance to mefloquine and quinine. 

Classiflcation and pharmacokinetics Mefloquine is a synthetic 4-quinoline derivative chemically related to quinine. Because of local irritation, mefloquine can only be given orally, though it is subject to variable absorption. Its mechanism of action is not known. 

This is the outcome of many years of research by the United States department of the Army. It belongs to the 4-quinoline methanol series, several of which were foimd to have potent schizonticidal activity but could not be used clinically, because they possessed photosensitizing activity in man. Mefloquine is devoid of this effect. 

The same method was also used for the synthesis of the anti-malarial compound mefloquine. Heterocyclization of 2-trifluoromethylaniline with trifluoroacetic acid ethyl ester provides 2,8-6w-(trifluoromethyl)-4-hydroxyquinoline. Bromination with phosphorous tribromide, followed a carbon monoxide introduction, affords 2,7-trifluoromethyl-4-carboxylic acid quinoline. Amide formation and pyridine reduction completes the synthesis providing mefloquine in high yields. ... 

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