O

CH3O.

37.1146 37.1.1.47

In terms of its type of action, quinine is an antimalarial drug similar to chloroquine, although it is inferior in its activity.

Like chloroquine, quinine binds with plasmodium DNA, thus interfering in the synthesis of nucleic acids and preventing its replication and transcription. Quinine also suppresses a large portion of the enzymatic system and therefore it is characterized as a general protoplasmid toxin. This fact agrees well with the action of quinine on membranes, its local anesthetizing and its cardiodepressive effects.

Upon oral administration, quinine effectively acts in combination with pyrimethamine, sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquine-resistant forms of P. falciparum. Because of the many associated side effects, its use is extremely limited. Currently, the only indication for use is for forms of malaria that are resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv, quinnam, and others.

Mefloquine: Mefloquine, D,L-erythro-a-2-piperidyl-2,8-to-(trifluoromethyl)-4-quinolin-methanol (37.1.1.53), is made in various ways from 2-trifluoromethylaniline. According to the first method, heterocyclization of the reaction product 2-trifluoromethylaniline with trifluo-roacetoacetic ester gives 2,8-te-(trifluoromethyl)-4-hydroxyquinoline (37.1.1.48). Reacting the product with phosphorus tribromide replaces the hydroxyl group in the fourth position of the quinoline ring with a bromine atom, giving 2,8-fe-(trifluoromethyl)-4-bromoquinoline

(37.1.1.49). Reaction of the last with butyllithium gives a organolithium derivative—2,8-to-(trifluoromethyl)-4-lithiumquinoline (37.1.1.50). Reacting this with carbon dioxide makes 2,8-to-(trifluoromethyl)-4-quinolincarboxylic acid (37.1.1.51). Interaction of the resulting acid with 2-lithiumpyridine gives the ketone (37.1.1.52). Reducing both the keto group and the pyridine ring with hydrogen using a platinum catalyst gives the desired mefloquine [23].

The second way of making mefloquine is from 2,8-to-(trifluoromethyl)-4-lithiumquini-line described above (37.1.1.50), which is reacted with 2-formylpyridine to make a-2-pyridyl-2,8-fe-(trifluoromethyl)-4-methanolquinoline (37.1.1.54). The pyridiyl group in this compound is also reduced as described above, resulting in the formation of the desired mefloquine [24].

Finally, the third way of making mefloquine also begins with 2-trifluoromethylaniline, except in this case it is reacted with chloralhydrate and hydroxylamine to make isoni-trosoacetyl(2-trifluoromethyl)anilide (37.1.1.55), which when heated in the presence of sulfuric acid cyclizes to 7-trifluoromethylisatine (37.1.1.56) (Sandmeyer reaction). The resulting 7-trifluoromethylisatine (37.1.1.56) is then reacted with 1,1,1-trifluoroacetone in the presence of a base in a Friedlaender reaction conditions to make 2,8-to-(trifluo-romethyl)-4-quinoline carboxylic acid described above (37.1.1.51). Reacting this with lithium hydroxide turns it into a lithium salt, which is reacted with a Grignard reagent, 2-magnesiumbromopyridine (made from 2-bromopyridine and magnesium). The resulting ketone (37.1.1.52) is again reduced with a platinum catalyst to make the desired mefloquine [25].

Cl3CH(OH)2 + NH2OH

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