Antimalarials

Commercial trifluoromethylquiaoline-based products are mefloquiae [53230-10-7], an antimalarial, and floctafenine [23779-99-9], an analgesic. The cycli2ation step to constmct the 2,8-bis(trifluoromethyl)quiaoiine nucleus ia mefloquiae employs 2-amiaobea2otrifluoride [88-17-5] and ethyl 4,4,4-trifluoroacetoacetate [372-31-6] (448). 

Of industrial significance are ethyl 4,4,4-trifluoroacetoacetate [372-31-6] methyl 4,4,4-trifluoroacetoacetate, and isopropyl 4,4,4-trifluoroacetoacetate for the production of herbicides (eg, Monsanto s Dimension) and antimalarial agents such as Roche s Mefloquin [51773-92-3] as weU as ethyl 4,4,4-trichloroacetoacetate [3702-98-5] for the production of pharmaceuticals. 

Many substituted quinolines are intermediates for antimalarials. The 2,4-di-substituted quinolines are produced from aniline and 1,3-diketones by the Combes quinoline synthesis (28). The reaction of aniline with nitrobenzene in the presence of dry sodium hydroxide at 140°C leads to formation of phenazine [92-82-0] and by-products (Wohl-Aue synthesis) (29). 

Antimalarials. Antimalatials can be categorized according to their mode of action (15). 

It should be noted that dmgs may operate by more than one mechanism, and may possess a specific mode of action against one species of plasmodium but lack efficacy against others. In addition, antimalarial dmgs may be classified according to their stmctural types. 

Although quinine is a favored antimalarial for parenteral adrninistration, it is nevertheless hazardous by this route. Quinidine (64), has been shown to be even more effective in combatting the disease (Table 8). However, it has undesirable cardiac side effects that reduce its suitabiHty as an antimalarial. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

Quinones and naphthoquinones were explored during the World War 11 Antimalarial Dmg Program. Now that chloroquine resistance is a serious problem, compounds of this group such as menoctone (76) are being reinvestigated. 

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

Some antibiotics, such as the tetracyclines, tetracycline (7), doxycycline (78), and minocycline (17), chloramphenicol (79), and clindamycin (23) have modest antimalarial properties, but are slow-acting. 

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

Woodward s synthesis, 4, 416-419 Chlorophyll b, 4, 382 Chlorophyll c, 4, 382 Chlorophyll d, 4, 382 Chlorophylls, 4, 378 biosynthesis reviews, 1, 99 structure, 4, 370 substituents reactions, 4, 402 Chloroporphyrin e, 4, 404 Chloroprothixene pharmacology, 3, 942 Chloropyramine as antihistamine, 1, 177 Chloropyrifos synthesis, 2, 201 Chloropyrifos-ethyl as insecticide, 2, 516 Chloropyrifos-methyl as insecticide, 2, 516 Chloroquine, 1, 145 adsorption on nucleic acids, 1, 179 as antimalarial, 1, 173, 2, 517 Chloroquine, hydroxy-as antimalarial, 2, 517 Chlorosulfonyl isocyanate cycloaddition reactions... 

Quinoline, 6-amino-protonation, 2, 341 Quinoline, 7-amino-protonation, 2, 341 Quinoline, 8-amino-alkylation, 2, 179 methylation, 2, 342 Quinoline, 4-amino-7-chloro-as antimalarial, 2, 517 Quinoline, 2-amino-3-cyanotetrahydro-synthesis... 

Q lllllflCrillC [Atebrine, 3-chloro-9(4-diethylamino-l-methyl)butylamino-7-methoxy)acridine] dihydrochloride. [69-05-6] M 472.9, m 248-250 (dec), pK -6.49 (aq H2SO4), pKj 7.73 (ring NH ), pKj 10.18 (Et2N). Cryst from H2O (sol 2.8% at room temp) as yellow crystals. Slightly sol in MeOH and EtOH. Antimalarial, antiprotozoal and intercalates DNA. [Wolfe Antibiot 3 (Springer-Verlag) 203 1975.]... 

Another improvement was reported by Leonard et al. in their preparation of a promising antimalarial, Endochin. The improvement was the alkylation of intermediate enamino-ester 28 by reaction with NaOEt followed by alkylation with an alkyl bromide, rather than forming 29 by reaction of 27 and a suitable P-keto-ester. This provided the important intermediate 29 required for cyclization to Endochin (30). Endochin was first reported by German scientists but was not publicly disclosed until the Department of Commerce made this information available after World War II.Leonard was able to improve upon the chemistry reported by Andersag and Salzer in 1940 and isolated Endochin in 40% overall yield from m-anisidine (27). 

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