Halogenated Hydroxyquinolines

Certain halogen derivatives of 8-hydroxyquinoline have a record of therapeutic efficacy in the treatment of cutaneous fungus infections and also of amebic dysentery. Among these are 5-chloro-7-iodo-8-quinolinol [130-26-7] (iodochlorhydroxyquin, Vioform), 5,7-diiodo-8-hydroxyquinoline [83-73-8] (diiodohydroxyquin), and sodium 7-iodo-8-hydroxyquinoline-5-sulfonate [885-04-1] (chiniofon) (196—198). 

Among the nucleophilic processes available for introduction of bromine to quinolines are reactions of the diazonium salts (87JHC181) and syntheses based on hydroxyquinolines or quinolones (91M935) (Scheme 36). The former processes are especially useful for making 5-, 6-, 7-, and 8-bromo derivatives. Halogen-halogen exchange reactions have also been reported, but they are not common. When perfluoroquinoline was heated... 

The halogenated hydroxyquinolines include iodoquinol and clioquinol. Their mechanism of action is unknown. These agents can produce severe neurotoxicity and clioquinol is believed to have been responsible for the neurotoxic syndrome subacute myelo-optic neuropathy (SMON). 

Borg K, Tjalve H. 1989. Uptake of Ni2 in the central and peripheral nervous system of mice after oral administration Effects of treatment with halogenated 8-hydroxyquinolines. Toxicology 54 59-68. 

Liquid oral antidiarrhoeals of any other dosage form for paediatric use containing halogenated hydroxyquinolines. 

Figure 8-39. The halogenation of 8-hydroxyquinolines may be controlled by co-ordination to a metal ion.

Iodoquinol (diiodohydroxyquin) is a halogenated hydroxyquinoline. It is an effective luminal amebicide that is commonly used with metronidazole to treat amebic infections. Its pharmacokinetic properties are poorly understood. Ninety percent of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11-14 hours, and is excreted in the urine as glucuronides. 

With 20% oleum at 200°C, 3-hydroxyquinoline and 4-hydroxyisoquino-line undergo sulfonation in the 5- and 8-positions in 61 and 57% yield, respectively (72BAU406). These results contrast with the behavior of these molecules in nitration (Section 4.A), halogenation (Section 5.A), and diazonium coupling (Section 6.C), and demonstrate the usual high steric hindrance to sulfonation. However, under basic conditions, the very powerful activation by O is sufficient to produce the normal 4- and 3-substitution, respectively, in yields of 80 and 60% (72BAU404). 

A major epidemic of subacute myelo-optic neuropathy (SMON) in Japan during 1956-70 was identified as being due to choquinol, which led to the withdrawal of halogenated quinolines in Japan itself and subsequently elsewhere. There is every reason to believe that the adverse effects seen with choquinol can occur with the other hydroxyquinolines, but some of them are still sold freely in various parts of the world (1). 

Formation of complexes with ratio M L = 1 3 is observed for the 8-hydroxyquinoline and its derivatives [44]. Americium and plutonium solid compounds were obtained in the form of complexes [Am(Ox)3], [Pu(Ox)3], [Am(DCOx)3], [Am(MCOx)3]. Chelates with halogenated 8-hydroxyquinoline are better extractable from the solution than complexes with 8-hydroxyquinoline. Plutonium (111) easily oxidizes in the presence of 8-... 

Electrophilic catalysis of the departure of halogens in the century-old Koenigs-Knorr reaction is implicit in the use of heavy metal bases such as silver oxide and mercuric cyanide, but the first demonstration of electrophilic catalysis in water (in the hydrolysis of the p-glucoside of 8-hydroxyquinoline by first-row transition metals (Cu Np > C")) was by Clark and Hay in 1973. The observations were expanded to the more conveniently followed (because more labile) benzaldehyde methylacetals or tetrahydropyranyl derivatives of 8-hydroxyquinoline, whose hydrolysis is now known to give solvent-equilibrated oxocarbenium ions (Figure 3.19). Surprisingly, however, the observation of electrophilic catalysis of glycoside hydrolysis itself was not picked up by paper... 

Halogenated 8-hydroxyquinolines such as 5,7-diiodo-8-hydroxyquinoline (Diiodo-hydroxyquin, Fig. 7-9) and 5-chloro-7-iodo-8-hydroxyquinoline (Vioform) are useful as oral amebicides. Only the former is available in the United States for this purpose. (Iodochlorhydroxyquin is available in topical formulation for its dubious antifungal action.) The mechanism of action of these quinolines has not been established. 

In 8-hydroxyquinoline the OH group has a phenolic, or naphtholic character, and the molecule can therefore be easily halogenated or nitrated in positions 5 and... 

The ligand 8-hydroxyquinoline, which is a phenol, is readily halogenated in the 5- and 7-positions. Studies carried out on the halogenation of metal chelates of 8-hydroxyquinoline and its derivatives show that the effect of the metal ion is generally in accord with what is expected, i.e., the metal ion alters the reactivity of the ligand somewhat but not the orientation of substitution. 

The following example illustrates the manner in which changes that occur in the rate of a ligand reaction upon metal chelate formation can be used for synthetic purposes. Two halogen atoms are introduced into a molecule of 8-hydroxyquinoline rapidly and almost simultaneously to give the 5,7-dihalo derivative (118). Studies on the rate of bromination of the Cr(III) or Cu(II) chelates of 8-hydroxyquinoline showed that mono-bromination in the 5-position occurred extremely rapidly, whereas the subsequent introduction of another bromine atom in the 7-position was quite slow. Advantage was taken of this difference in reaction rates to prepare the 5-bromo-, 5-chloro-, and 5-iodo-substituted compounds of 8-hydroxyquinoline and its 2-methyl and 4-methyl derivatives in good yields (169). 

Many quinoline derivatives are important biologically active agents. 8-Hydroxyquinoline and some of its halogenated derivatives are used as antiseptics. Chloroquine 111 is one of the older but still important antimalarials. A -Alkyl-4-quinolone-3-carboxylic acid and systems derived therefrom are constituents of antibacterials (gyrase inhibitors [112]) such as nalidixic acid 112, ciprofloxazin 113 and moxifloxazin 114. The quinoline-8-carboxylic acid derivative 115 (quinmerac) is employed as a herbicide for Galium aparine and other broad-leaved weeds. Methoxatin 116, known as coenzyme PQQ is a heterotricyclic mammalian cofactor for lysyl oxidase and dopamine P-hydroxylase [113]. 

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