Salicylanilides

Closantel, niclosamide, oxyclozanide, rafoxanide, dibromsalan, and tribromsalan are the better-known members of the salicylanilides group of anthelminthics (Fig. 4.5). They are all used to control primarily liver flukes in animals. On absorption, most salicylanilides are bound strongly to plasma proteins, with the exception of the tapeworm remedy niclosamide. These drugs are not soluble in water nevertheless, solutions have been formulated that enable closantel and rafoxanide to be administered parenterally. 

Closantel is used primarily in cattle and sheep for treatment of mature and immature liver flukes, hematophagous nematodes, and larval stages of some arthropods. It is administered orally or parenterally at dosages of 5-15 or 2.5-7.5 mg/kg bw, respectively. Closantel does not exhibit carcinogenic, teratogenic, or embryotoxic activities. 

Closantel is well absorbed, achieving peak plasma levels within 24 h after its oral administration. With parenteral treatment, peak plasma levels are reached within 24-48 h. The primary route of metabolism of closantel is reductive deiodi-nation leading to monoiodoclosantel metabolites (42). Although complete deiodi-nation is possible, no evidence for deiodinated closantel has been yet presented. 

Metabolism studies in sheep with radiolabeled closantel showed that the parent drug accounted for nearly all the radioactivity in muscle, fat, and kidney. In contrast to tissues in which no metabolism occurred, liver contained two closantel metabolites, 3-monoiodoclosantel and 5-monoiodoclosantel, besides the parent drug. The same metabolites were also identified in feces, although 80-90% of the total radioactivity was due to the parent drug. While amide hydrolysis would also appear to be an alternative metabolism pathway, metabolites that would result from this pathway, such as 3,5-diiodosalicylic acid, have not yet been identified. It might well be that steric hindrance around the amide bonds prevents their hydrolysis (42). 

The residue depletion profiles of closantel in cattle and swine are almost similar. Highest concentrations of closantel are seen in kidney, whereas the depletion of closantel from all edible tissues is very slow over the first 28 days of withdrawal. Within animal species, the parenteral and the oral routes of adminis-fration yield comparable residue concentrations provided that the oral dose is twice the parenteral dose. A dose linearity is also observed for residue concentrations in tissues doubling the dose for a particular route of administration doubles the residue level. 

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Salicylanilide (m.p. 131-132°) is obtained by heating the mixture without a diluent for 3 hours at 180-200° with a short air condenser, pouring the melt into 100 ml. of alcohol and working up as above. The persistent pink color is not easily removed. 

Salicyl-u-toluide has been prepared only by the action of phosphorus oxychloride upon a mixture of salicylic acid and o-toluidine. The useful methods of preparation of salicylanilide are by the interaction of salicylic acid and aniline in the presence of phosphorus trichloride, by heating phenyl salicylate and aniline, and from o-hydroxybenzamide and bromobenzene in the presence of small amounts of sodium acetate and metallic copper. A number of these and other anilides have been described. ... 

Salicylanilide is ordinarily made by reacting salicylic acid with aniline in the presence of phosphorus trichloride at an elevated temperature. The theoretical proportions of reactants are usually employed for best results, that is, one mol each of aniline and salicylic acid to a third of a mol of phosphorus trichloride. An improved process employs an inert organic solvent as a reaction diluent. 

Methenolone acetate A ndro tardy 1-0 estradiol Estradiol valerate Aniline Fentanyl Salicylanilide Anisoyl chloride Benzobromarone... 

A typical Hansch analysis has been applied to the 50% inhibitory concentrations (ICjo) of oxidative phosphorylation of 11 doubly substituted salicylanilides (Table 37.1) as reported by Williamson and Metcalf [17]. Multiple linear regression leads to the following model ... 

Lipophilicity (log P), Hammett electronic parameter (a) and inhibitory concentration (ICj,) for oxidative phosphorylation of 11 doubly substituted salicylanilides [17], The two substitution positions are labeled A and B. 

As an illustration of PLS regression (PLSl) we reconsider the inhibitory potencies of oxidative phosphorylation of 11 doubly substituted salicylanilides [ 17] in Table 37.1. An extended Hansch model is defined by the linear free energy relation ... 

R.L. Williamson and R.L. Metcalf, Salicylanilides a new group of active uncouplers of oxidative phosphorylation. Science, 158 (1967) 1694-1695. 

Polarographic studies of a mitochondrial fraction from Hymenolepis diminuta showed that of four substrates tested, DL-glycerol-3-phosphate was the most rapidly oxidized, but the highest respiratory control ratio (1.7) was obtained with dl-isocitric acid. With isocitrate as substrate oxyclozanide at 1.61 nM stimulated O uptake and relieved oligomycin inhibition of adinosine diphosphate-stimulated respiration, but at concentrations above 2 pM progressively inhibited O uptake. Rafoxanide, niclosamide, 3,4,5-tribromo-salicylanilide, nitroxynil, resorantel, di-chlorophen, and 2,4-dinitrophenol exhibited effects similar to those of oxyclozanide on the respiration in cestode mitochondria. The relative potencies were compared and the possible mode of action discussed [38]. 

Toma and coworkers have described the solvent-free synthesis of salicylanilides from phenyl salicylate or phenyl 4-methoxysalicylate and substituted anilines (Scheme 6.155) [302]. By exposing an equimolar mixture of the ester and the amine to microwave irradiation at 150-220 °C for 4—8 min under open-vessel conditions, good yields of the corresponding salicylanilides were obtained. This synthesis was carried out on a multigram scale (0.1 mol). 

The answer is d. (Hardman, p 1019J Niclosamide is a halogenated salicylanilide derivative. It exerts its effect against cestodes by inhibition of mitochondrial oxidative phosphorylation in the parasites. The mechanism of action is also related to its inhibition of glucose and oxyrgen uptake in the parasite. 

Niclosamide is poorly absorbed from the gastrointestinal tract. Unlike other salicylanilides, niclosamide is very rapidly excreted. The small amount absorbed is transformed into the inactive metabolite, aminoniclosamide (32). 

Dibromsalan and tiibiomsalan are both closely related salicylanilides are commercially available as a mixture for treatment of adult and juvenile fluke infections in sheep at oral dosages of 30 and 60 mg/kg bw, respectively. 

Niclosamide Synthetic Salicylanilide Q13H8CI2N2O4 327 EtOH, ether. H2O... 

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