Phenothiazines anthelmintic activity

The existence of a correlation between anthelmintic activity and redox potentials of phenothiazine derivatives stimulated extensive work on oxidation of (7-substituted phenothiazines, and some results are presented in Table III. 

Phenothiazine drugs have been the subjects of various electrochemical investigations. The motivation for these studies has been the search for means of analyzing drugs and their derivatives. Tozer et examined the correlation between C-substitution, standard electrode potential, cation-radical formation constants, and the anthelmintic activity of the heterocycles. 

Although several chemicals, e.g. arsenicals and organophosphorus compounds, had been used with some effect to treat specific helminth infections, the introduction in 1930 of phenothiazine (1) was a revolutionary event in the control of gastrointestinal worms. Although its spectrum of activity was narrow compared to modern anthelmintics and its dose level was rather high (600-800 mg kg-1), it was the veterinary anthelmintic of choice until the 1960s. 

The next novel anthelmintic after phenothiazine (1) was methyridine (2) which was active at 200 mg kg-1 both orally and parenterally (i.e. other than intestinally). It had a wide range of activity but was erratic against abomasal parasites and did not have a wide safety margin. 

The first synthesis of phenothiazine was reported by Bernthsen about 80 years ago. In the evolution of the chemistry of this heterocycle, three periods can be discerned. First, phenothiazine was of interest owing to its quinonoid derivatives—an important chapter in sulfur dye chemistry. Research work in the field of phenothiazine was then stimulated by the discovery of the anthelmintic action of unsubstituted and of some C -substituted phenothiazines. During the last two decades, the exceptional pharmacological properties of some A-substituted phenothiazines, e.g., the antihistaminic activity of promethazine, 10-(2-dimethylamino-l-propyl)phenothiazine, and particularly the psychotherapeutic action of chlorpromazine, 2-chloro-10-(3-dimethylamino-1 -propyl )phenothiazine, focused interest mainly on the synthesis and testing of a great number of compounds of this type. The phenothiazine drugs now play a very important part in chemotherapy. 

It was with the action of phenothiazine that the importance of particle size was first recognised, in 1939, in relation to its toxicity to codling moth larvae, and in 1940 in relation to its anthelmintic effect, in both of which it was shown that reduction in particle size increased activity. The improvement in biological response to griseofulvin on microni-sation is well known similar blood levels of the dmg were obtained with half the dose of micronised dmg compared to those of non-micronised griseofulvin. The influence of... 

These include amitraz (110), prepared from 54, a member of the form amidine class, active against mites and ticks, that have replaced organophosphorus compounds. Notably, amitraz is active against newer strains of pyrethroid-resistant ticks. The reaction of diphenylamine (8) with sulfur in the presence of iodine as catalyst yields the anthelmintic (worming agent) phenothiazone (phenothiazine) (111) (Scheme 24). It is too toxic for human use, though it is an intermediate in the production of antipsychotic drugs. 

Phenothiazine and many of its substituted derivatives possess important and various biological activities, and have been shown to present significant insecticidal, antifungal, antibacterial and anthelmintic properties. Unsubstituted phenothiazine has also been used for vermifugal application, which has earned this molecule a good place alongside penicillin and DDT for its great impact on mankind, as recently pointed out by Mitchell [111]. 

In the phenothiazine area, it has been amply demonstrated that structural changes, in addition to producing expected quantitative changes in tranquilizing activity, also produce unexpected qualitative changes in biological activity. As a result antipruritic, antispasmodic, anticonvulsant, antibacterial, antiemetic, antimotion sickness, anthelmintic, and antidepressant compounds have been developed by molecular modification of the phenothiazines. 

Unsubstituted phenothiazine (XVI) is, of course, well known as an anthelmintic agent, and is devoid of tranquilizing properties (12). Another unalkylated phenothiazine, methylene blue (XVII) (21), is known to have antibacterial activity and to be devoid of tranquilizing properties. Antibacterial activity is also claimed for XVIII (28). Compound XIX with a dimethylsul-... 

Phenothiazines are not naturally occurring substances but a number of phenothiazine derivatives have useful medicinal applications. For example, phenothiazine and some C-substituted derivatives have anthelmintic properties (i.e., the ability to destroy worms). Various N-substituted phenothiazines have important pharmacological properties. For example, promethazine [10-(2-dimethylamino-l-propyl)phenothiazine] possesses antihistaminic activity and chlorpromazine [2-chloro-10-(3-dimethylamino-l-propyl)phenothiazine] has a profound psychotherapeutic activity and is widely used, as are related phenothiazines, for the treatment of various mental illnesses. 

Mebendazole 6.34) and its variants in which the 5-benzoyl-group is replaced by a butyl (parbendazole), phenylthio (fenbendazole) or propylthio (albendazole) group are highly selective variants of thiabendazole. Albendazole has a particularly broad spectrum of activity (Theodorides et al. 1976). Phenothiazine, the first of the selective anthelmintics for sheep, is now little used because of the large dose needed. 

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