Anthelmintics broad spectrum activity

S-Hydroxylation of milbemycins 54a-c, 16-membered ring macrolides isolated from Streptomyces hygroscopicus and showing potent and broad spectrum activity as anthelmintics, acaricides and insecticides, was found to be relatively efficient (yields around 50%) by selenium dioxide oxidation in formic acid and subsequent acidic hydrolysis (Scheme 6) [21]. 

Although thiabendazole shows broad-spectrum activity against different helminths in humans and animals, it suffers from the limitation of being readily metabolised to form the inactive 5-hydroxythiabendazole (3, R=OH), with a half-life of only n minutes in rats [7]. To prevent this enzymatic hydroxylation of the drug at 5-position, Merck scientists synthesized a variety of 5-substituted thiabendazoles, of which 5-aminothiabendazole (4) and 2-(thiazol-4-yl)-5-isopropylcarbonylami-nobenzimidazole (5, cambendazole) showed promising activity. The better anthelmintic activity of 4 and 5 compared to thiabendazole has been attributed to their longer half-life [8,9]. 

The benzimidazoles have emerged as the most versatile group of anthelmintics possessing broad-spectrum activity against a variety of helminths in humans. These drugs show powerful activity against roundworms [4,167,171,198], tapeworms [199], but are less active against flukes [57],... 

It is a broad spectrum anthelmintic effective in pinworm, ascariasis and hook worm infestation. It exerts its action by producing persistent nicotinic receptor activation which results in spastic paralysis of worms. 

In 1966 the second modern broad spectrum anthelmintic, tetramisole (9), was introduced by Jannsen. The discovery of this drug followed the observation that the thiazothienol (10) was metabolized to an active compound in chickens. This was shown to be the thiazothielite (11) which led ultimately to the discovery of tetramisole (9). Later investigations showed that most of the activity of tetramisole (9) was due to the L-isomer, levamisole, which was more potent and less toxic than the D-isomer. Since their introduction, tetramisole (9) and levamisole have probably become the most widely used anthelmintics against a broad range of nematodes in pigs, sheep and poultry. Furthermore, unlike most benzimidazole carbamates, which are rather insoluble and must be given as an oral drench, levamisole may be given by the more convenient injectable route at a dose of 7.5 mg kg-1. 

Pyrantel pamoate is a broad-spectrum anthelmintic highly effective for the treatment of pinworm, ascaris, and Trichostrongylus orientalis infections. It is moderately effective against both species of hookworm. It is not effective in trichuriasis or strongyloidiasis. Oxantel pamoate, an analog of pyrantel not available in the USA, has been used successfully in the treatment of trichuriasis the two drugs have been combined for their broad-spectrum anthelmintic activity. 

Of the anthelmintic 2-acyl-l,2,3,5,6,116-hexahydro-4//-pyrazino[2,l-a]-isoquinolin-4-ones, the orally effective 1-cyclohexylcarbonyl derivative, praziquantel (24), exhibits a broad spectrum with excellent activity against schistosomes and cestodes, and it is widely used in human and veterinary therapy [77E1036 78H(11)521 83MI2 90KFZ(9)60]. 

Tetrahydro-6-phenylimidazo[2,l-6]thiazoIe hydrochloride (tetramisole) is a broad-spectrum anthelmintic the D-form is an antidepressant the L-form (levamisole) is known to possess immunoregulatory or immunostimulatory activity. Some phenacylthio-imidazolines which are tautomeric to cyclic carbinolamines are very potent antagonists of reserpine-induced hypothermia in mice. The corresponding 3-aryl-5,6-dihydroimidazo[2,l-6]thiazoles are also potent antidepressants. 5,6-Bis(4-methylsulfinylphenyl)-2,3-dihy-droimidazo[2,1 -b Jthiazole is used especially in the treatment of rheumatic arthritis. 

Three principal chemical classes of anthelmintic with a broad spectrum of activity are in common... 

While broad spectrum anthelmintics (macrolide endectocides, benzimidazole carbamates, tetrahydropyrimidines) largely overlap in the range of endoparasites (mainly nematodes) they affect, the various anthelmintic classes (based on chemical structure) differ in mechanism of action, degree of activity and in pharmacokinetic properties (bioavailability, tissue distribution and... 

Dutton and coworkers [21] have isolated about 36 avermectins (10) which are produced through mutational biosynthesis by Streptomyces avermitilis, a mutant strain ATCC-53568. These antibiotics exhibit broad-spectrum of antiparasitic activity. Several avermectin homologues (11) were produced by S. avermitilis in presence of externally supplied sodium 2-methylpentanoate and sodium 2-methylhexanoate. The homologues, thus produced, carry 2-pentyl and 2-hexyI groups, respectively, at the C-25 position of the aglycone moiety. These antibiotics are designated as avermectin "c" and "d", respectively, which possess high anthelmintic and insecticidal activities 1221. 

The discovery of the anthelmintic activity of the pyrazinoisoquinolines [25,31,32] initiated the synthesis of a variety of substituted pyrazinoisoquinolines. Praziquantel was picked up from more than 400 l,2,3,6,7,llb-hexahydro-4H-pyraz-ino[2,l-a]isoquinolin-4-ones and related compounds, because of its potent and broad spectrum biological activity [26]. The structure activity relationship in the analogues of praziquantel would indicate that positions 2 and 4 are the most critical positions, which govern the cestodicidal as well as antischistosomal activities in the pyrazinoisoquinolines. 

The avermectins (AVM) are a family of naturally occurring macrolides which are produced by Streptomyces avermitilis and possess potent broad-spectrum anthelmintic, acaricidal and insecticidal activity (25-27). One of the major components of the avermectin complex is AVM Bla. This has been shown to interfere with neurotransmission at excitatory neuronal (nerve-nerve) synapses in the ventral nerve cord of A. suum where the mode of action seems to involve a GABA-ergic mechanism (1, 3) AVM Bla also abolishes the hyper polarizing potentials recorded from muscle bags of A. suum in response to stimulation of inhibitory motorneurones O, 3.). Kass and co-workers (2, 28) suggest that the effect on inhibitory neuromuscular transmission results from blockade of GABA receptors present on the postsynaptic muscle membrane. As the postsynaptic receptors are... 

Avermectins and milbemycins are naturally occurring 16-membered macrolactones that show a broad spectrum of anthelmintic and pesticidal activity with relatively low toxicity to both humans and animals. The milbemycins differ from the avermectins primarily in the lack of a disaccharide moiety and oxygen functionality at Cl3,... 

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