Activity, mechanism of action and pharmacokinetics of 2-tert-butylbenzothiazole and CGP 6140 (amocarzine) antifilarial drugs.

A variety of recently developed drugs, designed to be used in antifilarial chemotherapy, contain a thiocarbonylamide group as a common structural element. One group of these compounds is based on a 2-tert-butylbenzothiazole ring in which the carbonylamide linkage is present as an isothiocyanate, dithiocarbamic acid ester or thiourea derivative. The single representative of another series is an N-methylpiperazine adduct of amoscanate (CGP 6140 or amocarzine). CGP 6140 is currently undergoing clinical trials in patients suffering from onchocercosis. All of the drugs with antifilarial activity affect the motility of filarial worms in vitro. The primary site of action of most of these compounds is the mitochondrion. The drugs result in the swelling of this organelle and also the inhibition of respiration and other associated metabolic functions. The dithiocarbamic acid esters (e.g., CGP 20376) are devoid of intrinsic antifilarial activity. Activity of these compounds requires conversion to the corresponding isothiocyanates. This occurs spontaneously in aqueous solution at physiological pH. The thiourea compounds were found to inhibit acetylcholinesterase activity by competing with its substrate. There is also evidence that the latter drugs are metabolized by a host-derived enzyme to their isothiocyanate analogs. CGP 6140 affects both mitochondrial function and acetylcholinesterase activity. The biochemical effects of the antifilarial compounds were not found to be significantly different between mammalian and parasite test systems. Biochemical and pharmacokinetic studies suggest that the selective toxicity of the new series of drugs towards filarial parasites is most likely preferential drug uptake by the pathogen. The lack of a unique target for these compounds in the parasite may explain the side-effects seen upon their administration to humans.