THE BIOLOGICAL ACTIVITY OF ARSENOSOBENZENES IN RELATION TO THEIR STRUCTURE
Authors: HARRY EAGLE, GEORGE O. DOAK
Journal: Pharmacological Reviews (1951)

1. Of the three types of arsenicals used in the treatment of spirochetal and protozoal diseases, only the arsenoso compounds have a direct parasiticidal activity, the arsonic acids and arseno compounds being active by virtue of their conversion to arsenoso compounds in the animal host. 2. Unsubstituted arsenosobenzene was one of the most toxic and most actively parasiticidal compounds in the entire series tested, with no demonstrable selective action among the organisms studied. a) Substitution with a single -CH3, -NO2, -Cl, -NH2, -OH, or -F group either did not significantly affect the toxicity or parasiticidal activity of the parent arsenosobenzene, or reduced them both to the same slight degree. b) Acid-substituents strikingly decreased both the direct parasiticidal and toxic action of arsenosobenzene. The ionized form was generally inactive, the undissociated acid highly active, and the effect of pH on parasiticidal activity could be related to its effect on dissociation. However, there were important exceptions to the general inactivity of the ionized compounds ( e.g. , the 3-NO2-4-COOH and p-(CH2)3COOH arsenosobenzenes); several compounds in this series are of distinct therapeutic interest. c) Amide substituents usually caused a slight decrease in treponemicidal and trypanocidal activity, but a striking decrease in toxicity. As a class, they are therapeutically the most promising group of arsenoso compounds so far studied. Substitution in the amide hydrogens usually diminished its favorable effect on toxicity, exceptions being noted in groups which also reduced the toxicity of arsenosobenzene when substituted directly onto the benzene ring ( e.g. ,-C2H4OH, -C6H4NHCOCH3). d) Unlike amidification, esterification of acid substituents resulted in compounds approaching arsenosobenzene in their high toxicity and general parasiticidal action. Many of these compounds readily hydrolyzed in aqueous solution, their biological activity then corresponding to that of the free acid. e) The effect of complex substituents was usually determined by the nature of the terminal group in the substituent ( e.g. , (CH2)3CONH2; CON(CH3)2). f) Two substituent groups had an effect which could not be predicted from those of the substituents taken singly. Unlike the case of the single substituents, in these di-substituted compounds the position on the benzene ring profoundly modified the activity of the compound. g) Both the toxicity and direct parasiticidal activity of thioarsenites were somewhat less than those of the corresponding arsenosobenzene; in the treatment of rabbit syphilis and mouse trypanosomiasis, the therapeutic index was no better than that of the parent compound. 3. There are several instances of arsenoso compounds with a therapeutic index in a particular infection greatly exceeding that of chemically closely related compounds ( e.g. , mapharsen, melarsen oxide, p-arsenosophenylbutyric acid). These exceptions emphasize the unreliability of generalizations with respect to the effect of a given type of substituent on the biological activity of arsenosobenzene. 4. There is considerable evidence to support the view that the toxicity and therapeutic activity of arsenoso compounds are determined by the amounts which enter into combination with cellular components. The widely varying activity of a single arsenoso compound against different organisms, and of a series of such compounds against the same organism, is related to the amount of arsenical bound. 5. It is a reasonable working hypothesis that arsenoso compounds combine reversibly with sulfhydryl groups in essential enzyme proteins, and that their cytotoxic effect is due to that combination. Many essential enzymes contain sulfhydryl groups, and most such enzymes can be inactivated by arsenoso compounds and reactivated by sulfhydryl or other agents which can compete with the enzyme protein for the arsenical. 6. The highly selective action of particular arsenoso compounds against certain cells could be explained on the basis of either (a) the varying affinity of different enzymes for the same arsenical, or of different arsenicals for the same enzyme, or (b) differences in the permeability of a given cell to different arsenicals. While the evidence is not conclusive, the latter assumption appears best to explain the available data.