THE EFFECT OF MULTIPLE SUBSTITUENTS ON THE TOXICITY AND TREPONEMICIDAL ACTIVITY OF PHENYLARSENOXIDE

¹ From the United States Public Health Service, Washington, D. C., and the Syphilis Division of the Department of Medicine, Johns Hopkins Medical School, Baltimore, Maryland

The effect of multiple substituent groups on the potential therapeutic utility (ratio of treponemicidal activity in vitro: mouse toxicity) of phenylarsenoxide could not be regularly anticipated from the effect of each of the groups acting singly.

In general, however, and except for certain of the aminophenols, combinations of 2 or 3 groups were no more favorable, and often were distinctly less favorable, than the best one of the constituent groups:

1) Groups without any significant effect on the ratio of activity:toxicity (2-CH₃, 3-NH₂, ₂-Cl, 4-OCH₃), when used in combination either remained inert, or lowered the activity:toxicity ratio.

2) Combinations of one "good" group (3- or 4-NH₂, 3- or 4-OH), and one "inert" or "favorable" group (3- or 4-Cl, 4-OCH₃, 3-NO₂, 4-COOH, 2-NH₂) were, with only one exception, not as good as the one favorable group alone, and were often even worse than the unsubstituted parent phenylarsenoxide (cf. the 3-NO₂-4-OH, 3-Cl-4-OH, 2-OH-3-NH₂, compounds).

3) Combinations of two or three "good" groups (3- or 4-NH₂, 3- or 4-OH, 4-C₂,H₄OH, 3- or 4-NHCOCH₃, 4-CONH₂) were usually no more favorable than the best of the component groups (cf. 3-NH₂-4-C₂H₄OH, 3-NHCOCH₃-4-OH, 3-NH₂-4-CONH₂), and in several instances were distinctly less so (cf. 3,4-diNHCOCH₃, 3,4-diOH, 3-OH-4-CONH₂, 3-OH-5N₂, 3-NH₂-4-OH-5-NH COCH₃). One combination of favorable groups has, however, proved actively synergistic, causing a striking decrease in toxicity, with only a slight decrease in treponemicidal activity. That favorable combination is the aminophenol group. Six of the ten possible isomeric phenylarsenoxides containing one amino and one phenolic group have been studied here, and three of these (3-NH₂-4-OH ("Mapharsen") 3-OH-4-NH₂, 2-NH₂-3-OH) gave activity: toxicity ratios of 5.5, 3.9, and 3.3 respectively, referred to that of phenylarsenoxide as 1, and to be compared with a maximum index of 1.6 for the single substituent groups. No such synergistic effect was observed in the 2-OH-5-NH₂, 3-OH-5-NH₂, or 2-OH-3-NH₂ phenylarsenoxides, with indices of 1.8, 0.8 and 0.54 respectively. The favorable index of the 3,4-diNH₂, phenylarsenoxide (3.5) may be related to the fact that it could be converted to the corresponding aminophenol by partial oxidation in vivo.

The favorable effect of the 3-NH₂-4-OH combination was impaired by introducing a 5-NH₂ group as a third substituent in the ring, and was altogether obliterated by acetylation of the amino group, methylation of the hydroxyl group, or by introducing 5-NHCOCH₃ as a third substituent in the ring.

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