THE TOXICITY, TREPONEMICIDAL ACTIVITY, AND POTENTIAL THERAPEUTIC UTILITY OF SUBSTITUTED PHENYLARSENOXIDES II. MONOSUBSTITUTED PHENYLARSENOXIDES (Cl; NO₂; CH₃; C₂H₄OH; C(CH₃):NOH; NH₂, OH, CH₂NH₂ AND DERIVATIVES)

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, Md.

Twenty-seven monosubstituted phenylarsenoxides (o-, m-, and p-OH, -NH₂, -Cl, -NO₂, and -CH₃, p-C₂H₄OH; pC(CH₃):NOH; p-CH₂NH₂, p-CH₂NHCOCH₃; p-NHCOC₆H₄NH₂, p-NHCOC₆H₄NHCOCH₃; p-OCH₃, p-OCOCH₃, p-OCH₂CH₂OH; m-NHCOCH₃, p-NHCOCH₃ and p-N(CH₃)₂) have been studied from the point of view of toxicity in mice and rabbits, treponemicidal activity in vitro, and therapeutic activity in syphilitic rabbits.

1. The toxicity for white mice per gram arsenic ranged between 7 and 120, referred to that of the unsubstituted phenylarsenoxide as 100.

2. The treponemicidal activity, similarly expressed, varied between 21 and 147. Most of the compounds were both less active and less toxic than phenylarsenoxide, i.e., substitution in the benzene ring inhibited both these properties.

3. The ratio of relative treponemicidal activity in vitro:relative mouse toxicity, varied from 0.68 to 4.0 referred to that of phenylarsenoxide as 1. Only the m-OH, p-OH, m-NH₂, p-NH₂, p-CH₂NH₂, p-NHCOC₆H₄NH₂ phenylarsenoxides, their acetyl derivatives, p-C₂H₄OH, and p-NO₂ phenylarsenoxides had activity:toxicity ratios significantly exceeding that of the unsubstituted phenylarsenoxide. Since the corresponding value for "Mapharsen" (3-NH₂-4-OH-phenylarsenoxide) was 6.0, it would seem that none of these twenty-seven derivatives is potentially as valuable as "Mapharsen" in the treatment of syphilis. This was confirmed for seven of these compounds by the assay of therapeutic activity and toxicity in syphilitic rabbits. The close agreement between their chemotherapeutic index as determined in rabbits, and the ratio of their relative treponemicidal activity in vitro: relative toxicity in white mice, suggests that the latter comparatively simple assays may prove useful as an orienting clue to the potential therapeutic utility of substituted phenylarsenoxides.

4. The present study indicates that different substituent groups may affect treponemicidal (therapeutic) activity and toxicity to varying degrees, and not necessarily in parallel. It follows that compounds may well be discovered in which the ratio of these two properties is more favorable than it is in "Mapharsen". The generally favorable effect of acetylating the amino-substituted phenylarsenoxides, the absence of any similar improvement on acetylating the p-OH derivative, and the unfavorable effect of methylating the p-OH or p-NH₂ groups, are of interest in this connection. Except for the three nitro compounds, the position of the substituent group relative to the arsenoxide group had relatively little effect on either activity or toxicity in this particular series of compounds.

This article has been cited by other articles:

				C. F. MOHR, P. PADGET, R. HAHN, and J. E. MOORE SYPHILIS: REVIEW OF THE RECENT LITERATURE Arch Intern Med, March 1, 1942; 69(3): 470 - 545. [Abstract] [PDF]