Trypanocidal Action of 3-Nitrobenzoic Acid and Some Derivatives

Abstract

Various sulfonamide derivatives prepared in this laboratory have been tested against Trypanosome equiperdum with negative results. 4-Nitrobenzoic acid which has a slight antibacterial action 1 , 2 was found to have a trace of trypanocidal activity. Investigation of the isomers revealed that the meta derivative showed increased activity against trypanosomes, although without effect upon bacteria; 2-nitrobenzoic was inactive against both types of infection. A review of the literature revealed that Morgenroth found 3-hydroxybenzoic acid to possess some trypanocidal action. 3

A more detailed study of 3-nitrobenzoic acid and some derivatives was undertaken. Mice were inoculated intraperitoneally with a quantity of trypanosomes that would cause death in 3 to 5 days. Therapy was usually begun on the second day after inoculation. The dosage used was in most cases one-half of the maximum tolerated single dose; this was repeated daily for 3 to 6 days to surviving animals. A few of the compounds were synthesized by one of us (H.B.). The others were obtained from Eastman Kodak Company.

The average survival time was calculated from the day of inoculation, using a maximum of 30 days.

Compounds with some activity are shown in Table I. The following derivatives also showed traces of activity; dosages in grams per kilo, administered subcutaneously, are shown in parenthesis. The soluble sodium salts of the acids were employed. Insoluble compounds were injected in olive oil. Dosages represent approximately one-half the single M.T.D.

3-Nitrobenzyl chloride (0.5), 3-nitrohippuric acid (2.0), 5-nitrosalicylic acid (0.5), and 3,5-dinitrosalicylic acid (0.1).

The following compounds were inactive:

2-Nitrobenzoic acid (0.5), 3-nitrophenol (0.25), 3-nitrochlorobenzene (0.25), 3-nitrobenzene sulfonamide (0.25), 3-nitrobenzene sulfonic acid (1.0), 3-nitrobenzoyl-2-amino-pyridine (0.4), 3-nitroanisole (0.5), 3-nitrophenetole (0.5), 3-nitroacetophenone (0.5), 3-aminobenzoic acid (2.0), 3-aminobenzene sulfonamide (1.5), nicotinamide (1.0), isophthalic acid (1.5), 3-nitrophthalic acid (2.0), 4-nitrophthalic acid (2.0), 3-nitrophthalimide (1.0), 3-nitrosalicylic acid (0.5), 3,5-dinitro-benzoic acid (0.25), 2,4-dinitro-benzoic acid (0.5), 3-nitro-4-hydroxy-toluene (0.5), 3-nitro-2-aminotoluene (0.25), 3-nitro-4-aminotoluene (0.5), 3-nitro-2-iodotoluene (0.4), 3-nitro-4-amino-anisole (0.5), 3-nitro-4-amino-phenetole (0.75), 3-nitro-4-acetylaminophenyl acetate (0.5), 3-nitrodiphenylene oxide (0.5).