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Antitumor Phthalanilides Active in Acute and Chronic Trypanosoma Brucei Brucei Murine Infections^*

Henry C. Nathan, Cyrus J. Bacchi, Charles A. Nichol, David S. Duch, Elizabeth A. Mullaney AND Seymour H. Hutner

Biology Department and Haskins Laboratories of Pace University, New York, New York 10038
The Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709

A series of phthalanilides and related compounds were tested on a short-term, fulminating, mouse infection of Trypanosoma brucei brucei (EATRO 110 isolate). The most effective compound was [4,4'-bis(4-methylimidazolin-2-yl)-terephthalanilide] which had a cure rate of 75% at 0.1 mg/kg body weight and 100% at 0.5 mg/kg when administered as three single daily intraperitoneal injections starting 24 hours post-infection. Several related phthalanilides and similarly substituted ureas showed definite but lower activity. In tests with a chronic neurotropic T. b. brucei isolate (TREU 667), cure rates greater than 90% were obtained with 10 or 25 mg/kg [4,4'-bis(4-methylimidazolin-2-yl)-terephthalanilide]. Cured animals survived for at least 200 days after infection with no evidence of recrudescence of parasitemia or of toxicity; blood or brain homogenates of cured animals were non-infective to immunosuppressed animals. These studies indicate that this series of compounds, previously studied as antitumor agents, should be re-examined as potential trypanocides.

Accepted for publication March 9, 1984.

^* This research was supported by grant AI 17340 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and a grant from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (CJB).