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

Henry C. NathanBiology Department and Haskins Laboratories of Pace University, New York, New York 10038

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Cyrus J. BacchiBiology Department and Haskins Laboratories of Pace University, New York, New York 10038

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Charles A. NicholThe Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709

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David S. DuchThe Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709

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Elizabeth A. MullaneyBiology Department and Haskins Laboratories of Pace University, New York, New York 10038

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Seymour H. HutnerBiology Department and Haskins Laboratories of Pace University, New York, New York 10038

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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.

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