Molecular and Biochemical Parasitology, 9 (1983) 197-208 197 Elsevier MBP 00360 TRYPANOCIDAL ACTION OF NEUROLEPTIC PHENOTHIAZINES IN TR YPANOSOMA BR UCEI THOMAS SEEBECK~ and PETER GEHR 2 ~lnstitut fiir Allgemeine Mikrobiologie, University of Bern, Baltzerstrasse 4, CH-3012 Bern, and2Anatomisches lnstitut, University of Bern, Baltzerstrasse 2 CH-3012 Bern, Switzerland (Received 4 March 1983;accepted 15 April 1983) This paper reports the effects of a series of phenothiazine derivatives on trypanosomes in vitro. Our results demonstrate that trypanosomes are very sensitive to some of these compounds at micromolar concentrations. Electron microscopic analysis of drug-treated cells shows that the pellicular layer of microtubules is selectively disintegrated by phenothiazine treatment, while the flagellaraxoneme is entirely resistant to the drug. These observations suggest that phenothiazines might constitute a promising candidate group for the development of new trypanocidal drugs. Furthermore, they indicate that the mechanism of drug action is mediated through a specific interaction of phenothiazines with the pellicular, but not with the flagellar, microtubules. Key words: African trypanosomiasis; Chemotherapy; Neuroleptic phenothiazines; Microtubules INTRODUCTION Curative and preventive chemotherapy of African trypanosomiasis is still in an unsatisfactory state. Despite considerable efforts over the past 75 years, comparative- ly few trypanocidal drugs of lasting value have been found, and the current WHO list of trypanocides approved for human use consists of just three drugs (Melarsoprol, Pentamidine and Suramin) [1], all of which are between 25 and 60 years old. Severe side effects are frequently encountered, and drug resistance is becoming an increasing problem [2,3]. We are currently studying the microtubular system of trypanosomes as a potential target structure for drug attack. The cell body oftrypanosomes is tightly enveloped by regularly packed pellicular microtubules [4,5], which confer both motility and mecha- nical stability to these cells. Microtubules are also involved in the structure of the flagellum, which is another important component of the cellular motility system. Any disruption of these systems can be expected to severely restrict the viability of the Abbreviations: DMSO, dimethylsulfoxide; CAPP, 2-chloro-10-(3-aminopropyl)phenoth-~ine; TCA, tri- chloroacetic acid. 0166-6851/83/$03.00 © 1983 Elsevier Science Publishers B.V.