Short communication Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes Jose L. Gonzalez a , Chad E. Stephens a , Tanja Wenzler b , Reto Brun b , Farial A. Tanious a , W. David Wilson a , Todd Barszcz c , Karl A. Werbovetz c , David W. Boykin a, * a Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, University Plaza, Atlanta, GA 30303-3083, USA b Parasite Chemotherapy, Swiss Tropical Institute, Basel CH4002, Switzerland c Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA Received 14 August 2006; received in revised form 12 November 2006; accepted 16 November 2006 Available online 22 November 2006 Abstract A series of bis-2,5-[4-guanidinophenyl]thiophenes were prepared in a five step process starting from 2,5-bis[trimethylstannyl]thiophene. The compounds were evaluated in vitro against Trypanosoma brucei rhodesiense (T. b. r.), Plasmodium falciparum (P. f.), Leshmania donovani (L. d.) and Trypanasoma cruzi (T. c.), and in vivo against T. b. r. Certain compounds show promising in vitro activity against T. b. r. and P. f. and have superior in vivo activity against T. b. r. to that of pentamidine and furamidine. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Diguanidino thiophenes; Antiparasitic agents 1. Introduction Over three billion people are estimated to be at risk for the parasitic diseases such as malaria, African (sleeping sickness) and American (Chagas disease) trypanosomiasis and leish- maniasis [1]. Furthermore, the combined number of cases of these diseases is estimated to be approximately 300 million [1,2]. A relatively new development further increases the pub- lic health burden, through transmission of Chagas disease by travelers with blood transfusions in countries not normally af- fected by the diseases [3]. Malaria is widely distributed throughout the tropics and it is estimated that between 350 and 500 million clinical episodes occur annually in areas where some 3.2 billion people are at risk [4]. Plasmodium fal- ciparum (P. f.) and Plasmodium vivax cause the majority of human cases. Sleeping sickness caused by the parasites Trypa- nosoma brucei rhodesiense (T. b. r.) and Trypanosoma brucei gambiense, is fatal if not treated and impacts the socioeco- nomic well being of millions of people in central Africa [1]. Chagas disease, caused by Trypanosoma cruzi (T. c.), is found in much of South America, all of Central America and in Mex- ico. The Leishmania parasite is broadly distributed in humans and animals. It is found in the Far East, southern Europe and now even in the United States [1]. Many of the drugs currently in use for the treatment of these parasitic infections were de- veloped over 50 years ago and have major limitations includ- ing significant toxicity, variable efficacy, lack of oral bioavailability, extensive courses of parenteral administration, and problems of cost and supply. Furthermore, there is consid- erable evidence that extended use of these drugs is leading to the development of resistance [5]. The need for the discovery of new drugs to treat these diseases is clear. Dicationic molecules were first reported to have significant antiprotozoal activity in the 1930’s [5]. Despite numerous studies of various classes of dications, the diamidine pentam- idine (I) is the only compound from this class which has seen significant human use. Pentamidine is used to treat early stage * Corresponding author. Tel.: þ1 404 651 3798; fax: þ1 404 651 1416. E-mail address: dboykin@gsu.edu (D.W. Boykin). 0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2006.11.006 European Journal of Medicinal Chemistry 42 (2007) 552e557 http://www.elsevier.com/locate/ejmech