Sep-Oct 2008 Synthesis of Conformationally Constrained Adamantane Imidazolines with Trypanocidal Activity 1401 Ioannis Papanastasiou 1 , Andrew Tsotinis 1 , George B. Foscolos 1* , S. Radhika Prathalingam 2 , John M. Kelly 2 1 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece. 2 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K. tsotinis@pharm.uoa.gr Received February 29, 2008 N N R' R H N N R' R 8a-f, 9a-c 14a-f, 15a,b Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we report on the synthesis of spiro adamantane 2-imidazolines 8a-f and 9a-c, and their congeneric 5-(1- adamantyl)imidazolines 14 and 15. The potency of these compounds against Trypanosoma brucei was compared to that of rimantadine and found, in the case of compound 14e, to be three fold higher. Together with the other active compounds, 14b and 15b, which were equipotent to rimantadine, the new molecules illustrate the synergistic effect of the lipophilic character of adamantane and the C1 amidine functionality on trypanocidal activity. J. Heterocyclic Chem., 45, 1401 (2008). INTRODUCTION Human African Trypanosomiasis (HAT) is endemic in several areas of Sub-Saharan Africa. Current estimates are that 70,000 individuals are infected, the number having fallen from 450,000 within the last 10 years as a result of co-ordinated public health campaigns [1]. HAT is caused by tsetse fly transmitted protozoan parasites of the Trypanosoma brucei species complex, and is invariably fatal unless treated. For more than fifty years, pentamidine and suramin have been the drugs of choice against first stage disease [2]. However, these compounds are unable to cross the blood brain barrier and are therefore ineffective against second stage HAT, which occurs once the parasites has accessed the central nervous system. The arsenical melarsoprol (Mel B, Asorbal) and eflornithine (Ornidyl) are the only drugs routinely used against this stage of the disease. New drugs are urgently required since melarsoprol is extremely toxic and eflornithine is only effective against T.b. gambiense and is relatively expensive. We have reported that bloodstream forms of Trypanosoma brucei are susceptible to the anti-influenza virus drug rimantadine, and to a lesser extent amantadine [3] (compounds 1 and 2, Fig. 1). This could have relevance for drug development against HAT, since both compounds readily cross the blood brain barrier and are well absorbed from the gastrointestinal tract. Further tests with substituted aminoadamantane derivatives identified compounds with enhanced potency (compounds 3-5, Figure 1), and we showed that this increased trypanocidal activity could be correlated with hydrophobic substitutions to the adamantane ring [4,5]. C CH 3 H NH 2 .HCl NH 2 .HCl NH 2 .HCl () 2 NH 2 .HCl NH 2 .HCl 2 1 3 4 5 Figure 1. Structures of trypanocidal aminoadamantanes [4]. The concentrations that inhibited growth of bloodstream form T. brucei by 50% (IC 50 ) were established as follows: (1) 7.04 μM; (2) > 132 μM; (3) 0.52 μM; (4) 0.62 μM; (5) 0.33 μM. To explore further the potential of this class of compound against T. brucei, these observations have prompted us to synthesise adamantane 2-imidazolines 8 and 9 (Schemes 1 and 2), and their 1-substituted congeners 14 and 15 (Scheme 3). These compounds combine two distinct structural components: amidine moieties, which have been widely shown to display trypanocidal activity, attached to adamantane, a lipophilic molecule which could facilitate passage of the new derivatives across the blood brain barrier.