Synthesis and Antiprotozoal Activity of Aza-Analogues of Furamidine

6-[5-(4-Amidinophenyl)furan-2-yl]nicotinamidine (<BO>8a</BO>) was synthesized from 6-[5-(4-cyanophenyl)furan-2-yl]nicotinonitrile (<BO>4a</BO>), through the bis-O-acetoxyamidoxime followed by hydrogenation. Compound <BO>4a</BO> was prepared via selective bromination of 6-(furan-2-yl)nicotinonitrile (<BO>2a</BO>) with N-bromosuccinimide, followed by Suzuki coupling with 4-cyanophenylboronic acid. In a similar way, diamidines <BO>8b</BO> and <BO>8c </BO>were prepared from the dicyano derivatives <BO>4c</BO> and <BO>4d</BO>, respectively. N-Methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine (<BO>6a</BO>) was prepared via methylation of the respective diamidoxime <BO>5a</BO> with dimethylsulfate. Prodrugs <BO>6b</BO> and <BO>6c</BO> were also prepared by methylation of the respective diamidoximes <BO>5b</BO> and <BO>5d</BO>. The symmetrical diamidines <BO>14a</BO>,<BO>b </BO>were synthesized through the corresponding bis-O-acetoxyamidoxime followed by hydrogenation. The key compounds <BO>11a</BO>,<BO>b</BO> were conveniently obtained by Stille coupling between 2,5-bis(tri-n-butylstannyl)furan and the corresponding heteroaryl halides. These compounds have been evaluated in vitro for activity against Trypanosoma b. rhodesiense (T. b. r.) and P. falciparum (P. f.). The diamidines <BO>8a</BO>, <BO>8c</BO>, and <BO>14b</BO> gave IC<INF>50</INF> values versus T. b. r. of less than 10 nM. Against P. f. <BO>8a</BO>,<BO> 8b</BO>, and <BO>14b</BO> exhibited IC<INF>50</INF> values less than 10 nM. In an in vivo mouse model for T. b. r. four compounds <BO>6a</BO>, <BO>6c</BO>, <BO>6d</BO>, and <BO>8a</BO> were curative. Compound <BO>6a</BO> produced cures at an oral dosage of 5 mg/kg.