| Abstract
| - 6-[5-(4-Amidinophenyl)furan-2-yl]nicotinamidine (8a) was synthesized from 6-[5-(4-cyanophenyl)furan-2-yl]nicotinonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation. Compound 4a was prepared via selective bromination of 6-(furan-2-yl)nicotinonitrile (2a)with N-bromosuccinimide, followed by Suzuki coupling with 4-cyanophenylboronic acid. In asimilar way, diamidines 8b and 8c were prepared from the dicyano derivatives 4c and 4d,respectively. N-Methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine (6a)was prepared via methylation of the respective diamidoxime 5a with dimethylsulfate. Prodrugs6b and 6c were also prepared by methylation of the respective diamidoximes 5b and 5d. Thesymmetrical diamidines 14a,b were synthesized through the corresponding bis-O-acetoxyamidoxime followed by hydrogenation. The key compounds 11a,b were conveniently obtainedby Stille coupling between 2,5-bis(tri-n-butylstannyl)furan and the corresponding heteroarylhalides. These compounds have been evaluated in vitro for activity against Trypanosomab.rhodesiense (T. b. r.) and P. falciparum (P. f.). The diamidines 8a, 8c, and 14b gave IC50 valuesversus T. b. r. of less than 10 nM. Against P. f.8a, 8b, and 14b exhibited IC50 values less than10 nM. In an in vivo mouse model for T. b. r. four compounds 6a, 6c, 6d, and 8a were curative.Compound 6a produced cures at an oral dosage of 5 mg/kg.
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