Synthesis and Antiprotozoal Activity of Aza-Analogues of Furamidine

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 a similar 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. Prodrugs 6b and 6c were also prepared by methylation of the respective diamidoximes 5b and 5d. The symmetrical diamidines 14a,b were synthesized through the corresponding bis-O-acetoxyamidoxime followed by hydrogenation. The key compounds 11a,b 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 8a, 8c, and 14b gave IC(50) values versus T. b. r. of less than 10 nM. Against P. f. 8a, 8b, and 14b exhibited IC(50) values less than 10 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.

Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines

“…No correlation between DNA binding and in vitro activity was observed which was not unexpected as this is a general trend that has been reported previously with related bisguanidines and other dicationic minor groove binders [11]. However, it was also noted in these reports that weak DNA binding results in reduced antitrypanosomal activity [15,29,32,33].…”

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

“…Four infected mice were treated with the drugs either by the intraperitoneal or for prodrugs by the oral route on days 3-6 post infection and parasitamia checked to day 60. The experiments were carried out as previously reported [37].…”

A new synthesis of 2,5-bis(4-cyanophenyl)furan

“…[1][2][3][4] Furamidine (2) is the parent compound of this class, and it's methoxime prodrug (3) (Pafuramidine) is currently in clinical trials for treatment of African Sleeping sickness, malaria, and pneumocystis carinii pneumonia. [4][5] Satisfactory methods for conversion of the intermediate bis-nitrile 1 to 2 and 3 are available.…”