Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans

Abstract

Eighteen substituted 2,5-bis(4-guanylphenyl)furans and related analogues, including "masked" amidines in which the guanyl function is incorporated into a heterocyclic ring, have been synthesized and their antimalarial and antitrypanosomal activity has been evaluated. None of the compounds exhibited high orders of antimalarial activity; however, 11 were very active against Trypanosoma rhodesiense in mice. Six compounds, including 2,5-bis(4-guanylphenyl)furan (4) and its 3-chloro (32), 3,4-dichloro (31), 3-methyl (25), 3,4-dimethyl (20), and 3-chloro-4-methyl (38) derivatives, produced cures in mice at submilligram dosage levels; the 3,4-dimethyl (20) analogue exhibited a prolonged curative effect providing protection for 30 days after a single dose against a challenge by T. rhodesiense. These six compounds are somewhat more active in this screen than stilbamidine, hydroxystilbamidine, and pentamidine. The "masked" amidines generally exhibited lower antitrypanosomal activity than their true guanyl counterparts. Compound 4 was synthesized from 1,4-di-p-bromophenyl-1,4-butanedione by cyclodehydrative furanization to 2,5-bis(4-bromophenyl)furan (2) which was allowed to react with Cu2(CN)2 to produce the corresponding bis-nitrile 3. The latter compound was ultimately converted by way of an imidate ester into 4. Similarly, the 3- and/or 4-substituted derivatives of 2 were employed to prepare the other members of the series.

Sequence and length dependent thermodynamic differences in heterocyclic diamidine interactions at AT base pairs in the DNA minor groove

“…DB75 was synthesized as previous described [31]. Its purity was verified by NMR and elemental analysis.…”

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

“…Furamidine, previously called DB75, is a diamidine analog of pentamidine in which the alkoxy chain linking the phenyl rings has been replaced with a furan ring ( Fig. 1) (Das and Boykin, 1977). Furamidine has shown excellent in vitro and in vivo activity in mouse and monkey models of early stage African trypanosomiasis (Barrett et al, 2007).…”

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

“…1) has been used as a first-line treatment for infections such as human African trypanosomiasis and drug-resistant leishmaniasis for more than half a century, and in the treatment of AIDS-related PCP for approximately 20 years, despite its loss of activity when administered orally and its toxicity when administered intravenously. The diamidine structure of pentamidine has been shown to be essential for its antimicrobial activity, which results from binding to DNA (Das and Boykin, 1977), although the exact mechanism of action is currently unknown.…”