Antimicrobial activity of the DNA minor groove binders furamidine and analogs

Abstract

Análogos arílicos de diamidinas da pentamidina e do berenil que interagem com a fenda menor de DNA estão sendo sintetizados com amplo espectro de atividade antimicrobiana. Várias séries de análogos da furamidina, 1,5-bis[4-amidinofenil]furano foram descritas e apresentaram boa potência quando administradas de forma intravenosa. Entretanto, elas foram inativas quando administradas oralmente. As pró-drogas do tipo amidoxima e carbamato dessas furamidinas são potentes quando administradas oralmente. Atualmente uma dessas pró-drogas, a bis-O-metiloxima está em estudos clínicos de Fase II.Aryl diamidine analogs of pentamidine and berenil that bind to the minor groove of DNA have been developed which show broad spectrum antimicrobial activity. Several series of analogs of 2,5-bis[4-amidinophenyl]furan (furamidine) have been described which are quite effective when given intravenously, however they are ineffective on oral administration. Amidoxime and carbamate prodrugs of furamidine are quite effective when given orally. One of these prodrugs, a bis-O-methylamidoxime is currently in Phase II clinical trials.

Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African Trypanosomes

“…Trypanosomes growing in vitro were exposed to DB75 or DB820 at concentrations of 7.5 M, approximately 1,000 times the IC 50 values. This concentration is similar to that used in previous studies with pentamidine (5). Uptake of both DB75 and DB820 increased over time, with millimolar concentrations in trypanosomes at 24 h (Fig.…”

“…Diamidines, such as DB75, DB820, and pentamidine, are able to bind DNA in AT-rich regions of the minor groove (5,28). In fact, one of the long-hypothesized mechanisms of action has been binding to DNA and/or interference with DNA-associated enzymes such as topoisomerase II (21, 22).…”

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

“…Heterocyclic diamidines that target AT sequences and that have significant biological activity against specific DNA target sites in parasitic microorganisms [19][20][21] are of particular interest for drug development. A prodrug of the lead compound, DB75 (Figure 1), is currently in phase III clinical trials against trypanosome induced sleeping sickness and other compounds of this type are being tested against trypanosomes and other diseases in humans [19,22].…”

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.…”

“…[4][5] Satisfactory methods for conversion of the intermediate bis-nitrile 1 to 2 and 3 are available. 1,6 Several methods for the synthesis of bis-nitrile 1 are also available; 6-8 however many of these methods require multiple steps and/or are not high yielding. In some cases, there have been problems in scaling the synthesis of intermediate 1 to kilogram scale.…”