Trypanosoma rhodesiense: Evaluation of the antitrypanosomal action of 2,5-bis(4-guanylphenyl)furan dihydrochloride

Antimicrobial activity of the DNA minor groove binders furamidine and analogs

“…The effectiveness against trypanosomes was described sometime ago in both murine and simian models. 16, 17 Hall and co-workers 36 have recently demonstrated that one intravenous dose of 2.5 µmol kg -1 of furamidine in a Trypanosomaisis brucei rhodesience mouse model is highly effective (Table 1). A fourteen day intravenous dosing regimen of 13.3 µmol kg -1 of furamidine in an immunosuppressed rat model of Pneumocystis carinii pneumonia (PCP) was quite effective as judged by the reduction of lung cyst counts.…”

“…Sometime ago it was reported that 2,5-bis [4-amidinophenyl]furan (3,furamidine) was effective against trypanosomes in both murine and simian models. 16,17 More recently furamidine was found to be highly active in animal models for Pneumocystis carinii and Cryptosporidium parvum. 18,19 Extensive biophysical studies including NMR, X-ray crystallographic and footprinting investigations have shown that the primary mode of DNA binding for furamidine is at AT-rich sites of the minor groove.…”

“…17,19,35,36 Development of potent dicationic antimicrobial agents alone is not sufficient to be of public health benefit. Consequently, another major part of our investigation focuses on prodrug approaches for amidines as a means to effectively deliver these potent antimicrobial agents.…”

Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

“…[1][2][3][4][5][6][7] The prodrug undergoes a multistep bioconversion in vivo to yield the active drug furamidine (IIa). [8][9][10][11] The establishment of the bioconversion pathway of Ia into IIa was significantly aided by the synthesis of deuterium labelled Ia and IIa. 12 As part of an effort to develop antitrypanosomal compounds that are more effective than Ia/IIa we have found that aza-analogs of these compounds show excellent activity against Trypanosoma brucei rhodesiense (T. b. r.) both in vitro and in vivo in a mouse model.…”

Antileishmanial Mechanism of Diamidines Involves Targeting Kinetoplasts

“…Among them, pentamidine is used as a second-line agent for leishmaniasis and is widely used for the acute phase of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense (5). A diamidine analog of pentamidine, DB75 (furamidine), was discovered to have potent antitrypanosomal activity at a low dose (50% effective concentration [EC 50 ] in the nanomolar range), showing efficacy in vivo in mouse models (6,7). Additionally, its prodrug form, DB289, has been developed as an orally delivered drug candidate, but its development was discontinued during phase III human clinical trials due to toxicity (8).…”