Human African trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. Diamidine compounds such as pentamidine, DB75, and DB820 are potent antitrypanosomal compounds. Previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. However, the mechanism of action of this class of compounds remains unknown. A long-hypothesized mechanism of action has been binding to DNA and interference with DNA-associated enzymes. The fluorescent diamidines, DB75 and DB820, have been shown to localize not only in the DNA-containing nucleus and kinetoplast of trypanosomes but also to the acidocalcisomes. Here we investigate two series of analogs of DB75 and DB820 with various levels of in vitro antitrypanosomal activity to determine whether any correlation exists between trypanosome accumulation, distribution, and in vitro activity. Despite wide ranges of in vitro antitrypanosomal activity, all of the compounds investigated accumulated to millimolar concentrations in trypanosomes over a period of 8 h. Interestingly, some of the less potent compounds accumulated to concentrations much higher than those of more potent compounds. All of the compounds were localized to the DNA-containing nucleus and/or kinetoplast, and many were also found in the acidocalcisomes. Accumulation in the nucleus and kinetoplast should be important to the mechanism of action of these compounds. The acidocalcisomes may also play a role in the mechanism of action of these compounds. This investigation suggests that the extent of accumulation alone is not responsible for killing trypanosomes and that organelle-specific accumulation may not predict in vitro activity.Diamidine compounds, such as pentamidine, propamidine, and diminazene, have been used for many years as chemotherapeutic agents for infections caused by a variety of microbes, including parasites and fungi. Pentamidine has been used for almost 60 years as a treatment for human African trypanosomiasis and is also used to treat leishmaniasis and the opportunistic infection Pneumocystis pneumonia (32). Diminazene has been used widely for treatment of animal trypanosomiasis (9) and has also been used in humans (25). Recently, pafuramidine, or DB289, a methamidoxime prodrug of the diamidine DB75 (furamidine), has been developed as an oral treatment for early-stage sleeping sickness caused by Trypanosoma brucei gambiense. DB289 is currently in phase III clinical trials in sub-Saharan Africa (6). In addition to DB75 and DB289, a library of diamidines and prodrugs has been synthesized, with various activities against many parasites (1-3, 14-18, 32).Although diamidines have been used therapeutically for over half a century, their mechanism of action is not well understood. Many mechanisms of action have been proposed (32), but one mechanism of action of diamidines that has often been hypothesized is binding to DNA in the nucleus or kinetoplast, leading to interference of DNA-associated enzymes, such as topoisomerase II (27, 34)....

Dicationic 2,4-bis(4-amidinophenyl)furans 5-10 and 2, 4-bis(4-amidinophenyl)-3,5-dimethylfurans 14 and 15 have been synthesized. Thermal melting studies revealed high binding affinity of the compounds to poly(dA-dT) and to the duplex oligomer d(CGCGAATTCGCG)2. All of the new compounds were effective against Pneumocystis carinii pneumonia in the immunosuppressed rat model with up to 200-fold increase in activity compared to the control compound pentamidine. No toxicity was noted for 5, 7-10 at the dose of 10 micromol/kg/d; however, the isopropyl analogue 7 showed toxicity comparable to pentamidine at the dosage of 20 micromol/kg/d. Dimethylation of the parent compound on the furan ring resulted in reduced activity and increased toxicity.

A facile three step process, under mild conditions, for the synthesis of 2,4-diarylfurans with the same or different substituents on the two aryl rings, starting from benzaldehydes and acetophenones, employing HallerÐBauer type cleavage of 2-aroyl-3,5-diarylfurans is described.Synthetic routes to 2,4-diarylfurans are limited. 1,2 Convenient procedures for preparing 2,4-diarylfurans with the same or different substitutents on the two aryl rings are even more rare. One method which seems to be general for preparation of both types of substituted 2,4-diarylfurans involves the condensation of acetophenones with 1-amino-4,6-diphenyl-2-pyridone and subsequent metallation of the ketimines with butyllithium at Ð78 ¡ C followed by reaction with phenacyl bromides. 3 The addition of dimethylsulfonium methylide to -alkoxy-α , -unsaturated ketones is also a useful approach for synthesis of 2,4diarylfurans. 4 For most substituents, both of these methods require synthesis of starting materials and the former one requires low temperature operations. For the latter approach synthesis of the required -alkoxy-α , -unsaturated ketones is a multistep process which sometimes involves the use of diazomethane. 4,5 Synthesis of 2,4-diarylfurans directly from phenacyl bromides by electrochemical methods 6 , by reaction with nickel carbonyl in DMF 7 , by reaction with cuprous chloride 8 , and by reaction with sodium telluride 9 have been reported. These methods suffer from two or more of the following disadvantages: only furans with the same substitutents on the two aryl rings may be made, many of the phenacyl bromides are not commercially available, only modest yields are obtained, key reagents are toxic, and specialized equipment is required. As part of a program focused on the development of antiinfective agents we needed a convenient method for preparation of relatively large quantities of 2,4-diarylfurans. 10 This report describes a simple three step synthetic method starting from benzaldehydes and acetophenones which can be used for preparation of 2,4-diarylfurans with the same or different substitutents on the two aryl rings. The approach employed is presented in the Scheme below. The reaction of one equivalent of substituted benzaldehydes 1 with two equivalents of substituted acetophenones 2 mediated by boron trifluoride etherate in benzene has been reported for the synthesis of a large

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