Anti-pneumocystis activity of bis-amidoximes and bis-o-alkylamidoximes prodrugs

Efficient one-pot synthesis of 1-alkoxy-2-arylaminoimidazolines from N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides and arylisothiocyanates

“…In particular, the amidoxime prodrug strategy developed by Clement and co-workers 5 and used by the group of Boykin and Tidwell to improve the oral bioavailablity of a series of 2,5-bis(4-amidinophenyl)furan derivatives is a very promising approach [6][7][8][9] that proved also useful for the CNS delivery of the diamidine antitrypanosomal agents DB844 and DB289. [10][11][12] Encouraged by this data, we considered the preparation of 1-alkoxy-2-aminoimidazoline derivatives that could work as potential prodrugs for the 2-aminoimidazoline group.…”

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)

“…From the many structurally related compounds that have been synthesized and tested to date, the dicationic agent DB75 (furamidine dihydrochloride; 2,5-bis(4-guanylphenyl)furan dihydrochloride) has emerged as the most promising from the therapeutic/toxicity aspect when administered intravenously, but it lacks the desired property of good oral activity because of inadequate bioavailability. However, its bis(N-methoxyamidoxime) derivative, DB289 (pafuramidine maleate; 2,5-bis phenyl]furan monomaleate), acts as a prodrug for DB75 (Boykin et al, 1998) and exhibits high oral activity against the organisms in question as well as reduced acute toxicity in the animal models of PCP and trypanosomiasis (Boykin et al, 1996). In addition, DB289 has been shown to possess good in vivo activity against malaria in the mouse and in vitro activity against various Plasmodium strains, such that it is currently undergoing clinical trials for all these disease conditions.…”

Human Enteric Microsomal CYP4F EnzymesO-Demethylate the Antiparasitic Prodrug Pafuramidine

“…DB289 was synthesized by Medichem (Woodlake, IL) using previously described methods (Das and Boykin, 1977;Boykin et al, 1996). The intermediate Phase I metabolites (M1, M2, and M3), the active diamidine DB75, and deuterium-labeled DB289 (DB289-d 8 ) (internal standard) were a gift from Dr. David W. Boykin (Georgia State University, Atlanta, GA).…”

“…As a result, DB75 suffers from poor systemic exposure when given p.o. Pafuramidine (DB289) is a methylamidoxime prodrug of DB75 that has improved oral efficacy and reduced acute toxicity in animal models of Pneumocystis pneumonia and African trypanosomiasis (Boykin et al, 1996). In addition, an early clinical trial involving patients with first-stage African trypanosomiasis treated with p.o.…”