Trypanocide Diamidine mit drei isolierten Ringsystemen

The antifungal and antibacterial properties of a series of 70 diarylamidine derivatives were evaluated. Several of these compounds exhibited considerable antimicrobial potency. A survey of the structure-activity relationship demonstrated that minor structural variations resulted in significant changes of antimicrobial activity. In general, the structural features required for antifungal activity coincided with those required for antibacterial activity. Both the antifungal and the antibacterial properties of the diarylamidines depended on the presence and the positions, of both amidino groups, on the nature of the central bridge connecting the two aryl moieties, and on the nature of these aryl residues (preferably indole). The most active compound was evaluated for its activity against Candida albicans infection in mice.

Section: Resultsmentioning

confidence: 99%

Antifungal and antibacterial activities of diarylamidine derivatives

Anné¹,

Clercq²,

Eyssen³

et al. 1980

“…DB75 is active against Trypanosoma spp. in vitro (11,12) and is a structural analogue of the aromatic diamidine drug pentamidine.…”

Section: Human African Trypanosomiasis (Hat) Is a Fatal Tropical Disementioning

confidence: 99%

“…DB75 is active against Trypanosoma spp. in vitro (11,12) and is a structural analogue of the aromatic diamidine drug pentamidine.DB75 and pentamidine are antimicrobial diamidine-type compounds that are active against various fungal and protozoal infections. However, the mechanism through which diamidine drugs exert their activity is still not entirely known and continues to be a focus of extensive research (46).…”

mentioning

confidence: 99%

The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei

Lanteri¹,

Tidwell²,

Meshnick

2008

Human African trypanosomiasis (HAT) is a fatal tropical disease caused by infection with protozoans of the speciesNew therapies are desperately needed for the treatment of human African trypanosomiasis (HAT). This reemerging tropical disease afflicts as many as 500,000 people (2, 5). Current drugs, such as pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox, are often associated with deleterious side effects and cannot be administered orally (5,16,19,34).A promising new therapy, DB289 [2,5-bis-(4-amidinophenyl)-furan bis-O-methylamidoxime], is undergoing phase III clinical trials for registration as the first orally administered drug for early-stage HAT (19). The oral prodrug DB289 is metabolically converted to the trypanocidal agent DB75 [2,5-bis(4-amidinophenyl)furan] (6, 50, 51). DB75 is active against Trypanosoma spp. in vitro (11,12) and is a structural analogue of the aromatic diamidine drug pentamidine.DB75 and pentamidine are antimicrobial diamidine-type compounds that are active against various fungal and protozoal infections. However, the mechanism through which diamidine drugs exert their activity is still not entirely known and continues to be a focus of extensive research (46). We previously investigated the mechanisms of action of DB75 and pentamidine in yeast cells and found that both drugs appear to disrupt the mitochondrial function in Saccharomyces cerevisiae by collapsing the mitochondrial membrane potential (⌿ m ) and inhibiting mitochondrial respiration (24). We also showed that DB75 and pentamidine inhibit oxidative phosphorylation in isolated rat liver mitochondria (24), which is consistent with the results attained with pentamidine in a previous study (31).The purpose of this investigation was to gain insight into the mechanism of trypanocidal action of DB75. In particular, we investigated if DB75 acts against Trypanosoma brucei bloodstream forms (BFs) by targeting the mitochondrion. MATERIALS AND METHODSChemicals. DB75 [2,5-bis(4-amidinophenyl)furan dihydrochloride] was obtained from David Boykin at Georgia State University, Atlanta, and pentamidine isethionate [1,5-di(4-amidinophenoxy)pentane isethionate] was prepared by LyphoMed, Inc. (Melrose Park, IL). All other chemicals were of the highest quality available and were from Sigma-Aldrich (St. Louis, MO), unless otherwise stated.Collection and isolation of trypanosomes from infected blood. Male SpragueDawley rats and Swiss-Webster mice (Charles River Laboratories, Cambridge, MA) were infected by intraperitoneal injection of approximately 2 ϫ 10 6 and 5 ϫ 10 5 BFs of Trypanosoma brucei brucei strain 427 cells, respectively. Infected blood was collected through cardiac puncture at the time of peak parasitemia (usually day 5 postinfection for rats and day 4 postinfection for mice). The blood was centrifuged in heparinized tubes at 2,200 ϫ g for 10 min at 4°C, and the buffy coat was removed and diluted 1:3 in phosphate saline glucose buffer, pH 8.0. The trypanosomes were purified from the blood by the use of DE52 anion-exchange...

“…(8,9) in vitro. DB289 [2,5-bis-(4-amidinophenyl)furan bis-O-methylamidoxime] is the amidoxime prodrug of DB75 that is orally active and metabolically converted to DB75.…”

mentioning

confidence: 99%

DB75, a Novel Trypanocidal Agent, Disrupts Mitochondrial Function in Saccharomyces cerevisiae

Lanteri¹,

Trumpower

Tidwell³

et al. 2004

The aromatic diamidines represent a class of compounds with broad-spectrum antimicrobial activity; however, their development is hindered by a lack of understanding of their mechanism of antimicrobial action. DB75 [2,5-bis(4-amidinophenyl)furan] is a trypanocidal aromatic diamidine that was originally developed as a structural analogue of the antitrypanosomal agent pentamidine. DB289, a novel orally active prodrug of DB75, is undergoing phase IIb clinical trials for early-stage human African trypanosomiasis, Pneumocystis jiroveci carinii pneumonia, and malaria. The purpose of this study was to investigate mechanisms of action of DB75 using Saccharomyces cerevisiae as a model organism. The results of this investigation suggest that DB75 inhibits mitochondrial function. Yeast cells relying upon mitochondrial metabolism for energy production are especially sensitive to DB75. DB75 localizes (by fluorescence) within the mitochondria of living yeast cells and collapses the mitochondrial membrane potential in isolated yeast mitochondria. Furthermore, addition of DB75 to yeast cells or isolated rat liver mitochondria results in immediate uncoupling of oxidative phosphorylation and subsequent inhibition of respiration. We conclude that the mitochondrion is a cellular target of DB75 in yeast cells and anticipate that the results of this study will aid in the target-based design of new antimicrobial aromatic diamidines. Human African trypanosomiasis (HAT) is a life-threatening tropical disease caused by bloodstream infection with parasitic protozoans of the subspecies Trypanosoma brucei rhodesiense or T. brucei gambiense.HAT is resurgent and is currently estimated to afflict up to 500,000 people (5). New and improved therapies for HAT are urgently needed, since current drugs, like pentamidine, are marked by serious shortcomings, such as toxic side effects, difficulties in methods of administration, and lack of oral activity (4, 16).DB75 [2,5-bis(4-amidinophenyl)furan] is an important aromatic diamidine that is active against Trypanosoma spp. (8, 9) in vitro. DB289 [2,5-bis-(4-amidinophenyl)furan bis-O-methylamidoxime] is the amidoxime prodrug of DB75 that is orally active and metabolically converted to DB75. DB289 is currently undergoing phase IIb human clinical trials for treatment of early-stage HAT, Pneumocystis jiroveci carinii pneumonia (PCP), and malaria. DB75 belongs to a class of compounds, known as the aromatic diamidines, which exert broad-spectrum antimicrobial activity (reviewed in reference 3); however, the mechanism of action of these compounds is poorly understood. DB75 is a structural analogue of pentamidine [1,5-di(4-amidinophenoxy) pentane] (Fig. 1), a clinically important aromatic diamidine that is used to treat early-stage HAT, antimony-resistant leishmaniasis, and AIDS-related PCP. Many modes of action have been proposed for pentamidine. Studies in yeast have suggested that pentamidine inhibits mitochondrial metabolism (17,26). Further investigation into the mechanism of action of aromatic diamidines i...