Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis

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f African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed efficacy similar to that of DB829 in dose-response studies in mouse models of first-and second-stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry, and the parasite clearance time in mice were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested Trypanosoma brucei gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second-stage African sleeping sickness.

Section: Discussionsupporting

confidence: 54%

In Vitro and In Vivo Evaluation of 28DAP010, a Novel Diamidine for Treatment of Second-Stage African Sleeping Sickness

Wenzler

Yang

Patrick

et al. 2014

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“…Recent data demonstrate diamidines cross the blood-brain barrier (BBB) and have efficacy in late-stage animal models of human African trypanosomiasis (HAT) (32). Several of these pyridyl diamidine derivatives achieve steady-state levels of 10 to 40 M in brain of rodents dosed orally, and in recent studies DB820 cured Vervet monkeys of late-stage HAT disease (15,33). DB844, a prodrug that is rapidly converted to DB820, dosed at 5 mg/kg of body weight once a day for 5 days, cured monkeys infected with T. brucei rodiesense in the late-stage disease model (34).…”

mentioning

confidence: 99%

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

Rice

Colon

Alp

et al. 2015

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Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium-or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono-and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC 50 ) of 177 nM. Similarly, we identified 10 additional analogues with IC 50 s of <1 M, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono-and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. The first report of animal pathogenicity by free-living amoebae (FLA) was by Culbertson et al., who identified Acanthamoeba in necrotic lesions of monkeys and mice (1). He later suggested that FLA causes similar disease in humans. Fowler and Carter reported the first cases of an acute fatal disease caused by Naegleria fowleri in four victims in Australia in 1965 (2). Since the identification of primary amoebic meningoencephalitis (PAM), hundreds of cases have been reported worldwide, including 142 cases in the United States (3-5). Most infections with N. fowleri occur during the summer months, victims usually are symptomatic within 5 days, and the disease is almost always fatal. Infection usually occurs after the victim swam in warm, fresh, or brackish water or from exposure to contaminated tap water associated with the use of Neti pots for nasal irrigation (4-7). Amoebic invasion occurs via disruption of the olfactory mucosa, penetration of organisms into the submucosal nervous plexus, and ultimately passage through the cribriform plate to the frontal lobes of the brain (8, 9). Although most cases of PAM occur in warm climates, such as the southern tier states of the United States, pathogenic amoeba found in thermally polluted water sources, hot springs, and poorly chlorinated pools have been linked to infections (10, 11). Interestingly, most of the PAM cases have been diagnosed in developed countries, including the United States, Australia, and Europe. Although sporadic cases have been d...

“…Moreover, the dicationic diamidine DB829 is curative in the same murine model of late-stage trypanosomiasis, although its close analogues DB75 and diminazene have no activity at all against the cerebral infection (53). This is clear proof that highly specific transporters for diamidine analogues exist on the murine BBB, with sufficient capacity to facilitate the entry of curative levels of such compounds into the brain (54). Moreover, the fact that 14d hardly binds to plasma proteins (Ͻ20%) gives rise to a higher free plasma concentration of the compound, which in turn makes it more available to such solute transporters and leads to higher activity in vivo in the mouse model of stage 2 sleeping sickness.…”

Section: Discussionmentioning

confidence: 66%

A New Nonpolar N -Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines

Martinez

Miller

Ganeshamoorthy

et al. 2015

Treatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four new N-hydroxy and 12 new N-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluated in vitro against Trypanosoma brucei rhodesiense and in vivo in murine models of first-and second-stage sleeping sickness. Resistance profile, physicochemical parameters, in vitro BBB permeability, and microsomal stability also were determined. The N-hydroxy imidazoline analogues were the most effective in vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was found in vitro, suggesting that N-hydroxy imidazolines are metabolically stable and have intrinsic activity against T. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d in T. brucei was independent of known drug transporters (i.e., T. brucei AT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, the N-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents.