Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues

Hu, Linping; Patel, Alpa V.; Bondada, Lavanya; Yang, Sihyung; Wang, Michael Zhuo; Munde, Manoj; Wilson, W. David; Wenzler, Tanja; Brun, Reto; Boykin, David W.

doi:10.1016/j.bmc.2013.08.006

Cited by 12 publications

(16 citation statements)

References 35 publications

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“…Clearly, with type II compounds, we must diligently seek compounds with improved SI values. Often, cytotoxicity SARs are not obvious, and diamidines are no exception; however, we have found excellent SIs for numerous classes of diamidines (20,22,39), and we expect that we can successfully achieve similar results with type II compounds. Future studies will explore several approaches to determine the minimum size of the bis-benzimidazole diamidines (type II) that retain activity in an effort to identify a lead with physical properties that allow penetration of the BBB.…”

Section: Resultsmentioning

confidence: 76%

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

Rice

Colon

Alp

et al. 2015

Antimicrob Agents Chemother

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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...

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Section: Resultsmentioning

confidence: 76%

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

Rice

Colon

Alp

et al. 2015

Antimicrob Agents Chemother

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“…The diamidines (DB2236, DB2259, DB2260, DB2267) were synthesized using a methodology previously reported (17)(18)(19), and the synthesis of the monoamidines (DB2261, DB2262, DB2263, DB2266, DB2268, DB2269) has been described previously (20) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

Simões-Silva

Nefertiti

Araújo

et al. 2016

Antimicrob Agents Chemother

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The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono-and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC 50 ] ‫؍‬ 0.23 M; selectivity index ‫؍‬ 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC 50 ‫؍‬ 0.87 ؎ 0.05 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (␤-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD.

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“…Worryingly, currenty available chemotherapy against HAT and malaria suffer from serius limitations. 1,4,[7][8][9] Five trypanocidal drugs (pentamidine, suramin, melarsoprol, nifurtimox and eflornithine) are used alone or in combinations specifically for one or another form or stage of HAT, but their relatively high cost, the requirement for longlasting parenteral administration, often impracticable in the affected poor rural settings, the associated toxicity and emergence of parasite resistance, the two latter especially in the case of the arsenical melarsoprol, 10 challenge the widespread, safe and efficacious use of these drugs. 11,12 The emergence of resistance is the cause of the loss of effectivenes of chloroquine, after decades of being the mainstay for malaria treatment, and it starts to challenge also the effectiveness of the current first-line treatments based on artemisinin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

Sola

Castellà

Viayna

et al. 2015

Bioorganic & Medicinal Chemistry

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Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. Inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers but likely it is not their main biological target within Trypanosoma brucei. Regarding their antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis and cerebral malaria. Future optimization should mainly focus on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

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Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues

Cited by 12 publications

References 35 publications

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

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

Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

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