Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents

Hu, Linping; Kully, Maureen; Boykin, David W.; Abood, Norman

doi:10.1016/j.bmcl.2009.01.075

Cited by 28 publications

(32 citation statements)

References 30 publications

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“…This is consistent with the increased double bond character and with the shorter C-N(sp 2 ) bond length in comparison with the C-N(sp 3 ). 29 Overall, in this CSD search the tested structures had too many differences in substituents to give any other conclusion on the dependence of pyramidalization on the length of the hydrogen bond.…”

Section: Crystal Structure Of 34-diaminobenzamidinium Chloride (2)supporting

confidence: 85%

“…The yellow solid was collected by filtration, washed with anhydrous diethyl-ether and dried over KOH to yield 1.17 g (83 %) of imido ester hydrochloride. Absolute ethanol saturated with ammonia (50 cm 3 ) was added to the suspension of crude imido ester hydrochloride (1.17 g, 5 mmol) in absolute ethanol (20 cm 3 ) and the mixture was heated at 50 °C for 3 h, and then stirred over night at room temperature. Solvent was reduced under reduced pressure, and anhydrous ether was added.…”

Section: Synthesis Of 4-amino-3-nitrobenzamidinium Chloride (1)mentioning

confidence: 99%

“…1 The most studied DNA minor groove binders are aromatic amidines with cationic amidine moiety at terminal part of molecules. A large number of compounds from this class which comprise an amidino substituted benzimidazole ring show a potent antimicrobial, [2][3][4][5] antiviral 6,7 and anticancer activity. [8][9][10] The most convenient method of benzimidazole synthesis includes the condensation of 3,4-diaminobenzamidine with aldehyde in the presence of a suitable oxidative reagent such as: 1,4-benzoquinone, 10,11 sodium bisulfate, 12,13 ceric ammonium nitrate 14 or nitrobenzene.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Hydrogen Bonding on the Pyramidalization of the Amino Group: Structure of 3,4-diaminobenzamidinium Chloride

Stolić¹,

Bajić²,

Matković‐Čalogović³

2013

Croat. Chem. Acta

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Abstract. 3,4-diaminobenzamidinium was synthesized and spectroscopically and structurally characterized, both at room temperature and at 150 K. The crystal structure consists of two 3,4-diaminobenzamidinium cations and two chloride anions. The planar amidinium group is inclined by 35.35(5)° and 28.96(7)° in respect to the diaminobenzene moiety in the two crystallographically independent cations. The ions are interconnected by a large network of hydrogen bonds into a threedimensional structure. Pyramidalization of the amino group in relation to the hydrogen bond length in which the amino group is an acceptor is analized. Two amino groups are acceptors of N-H···N hydrogen bonds of 2.9565(14) Å and 2.9654(15) Å resulting in pyramidalization of 340(1)° and 337(1)°, respectively (the sum of the amino group bond angles is given as a measure of pyramidalization). A very weak hydrogen bond to one amino group results in a very flat pyramid (351(1)°), while one amino group is not acceptor of a hydrogen bonds and it is planar. The resonance effect has influence on the planar amino groups resulting in a shorter C-N(amino group) bond length than in the pyramidalized ones. (doi: 10.5562/cca2224) Keywords: pyramidalization of the amino group, 3,4-diaminobenzamidinium chloride, X-ray single crystal structure analysis

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Section: Crystal Structure Of 34-diaminobenzamidinium Chloride (2)supporting

confidence: 85%

Section: Synthesis Of 4-amino-3-nitrobenzamidinium Chloride (1)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Hydrogen Bonding on the Pyramidalization of the Amino Group: Structure of 3,4-diaminobenzamidinium Chloride

Stolić¹,

Bajić²,

Matković‐Čalogović³

2013

Croat. Chem. Acta

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“…These include more than 2,000 derivatives that include dozens of structural classes with various linkers, prodrug moieties, and physiochemical properties. (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Many of these compounds have potency in vitro and in vivo against a variety of parasitic protozoa, including Leishmania spp., Plasmodium falciparum, Trypanosoma cruzi, and T. brucei.…”

mentioning

confidence: 99%

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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“…10,11 Furthermore, bisbenzimidazoles possess topoisomerase-1 12 and serine protease inhibition, 13 antiviral, 14 antileishmanial, 15 and several other biological properties. 16 In continuation of our effort in designing small molecules as anticancer agents, bisbenzimidazoles drawn our interest to synthesize the novel bisbenzimidazoles and evaluate their anticancer activity both in vitro and in vivo. [17][18][19][20][21][22][23][24] Among the newly synthesized compounds, we selected the most potent cytotoxic compound against HeLa (Cervical cancer), HCT116 (Colon cancer), A549 (Lung cancer) and evaluated for its in vivo antitumor and antiangiogenic properties using Ehrlich ascites tumor (EAT) bearing mice.…”

Section: Introductionmentioning

confidence: 99%

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

Roopashree

Mohan

Swaroop

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents

Cited by 28 publications

References 30 publications

Effect of Hydrogen Bonding on the Pyramidalization of the Amino Group: Structure of 3,4-diaminobenzamidinium Chloride

Effect of Hydrogen Bonding on the Pyramidalization of the Amino Group: Structure of 3,4-diaminobenzamidinium Chloride

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

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

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