Identification of Isoflavone Derivatives as Effective Anticryptosporidial Agents in Vitro and in Vivo

Stachulski, Andrew V.; Berry, Neil G.; Low, Audrey; Moores, Shelley L.; Row, Eleanor C.; Warhurst, David C.; Adagu, I. S.; Rossignol, Jean‐François

doi:10.1021/jm050973f

Cited by 108 publications

(37 citation statements)

References 25 publications

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“…Finally, these experiments have validated the gerbil model of cryptosporidiosis even if the infection does not cause diarrhea and they are restricted to the drug's effect on oocyst shedding. It remains a reliable animal model that cor- relates with our efficient in vitro screening system and allowed us to test two families of effective compounds, the isoflavones (7,8) and the thiazolides (1).…”

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confidence: 99%

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Gargala

Audigier

Favennec

et al. 2013

Antimicrob Agents Chemother

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cNitazoxanide and three halogeno-thiazolides, RM-4850, RM-4865, and RM-5038, were tested against Cryptosporidium parvum in experimentally infected immunosuppressed Mongolian gerbils. Daily 400-mg/kg doses of the four test drugs for 5 to 8 consecutive days produced similar reductions of oocyst shedding. Using early-infected gerbils, a shorter 4-day treatment with RM-5038 reduced oocyst shedding by 95%, compared to 47% for nitazoxanide (P ‫؍‬ 0.02), suggesting that RM-5038 is more effective than nitazoxanide under the experimental conditions used. We have previously reported the in vitro activities of several thiazolides against Cryptosporidium parvum and Sarcocystis neurona, two apicomplexan protozoa (1, 2). Recent tests of RM-5038 showed the same level of activity as its active circulating metabolite RM-4848, which, with RM-4850 and RM-4865, had exhibited the highest level of in vitro activity against C. parvum development. These compounds deserved to be tested in vivo to confirm their anticryptosporidial activity.The in vivo activities of nitazoxanide and three halogenothiazolides were studied in experimentally Cryptosporidium parvum-infected gerbils (Meriones unguiculatus). Animals weighing 30 to 40 g at the beginning of the study were individually housed in plastic cages equipped with a grill ceiling providing rodent food granules and water ad libitum. The cage was protected by another top wrapped with sterile paper in order to comply with level II contamination requirements. Animals were handled according to the technical and ethical regulations of the French Ministry of Agriculture. Gerbils were immunosuppressed by injection of dexamethasone (Qualimed, Puteaux, France) at 0.8 mg every 2 days and fed a low-protein diet (white bread) for at least 10 consecutive days before infection, and dexamethasone was administered until the end of the experiment. Prior to the start of treatment, each gerbil was inoculated by oral gavage with C. parvum oocysts. The test compounds were suspended in pure dimethyl sulfoxide (DMSO) and administered at a dose of 200 mg/kg of body weight twice daily by oral gavage in a constant volume. One to 3 days after the cessation of treatment, all of the animals were killed by deep sodium thiopental anesthesia. To assess C. parvum infection, the volume of the cecal and colonic contents collected from each sacrificed gerbil was suspended in a 10% (wt/vol) formalin solution and homogenized. The suspension was vortexed for 30 s and allowed to settle for an additional 30 s. Ten percent of the suspension was diluted in phosphate-buffered saline (PBS) and centrifuged at 1,800 ϫ g for 30 min. After washing, the pellet was resuspended in PBS and half of the oocyst-containing pellet was incubated with an oocyst-specific monoclonal antibody conjugated with fluorescein isothiocyanate (Crypt-aGlo; Waterborne, New Orleans, LA) in the dark at 37°C for 30 min. A CytoSpin was prepared for each specimen, and oocysts were counted by epifluorescence microscopy at a magnification of ϫ400. The number of oocyst...

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confidence: 99%

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Gargala

Audigier

Favennec

et al. 2013

Antimicrob Agents Chemother

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“…It is one of the privileged scaffolds with a medicinal pharmacophore such as antivascular, antimicrobial, antioxidant, anticoagulant, estrogenic, anti-helminthic, anticancer 1 , anti-HIV, anti-inflammatory 2 , analgesic, herbicidal 3 and anticonvulsant. Chromenes are an important natural occurring compound such as flavonoids, alkaloids, tocopherol and anthocyanin [4][5][6] . Benzo[g]chromene contains naphthoquinone structural motifs which also have a broad spectrum in biological activities, as molecular probes for biochemical research 7 , emitters in electroluminescence devices and as fluorescent whitening agents 8 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and In Vitro Antibacterial Effect of 4H-Benzo[g]chromene Derivatives using Nano-NiO

2017

Chem Sci Trans

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Abstract:The domino Knoevenagel cyclocondensation reactions via substituted aldehydes, activated methylene reagent and 2-hydroxy-1, 4-naphthoquinone gives benzo[g]chromenes in presence of nano-NiO using acetonitrile as a solvent at ambient temperature. This method gives the desired products from good to excellent yield. The salient features of this atom economical procedure are ease of manipulation, simpler workup, high yield processing, easy handling, inexpensiveness, reusability of catalyst and tolerance to a wide range of functional groups. The synthesized chromene derivatives are screened for antibacterial activity and antifungal activity using Kirby-Bauer method. The synthesized compounds 3a-3k exhibits significant inhibition to antibacterial and antifungal activity compared with the standard drug Ciprofloxacin and Flucanazole respectively.

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“…Moreover, functionally substituted chromenes have played increasing roles in synthetic approaches to promising compounds in the field of medicinal chemistry. [1][2][3][4] Only few synthetic approaches to chromenopyridines employing different reaction conditions and using salicylaldehyde have been previously described in literature by Sakurai et al 5 and O'Callaghan et al 6,7 Sakurai et al 5 obtained two benzopyrano [3,4-c]pyridines in 7-10% yields working with salicylaldehydes, ethyl acetoacetic ester and ammonium acetate in ethanol. The main product of the reaction was a tetrahydropyridine derivative.…”

Section: Introductionmentioning

confidence: 99%

On the one pot syntheses of chromeno[4,3-b]pyridine-3-carboxylate and chromeno[3,4-c]pyridine-3-carboxylate and dihydropyridines

Navarrete-Encina¹,

Salazar²,

Vega-Retter³

et al. 2010

J. Braz. Chem. Soc.

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Os cromenos, dihidropiridinas e piridinas substituídos têm-se revelado importantes na síntese de compostos com propriedades farmacológicas interessantes. Consequentemente, achamos importante a síntese de cromenopiridinas e cromenodihidropiridinas (ou seja, anéis fundidos do cromeno e da dihidropiridina ou da piridina) de forma a pesquisar a sua atividade biológica. Neste estudo, propomos a síntese "one-pot" para 2,4-dimetil-5-oxo-5H-cromeno [4,3-b]piridina-3-carboxilatos de etilo, 2,4-dimetil-5-oxo-5H-cromeno[3,4-c]piridina-3-carboxilatos de etilo substituídos e as suas respectivas 1,4 dihidropiridinas, baseada numa síntese modificada da piridina de Hantzsch usando 2-hidroxiaril aldeído, com os grupos que retiram e doam elétrons no anel fenil, como reagentes iniciais. Dezesseis compostos foram sintetizados pelo método descrito e completamente caracterizados. Um rendimento médio de 37% foi obtido para os diferentes derivados.Substituted chromenos, dihydropyridines and pyridines have been important in the syntheses of compounds having interesting pharmacological properties. Therefore, we found of interest to synthesize chromenopyridines and chromenodihydropyridines (i.e., fused chromeno and dihydropyridine or pyridine rings) to further study their biological activity. Here, we propose one-pot syntheses for substituted ethyl-2,4-dimethyl-5-oxo-5H-chromeno [4,3-b]pyridine-3-carboxylates, ethyl-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-3-carboxylates and their respective 1,4-dihydropyridines based on a modified Hantzsch pyridine synthesis using 2-hydroxyaryl aldehydes, with electron withdrawing and electron donating groups on the phenyl ring, as starting reactants. Sixteen compounds were synthesized by the described method and fully characterized. An average yield of 37% was obtained for the different derivatives.

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Identification of Isoflavone Derivatives as Effective Anticryptosporidial Agents in Vitro and in Vivo

Cited by 108 publications

References 25 publications

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Synthesis, Characterization and In Vitro Antibacterial Effect of 4H-Benzo[g]chromene Derivatives using Nano-NiO

On the one pot syntheses of chromeno[4,3-b]pyridine-3-carboxylate and chromeno[3,4-c]pyridine-3-carboxylate and dihydropyridines

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