Synthesis of oxadiazole-2-oxide analogues as potential antischistosomal agents

Rai, Ganesha; Thomas, Craig J.; Leister, William; Maloney, David J.

doi:10.1016/j.tetlet.2009.01.120

Cited by 31 publications

(19 citation statements)

References 23 publications

(24 reference statements)

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“…Interestingly, compound 4 that was not among the best inhibitors of TR activity, exhibited a larvicidal effect comparable to the best inhibitors. Similarly, in S. mansoni this compound was one of the most active against the parasite but not the best TGR inhibitor [35]. Most benzofuroxans that were moderately active inhibitors of TGR were also moderately effective in killing E. granulosus protoscoleces.…”

Section: Resultsmentioning

confidence: 96%

“…In total, we examined 21 oxadiazole N -oxides (also known as furoxans), 26 benzofuroxans (these compounds represent a particular type of oxadiazole N -oxides), 11 thiadiazoles, 3 quinoxalines, 1 oxathiazole and 1 nitrooxy-derivative. The furoxan family included the compound 4 (4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide, see Table S1 ), a well-known S. mansoni TGR inhibitor with capability to release nitric oxide (NO) [12], [35]. An initial screening for inhibitors was carried out using the TR assay with DTNB as a substrate.…”

Section: Resultsmentioning

confidence: 99%

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Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites

et al. 2012

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Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 µM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites

et al. 2012

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“…14,15 Furoxan ( 1 , Chart 1) is an old heterocyclic system, well known to chemists because of arguments over its structure. 16 In the recent past, renewed interest has surrounded furoxan derivatives due to the discovery that they can release nitric oxide (NO) under the action of thiol cofactors.…”

Section: Introductionmentioning

confidence: 99%

New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni

Guglielmo

Cortese

Vottero

et al. 2014

European Journal of Medicinal Chemistry

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A series of NO-donor praziquantel hybrid compounds was obtained by combining praziquantel (PZQ) and furoxan moieties in a single entity. NO-donor properties of the furoxan derivatives were evaluated by detecting nitrite after incubation of the products in 7.4 pH buffered solution in the presence of L-cysteine. Structurally-related furazans, devoid of NO release capacity, were also synthesized for control purposes. All products were studied for their ability to inhibit recombinant Schistosoma mansoni thioredoxin glutathione reductase (TGR). Mobility and death of adult Schistosoma mansoni worms cultured in the presence of the products were evaluated versus PZQ. Analysis of the results showed that some products were endowed with both PZQ and NO-dependent antiparasitic properties. Compounds 6, 7, 18, and 24 emerged as the most interesting balanced hybrids, worthy of additional study on PZQ-resistant parasites.

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“…8 General method of preparation for different cinnamaldehydes was given in the ESI. † 14,15 Solvents have been dried according to standard procedures. Purication of products was carried out by silica gel column chromatography using ethyl acetate/hexane as eluent.…”

Section: Generalmentioning

confidence: 99%

De novo synthesis of functionalized 1,3-enynes and extended conjugated molecular systems

2015

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Pd-catalyzed coupling of 1,3-dienyldibromides with triarylbismuths was demonstrated for the synthesis of a diverse range of 1,3-enynes. This study provided easy access to a range of functionalized 1,3-enynes in high yields utilizing triarylbismuths in sub-stoichiometric amounts. A new and concise route was unveiled for the synthesis of extended p-conjugated molecular systems with the help of chemoselective couplings and in conjunction with Sonogashira, Heck and arylation reactions under combined catalysis.

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Synthesis of oxadiazole-2-oxide analogues as potential antischistosomal agents

Cited by 31 publications

References 23 publications

Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites

Identification of Thioredoxin Glutathione Reductase Inhibitors That Kill Cestode and Trematode Parasites

New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni

De novo synthesis of functionalized 1,3-enynes and extended conjugated molecular systems

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