A New Furoxan NO‐Donor Rabeprazole Derivative and Related Compounds

Sorba, Giovanni; Galli, Ubaldina; Cena, Clara; Fruttero, Roberta; Gasco, Alberto; Morini, Giuseppina; Adami, Maristella; Coruzzi, Gabriella; Brenciaglia, M.I.; Dubini, F

doi:10.1002/cbic.200300617

Cited by 20 publications

(10 citation statements)

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“…All these NO donor hybrids were reviewed [2,17]. More recently, NO donor furoxans were also joined to 1,4-dihydropyridine Ca 2+ -channel activators [18], as well as to the REC15/2739, a uroselective α 1 -antagonist [19], and to the rabeprazole, a potent inhibitor of H + /K + -ATPase enzyme [20]. One of the problems that must be addressed when working with hybrid drugs is their balance.…”

Section: Furoxan/drug Hybridsmentioning

confidence: 99%

NO donors: Focus on furoxan derivatives

Gasco

Fruttero

Sorba

et al. 2004

Pure and Applied Chemistry

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Abstract:The article focuses attention on furoxan derivatives (1,2,5-oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro antiaggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO-and drug-dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO-dependent, is a matter still to be explored.

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Section: Furoxan/drug Hybridsmentioning

confidence: 99%

NO donors: Focus on furoxan derivatives

Gasco

Fruttero

Sorba

et al. 2004

Pure and Applied Chemistry

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“…Gasco first reported the thiol mediated release of NO from furoxan ( 2 ) and the resulting vasodilatory properties in 1994 27. Since that time, the core oxadiazole-2-oxide moiety has been conjugated to numerous bioactive compounds in attempts to make chimeric small molecules with dual activities including NO-donating β–adrenoceptor agonists,28 NO-donating aspirin conjugates29 and NO-donating proton pump inhibitors 30…”

Section: Introductionmentioning

confidence: 99%

Structure Mechanism Insights and the Role of Nitric Oxide Donation Guide the Development of Oxadiazole-2-Oxides as Therapeutic Agents against Schistosomiasis

et al. 2009

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Schistosomiasis is a chronic parasitic disease affecting hundreds of millions of individuals worldwide. Current treatment depends on a single agent, praziquantel, raising concerns of emergence of resistant parasites. Here, we continue our explorations of an oxadiazole-2-oxide class of compounds we recently identified as inhibitors of thioredoxin glutathione reductase (TGR), a selenocysteine-containing flavoenzyme required by the parasite to maintain proper cellular redox balance. Through systematic evaluation of the core molecular structure of this chemotype we define the essential pharmacophore, establish a link between the nitric oxide donation and TGR inhibition, determine the selectivity for this chemotype versus related reductase enzymes and present evidence that these agents can be modified to possess appropriate drug metabolism and pharmacokinetic properties. The mechanistic link between exogenous NO donation and parasite injury is expanded and better defined. The results of these studies verify the utility of oxadiazole-2-oxides as novel inhibitors of TGR and as efficacious anti-schistosomal reagents.

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“…In addition, Treger et al [ 32 ] reported that oxadiazole-2-oxides kill Ancylostoma ceylanicum and proved that their target was not glutathione reductase. Besides these reasons, several studies [ 33 – 36 ] have shown that oxadiazole-2-oxides have many functions, which have been used in new drug developments against bacteria, fungi, viruses, worms, tumors, syncopes and immune suppressors. This indicates that oxadiazole-2-oxides may have a lot of function targets.…”

Section: Discussionmentioning

confidence: 99%

Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum

et al. 2016

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BackgroundSchistosomiasis is one of the world’s major public health problems. Besides praziquantel (PZQ), there is currently no other effective treatment against schistosomiasis. The development of new antischistosomal agents to curb the emergence of PZQ resistance should be a high priority. Oxadiazole-2-oxides have been identified as potential antischistosomal reagents, with thioredoxin glutathione reductase (TGR) being one of their molecular targets.MethodsTo develop novel treatment reagents against Schistosoma japonicum, 30 novel oxadiazole-2-oxides were synthesised and their antischistosomal activities on juvenile and adult S. japonicum were evaluated in vitro and in vivo. Their inhibitory activities against S. japonicum thioredoxin glutathione reductase (SjTGR) were also analysed.ResultsMost of the oxadiazole-2-oxides showed good juvenile and adult S. japonica killing activities in vitro. However, the antischistosomal effects of these compounds were not positively correlated with either their inhibition of SjTGR, or with nitric oxide (NO) release. Compounds 4a, 4b, 7c, 13, 16 and 20 resulted in 87.7 %, 83.1 %, 87.1 %, 84.6 %, 90.8 % and 69.5 %, respectively, mortality in the adult worms, when used to treat infected mice at schistosomula stage. These mortality rates were similar to or higher than that of artemisinin. Furthermore, compounds 4a and 16 resulted in 66.7 % and 69.4 % reductions in the worm burdens, respectively, when infected mice were treated at the adult worm stage. These treatment effects were similar to PZQ. No differences in activity of the oxadiazole-2-oxides against female and male adult worms were observed. The toxicity of the oxadiazole-2-oxides on mammalian cells appeared to be similar to, or less than, that of PZQ.ConclusionsThe antischistosomal activity of the oxadiazole-2-oxides does not depend on NO production or the inhibition of SjTGR activity. There may be other functional targets of the oxadiazole-2-oxides in S. japonicum. Several of the novel oxadiazole-2-oxides synthesised in this study could be used to develop novel antischistosomal drugs and explore potential molecular targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1301-3) contains supplementary material, which is available to authorized users.

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A New Furoxan NO‐Donor Rabeprazole Derivative and Related Compounds

Cited by 20 publications

References 23 publications

NO donors: Focus on furoxan derivatives

NO donors: Focus on furoxan derivatives

Structure Mechanism Insights and the Role of Nitric Oxide Donation Guide the Development of Oxadiazole-2-Oxides as Therapeutic Agents against Schistosomiasis

Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum

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