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

Abstract

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.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Transcriptomic analysis reveals increasing levels of transcripts encoding the ABC transporters SMDR1, SmMRP1, SmMRD2, and SMDR3 in juveniles exposed to PZQ1 in vitro, supporting the notion that ABC transporters participate in resistance to PZQ1 in schistosomes (75). Guglielmo et al (120) developed a series of PZQ NO-donors furoxans that are worthy of investigation in view of their potential activity against PZQ-resistant schistosomes. Involvement of Ca 2ϩ channel changes in resistance to PZQ has been widely described (121).…”

Something Old, Something New: is Praziquantel Enough for Schistosomiasis Control?

“…Real progress in this area has not been possible as evidence for development of praziquantel resistance is still mostly indirect and no field-derived clinically resistant isolates are available for detailed study. However, if and when they become available, the elegant approach that has recently been described for identification of the oxamniquine resistance mechanism could similarly be applied for praziquantel and praziquantel structural modifications explored [10,11]. …”

Lewis acid-catalyzed Wolff cyclocondensation in the synthesis of (1H-1,2,3-triazolyl)furoxans

“…Replacement of MeCN with DMF or [bmim]BF4 as well as variation of temperature and reactants ratio also did not improve the product's yield (entries 10-15). Iron (III) chloride and nickel nitrate were also ineffective in this reaction (entries 16,17). Therefore, the optimal conditions were found to include reactants ratio 1:1 and 20 mol.% BF3•OEt2 as catalyst in MeCN at room temperature.…”

“…[5][6][7][8][9][10][11][12] On the other hand furoxan derivatives reveal a wide spectrum of pharmacological activity owing to their ability to release NO under physiological conditions. [13][14][15][16][17][18][19] Our last developments resulted in new, effective one-pot approaches for the synthesis of a series of hybrid heterocyclic systems incorporating furoxan ring connected with various pharmacophoric and/or energy rich poly-nitrogen (nitrogen-oxygen) heterocycles (isomeric 1,2,3-and 1,2,4-triazoles, 1,2,4-and 1,3,4-oxadiazoles, tetrazole, pyridines, tetrahydroisoquinoline, indenopyridine, etc.). [20][21][22][23][24][25][26][27][28] Among synthesized compounds (1,2,3-triazol-1-yl)furoxan derivatives 1 attract special attention due to a wide variety of their pharmacological activity.…”