Furoxan Derivatives Research Articles

Reaction mechanisms of 3-amino-4-nitro-furoxan formation by 3-amide-4-nitro-furoxan and sodium hypochlorite in water and benzene solvents

Synthesis of new furoxan-based compounds has been a hot research topic in order to explore the energetic materials with good application prospect. 3-amino-4-nitro-furoxan is a precursor for synthesis of furoxan derivatives because that the amino groups are prone to be substituted by nucleophiles. A theoretical research is conducted for the formation reaction of 3-amino-4-nitro-furoxan by 3-amide-4-nitro-furoxan and sodium hypochlorite in water and benzene solvents using the density functional theory (DFT) and CCSD coupled cluster method to reveal the formation mechanism and explore new synthesis routes. The structures and energies of intermediates and transition states in the possible reaction pathways are given, and the potential energy surfaces of the every reaction channels are mapped. The results indicate that the formation mechanism is mainly through two stages: generation and hydrolysis of isocyanate. Hydrogen bond plays an important role for the hydrolysis process. The formation mechanism is shown to be dependent on the polarity of solvent. The hydroxyl ion (OH−), originated from the basic properties of sodium hypochlorite solution, is shown to be more likely first attacker than the hypochlorite ion (OCl−) for the reactant 3-amide-4-nitro-furoxan due to the low active barrier in the polar water solvent. But the OCl− dominates the reaction in benzene solvent where the isocyanate is formed via the dehydration chlorination by OCl− and Hofmann rearrangement with the elimination of chloride ion. The isocyanate is then hydrolyzed through addition of a H2O molecule to the NC double bonds, rotation of the hydroxyl hydrogen, transfer of hydrogen to the N atom in the amide group and the removal of a CO2 molecule to form the final product. The benzene solvent is more suitable than water solvent for the formation reaction due to the lower active barrier of 46.4 kcal/mol. The reaction is not feasible at room temperature and raising properly temperature of system would be requisite to realize the synthesis reaction.

Antiaggregant activity of water-soluble furoxans

The effect of the water-soluble furoxan derivatives on platelet aggregation has been estimated using a series of inducers. The most active compound, 3-carbamoyl-4-(hydroxymethyl)furoxan (CAS-1609), effectively inhibits aggregate formation induced by adenosine diphosphate and adrenaline. This result is a good basis for the search of new structures with antiaggregant activity among furoxancarboxylic acid amides.

Structural and biological characterization of new hybrid drugs joining an HDAC inhibitor to different NO-donors

HDAC inhibitors and NO donors have already revealed independently their broad therapeutic potential in pathologic contexts. Here we further investigated the power of their combination in a single hybrid molecule. Nitrooxy groups or substituted furoxan derivatives were joined to the α-position of the pyridine ring of the selective class I HDAC inhibitor MS-275. Biochemical analysis showed that the association with the dinitrooxy compound 31 or the furoxan derivative 16 gives hybrid compounds the ability to preserve the single moiety activities. The two new hybrid molecules were then tested in a muscle differentiation assay. The hybrid compound bearing the moiety 31 promoted the formation of large myotubes characterized by highly multinucleated fibers, possibly due to a stimulation of myoblast fusion, as implicated by the strong induction of myomaker expression. Thanks to their unique biological features, these compounds may represent new therapeutic tools for cardiovascular, neuromuscular and inflammatory diseases.

In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative

N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2μM and 2.1 to 18.2μM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1μM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis.

Furoxan Nitric Oxide Donors Disperse Pseudomonas aeruginosa Biofilms, Accelerate Growth, and Repress Pyoverdine Production.

The use of nitric oxide (NO) as a signal for biofilm dispersal has been shown to increase the susceptibility of many biofilms to antibiotics, promoting their eradication. The delivery of NO to biofilms can be achieved by using NO donors with different kinetics and properties of NO release that can influence their efficacy as biofilm control agents. In this study, the kinetics of three furoxan derivatives were evaluated. The effects of these NO donors, which have an advantageous pharmacological profile of slower onset with an extended duration of action, on Pseudomonas aeruginosa growth, biofilm development, and dispersal were also characterized. Compound LL4254, which showed a fast rate of NO release, induced biofilm dispersal at approximately 200 μM. While LL4212 and LL4216 have a slower rate of NO release, both compounds could induce biofilm dispersal, under the same treatment conditions, when used at higher concentrations. In addition, LL4212 and LL4216 were found to promote P. aeruginosa growth in iron-limited minimal medium, leading to a faster rate of biofilm formation and glucose utilization, and ultimately resulted in early dispersal of biofilm cells through carbon starvation. High concentrations of LL4216 also repressed production of the siderophore pyoverdine by more than 50-fold, via both NOx-dependent and NOx-independent mechanisms. The effects on growth and pyoverdine levels exerted by the furoxans appeared to be mediated by NO-independent mechanisms, suggesting functional activities of furoxans in addition to their release of NO and nitrite. Overall, this study reveals that secondary effects of furoxans are important considerations for their use as NO-releasing dispersal agents and that these compounds could be potentially redesigned as pyoverdine inhibitors.

Molecular modeling and structure–activity relationships studies of bioisoster hybrids of N-acylhydrazone and furoxan groups on cruzain

Chagas disease is a very important neglected disease and millions of people live in endemic areas at the risk of acquiring the infection. Due to scarce and ineffective current chemotherapy, the introduction of new drugs on therapeutics is highly necessary. Bioisoster hybrids derivatives were previously designed, synthesized, and assayed in terms of trypanocidal activity and permeability. Structure activity-relationships were performed with a set of N-acylhydrazone and furoxan derivatives aiming at identifying if the enzyme cruzain might be the target of the system. In addition, lowest unoccupied molecular orbital analysis and docking studies of the two most promising compounds were carried out with the purpose of elucidating the key properties and interactions between the ligands and cruzain. The analysis of cruzain inhibition tests showed that the position of the nitro group is important for the compounds inhibitory activity. The results lead to the conclusion that cruzain may not be the only target. This hypothesis was advanced because the most active in Trypanosoma cruzi, compound 6, is not the most effective in cruzain tests. Notwithstanding, this compound was considered the most promising hit for further in vivo studies, as it did not show toxicity in cycle cell tests.

New furoxan derivatives for the treatment of ocular hypertension

A small series of water-soluble NO-donor furoxans bearing a basic center at the 4-position, having a wide lipophilic-hydrophilic balance range, and endowed with different NO-release capacities, were synthesized and characterized. Selected members were studied for their IOP-lowering activity in the transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds 3 and 7, whose activity 60min after administration was similar to that of Timolol. Notably, 7 was characterized by a long-lasting action. The IOP-lowering activity in this series of products appeared to be modulated by the lipophilic-hydrophilic balance rather than by the NO-donor capacity.

Furoxan Derivatives of Pyrene – A DFT Study

ABSTRACTFuroxan-fused pyrenes and their dinitroso derivatives (obtained by furoxan ring opening) are considered for density functional treatment at the level of B3LYP/6-31G(d,p). Embedded benzofuroxan moiety in the furoxan-fused pyrene system is thought to undergo ring opening and reclosure process analogously to benzofuroxan itself. The stabilities, structural features, NICS(0) values, IR, and UV-VIS spectral aspects, etc., are investigated comparatively for these isomeric furoxan-fused pyrenes and their isomeric dinitroso derivatives.

Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation reactions

A general and simple method for the preparation of under explored 3-aryl-4-hydroxyfuroxans by nucleophilic substitution of the nitro group in 3-aryl-4-nitrofuroxans using NaOH in H2O-THF has been developed. The methylation of 3-aryl-4-hydroxyfuroxans was studied with various methylating reagents (CH2N2, MeI, (MeO)2SO2) which showed for the first time that 3-aryl-4-hydroxyfuroxans are prone to side-chain prototropic tautomerism. Furoxan derivatives of a novel type, N(5)-alkylation products (3-aryl-5-methyl-1,2,5-oxadiazol-4(2H)-one 2-oxides), were synthesized under mild conditions, along with regioselective formation of the O-alkylation products (3-aryl-4-methoxyfuroxans).

New insight into the antiaggregant activity of furoxans

The measurement of the antiaggregant properties of 3-cyano-4-phenylfuroxan and 3-nitro-4-phenylfuroxan has demonstrated that these compounds effectively inhibit platelet agglutination induced by adenosine diphosphate and adrenaline but not ristocetin. When collagen was used as an inducer, only a slight delay of aggregate formation was observed. Therefore, these furoxan derivatives could be considered as a basis for the development of next generation agents with improved antiaggregant activity.

STRUCTURAL FEATURE STUDY OF FUROXAN DERIVATIVES AS POTENT ANTI-TRYPANOSOMATID AGENTS: QSAR APPROACH

Two-dimensional quantitative structure–activity relationship (QSAR) studies of anti-trypanosomatid, furoxan alkylnitrate derivatives have been carried out. This study aims at establishing a quantitative structure activity relationship between furoxan alkylnitrate molecule and their anti-trypanosomatid property. A statistically best QSAR model was obtained with a correlation coefficient r2 of 0.8559, cross validation coefficient, q2 of 0.8072 and pred_r2 value of 0.8217. Various 2D descriptors were calculated and used in the present analysis. The descriptors SdssS (sulfone) count and SdsNE-index suggested that sulphone and NO2 groups at the R1 and R2 positions of furoxan moiety will increases anti-trypanosomatid activity. It will be useful to build a QSAR model to correlate the properties of new untested furoxan derivatives with their anti-trypanosomatid activity.

Theoretical studies on nitrogen‐rich furoxan‐based heterocyclic derivatives

AbstractThe density functional theory method was used to study the heats of formation (HOFs), energetic properties, electronic structure of a series of 4,4″‐dinitro(3,3′:4′,3′′)tris([1,2,5]oxadiazole)‐2′‐oxide (3,4‐bis[4′‐nitrofurazan‐3′‐yl]furoxan) derivatives. The results show that the substitution of the nitro group is very useful for improving their HOFs and detonation performances. The HOFs of the title compounds are all positive and larger than those of 1,3,5‐trinitro‐1,3,5‐triazinane and 1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocane. The analysis of oxygen balance shows that the studied compounds need the oxygen in the explosive. Compound A1 has larger detonation velocity and detonation pressure than those of 1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocane and can be regarded as a potential candidate for high‐energy compounds because of the moderate heat of detonation, high density, and high N. In addition, the energy gaps between the highest occupied molecular orbital and lowest unoccupied molecular orbital of the studied compounds are further investigated.

Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis

Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 μM (H37Rv) and 7.0–50.0 μM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25–34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.

Synthesis of Ursolic Acid Conjugates Containing a Furoxan Moiety

Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) combined with NO donors (NO-NSAIDs) are attracting attention and are considered promising anti-cancer chemotherapy agents [1]. Compared with ordinary NSAIDs, NO-NSAIDs have low toxicity and fewer side effects, in particular, damage to the gastrointestinal tract and kidneys [2]. The use of NO donors in hybrids with NSAIDs can lead to synergism and increased anti-inflammatory activity [3]. Derivatives of 1,2,5-oxadiazole-2-oxide (furoxan) can be used as the NO donor. The synthesis of the conjugate of diclofenac and a furoxan derivative that exhibited high anti-inflammatory activity was reported [4]. Furoxan derivatives have been reported to have also antithrombotic [5], vasodilating [6], and bactericidal [7] activities. According to the literature, slightly toxic ursolic acid (UA) and several of its derivatives also had noticeable antiinflammatory activity [8]. Ursane-type compounds are being actively studied as potential anti-cancer chemotherapy agents. Conjugates of UA succinate and furoxan derivatives were prepared [9]. Several of the new compounds exhibited cytotoxic activity that exceeded those of UA and 5-fluorouracil. Herein, we communicate the preparation of new hybrids of UA and furoxan derivatives with the heterocycle occupying different positions on the terpene framework.

ChemInform Abstract: Synthesis of Furoxan Derivatives: DABCO‐Mediated Cascade Sulfonylation/Cyclization Reaction of α‐Nitro‐Ketoximes.

AbstractThe cascade reaction proceeds best with tosyl chloride as mediator.

Synthesis of furoxan derivatives: DABCO-mediated cascade sulfonylation/cyclization reaction of α-nitro-ketoximes

A convenient and efficient method for the synthesis of furoxan derivatives from α-nitro-ketoximes and sulfonyl chlorides is reported. A wide variety of furoxan derivatives were smoothly obtained in good yields via a DABCO-mediated cascade sulfonylation/cyclization process under mild conditions. The usefulness of this method was also demonstrated by the conversions of the furoxan products into other promising compounds.

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

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.

Theoretical studies on energetic properties of s-triazine substituted aminofurazan and aminofuroxan derivatives—high performance energetic material systems

A series of s-triazine substituted aminofurazan and aminofuroxan derivatives are investigated theoretically as potential high energy density materials (HEDMs). The crystal density, condensed heat of formation (HOF), detonation performance, acceleration ability, and critical pressure of initiation are estimated using empirical relationships. It is shown that the title compounds are characterized by high HOFs (817–4067 kJ/kg) and crystal density values (1.76–1.95 g/cm3). The calculated detonation performance shows that derivatives substituted with -N3 and -C(NO2)3 are potential candidates for future HEDMs. Moreover, the values of the critical pressure of initiation indicate that furoxan derivatives are more sensitive to shock and impact compared to their furazan counterparts and that, for the substitutes -NH2 or nitrogen-containing heterocycles, a similar or lower impact sensitivity than that of TNT (2,4,6-trinitrotoluene) can be obtained.

Leishmanicidal activities of novel synthetic furoxan and benzofuroxan derivatives.

A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.

Study of Furoxan Derivatives for Energetic Applications

AbstractTwo novel energetic compounds, 3,4‐bis(1′,2′,4′‐triazole‐3′‐yl)furoxan (BTAF) and 3,4‐bis(1′‐nitro‐1′,2′,4′‐triazole‐3′‐yl)furoxan (BNTAF), were prepared and their structures were characterized by IR, 1H NMR, 13C NMR, MS techniques and elemental analysis. The properties of BTAF and BNTAF were estimated. The predicted performance data of BTAF are as follows: density (measured) is 1.75 g/cm3, nitrogen content 50.9%, detonation velocity 7277 m/s, detonation pressure 20.1 GPa and enthalpy of formation +419.7 kJ/mol. The predicted performance data of BNTAF are as follows: density is 1.84 g/cm3, nitrogen content 45.2%, enthalpy of formation +841.5 kJ/mol, detonation velocity 8490 m/s and detonation pressure 32.4 GPa. The main themal properties of BTAF and BNTAF were analyzed by DSC and TG techniques, the results show that BTAF melts with concomitant decomposition at 188.8°C, the melting point of BNTAF is at 99.2°C and its first decomposition temperature is 139.2°C.