Williams Porcal

Pharmacological Properties of Furoxans and Benzofuroxans: Recent Developments

The chemistry of furoxans (1, 2, 5-oxadiazole-2-oxides) and benzofuroxans (benzo[1, 2-c]1, 2, 5-oxadiazole-1-oxides) is very well known. These systems are widely used in organic chemistry as intermediate compounds for the synthesis of numerous heterocycles. In the other hand, furoxan and benzofuroxan derivatives were extensively studied as bioactive compounds. They possess remarkable biological activities, such as anti-microbial and anti-parasitic properties, mutagenic, immunosuppressive and anticancer effects, anti-aggregating and vasorelaxant activity, among others. In some cases, molecular mode of action was proposed. Recently, the research and development in the medicinal chemistry of these systems have produced hybrid compounds in which furoxan or benzofuroxan moieties together with a classical drug moieties are present in a single molecule. So, new anti-ulcer drugs, calcium channel modulators and vasodilator derivatives were described and they are currently in study. In this presentation recent developments in the medicinal chemistry of furoxans and benzofuroxans will be reviewed.

Heteroarylnitrones as Drugs for Neurodegenerative Diseases: Synthesis, Neuroprotective Properties, and Free Radical Scavenger Properties

New 1,2,4-thiadiazolylnitrones and furoxanylnitrones were developed and evaluated as neuroprotective agents on a human neuroblastoma (SH-SY5Y) cells model. They inhibited at low micromolar concentrations the oxidative damage and the death induced by exposure to hydrogen peroxide. These heteroarylnitrones showed excellent peroxyl free radical absorbance capacities, analyzed by oxygen radical absorbance capacity (ORAC) assay with fluorescein as the fluorescent probe, ranging from 1.5- to 16.5-fold the value of the reference nitrone, alpha-phenyl-N-tert-butylnitrone (PBN). The electron spin resonance spectroscopy (ESR) demonstrated the ability of these derivatives to directly trap and stabilize oxygen, carbon, and sulfur-centered free radicals. These results demonstrated the potential use of these heteroarylnitrones as neuroprotective agents in preventing the death of cells exposed to enhanced oxidative stress and damage.

New trypanocidal hybrid compounds from the association of hydrazone moieties and benzofuroxan heterocycle

Hybrid compounds containing hydrazones and benzofuroxan pharmacophores were designed as potential Trypanosoma cruzi-enzyme inhibitors. The majority of the designed compounds was successfully synthesized and biologically evaluated displaying remarkable in vitro activity against different strains of T. cruzi. Unspecific cytotoxicity was evaluated using mouse macrophages, displaying isothiosemicarbazone 10 and thiosemicarbazone 12 selectivity indexes (macrophage/parasite) of 21 and 27, respectively. In addition, the mode of anti-trypanosomal action of the derivatives was investigated. Some of these derivatives were moderate inhibitors of cysteinyl active site enzymes of T. cruzi, cruzipain and trypanothione reductase. ESR experiments using T. cruzi microsomal fraction suggest that the main mechanism of action of the trypanocidal effects is the production of oxidative stress into the parasite.

Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitrypanosomal drugs. Structure-activity relationships. Part II.

The preparation of new derivatives of benzo[1, 2‐c]1, 2, 5‐oxadiazole N‐oxide is described. These derivatives were chosen in order to investigate and confirmprevious structural features found necessary to display an adequate antitrypanosomal activity. The compounds synthesized were tested in vitro against epimastigote forms of Trypanosoma cruzi.The presence of a bromine atom in the benzo system produced compounds less active than the corresponding de‐halo analogues. However, 5‐(bromomethyl)‐7‐bromobenzo[1, 2‐c]oxadiazole N‐oxide (23) was the most cytotoxic compound against T. cruzi. For this, the 50% inhibitory dose (ID50) was determined, it was of the same order as that of Nifurtimox. From statistical analysis we could establish a relationship between lipophilic‐hydrophilic balance of the derivatives with their effectiveness as antichagasic compounds.

Novel Benzo[1,2-c]1,2,5-Oxadiazole N-Oxide Derivatives as Antichagasic Agents: Chemical and Biological Studies

This research was supported by FONDECYT 1000834, 7040037, 1020095, CSIC (UdelaR), CLEMENTE ESTABLE and TWAS grants. We thank a scholarship for C. Rigol from RELACQ.

Electrochemical and microsomal production of free radicals from 1,2,5-oxadiazole N-oxide as potential antiprotozoal drugs

The electron spin resonance (ESR) spectra of free radicals obtained by electrolytic or microsomal reduction of several potential antiprotozoal 1,2,5-oxadiazoles were characterized and analyzed. Ab initio molecular orbital calculations were performed to obtain the optimized geometries and the theoretical hyperfine constant was carried out using ZINDO semiempirical methodology. Density functional theory was used to rationalize the reduction potentials of these compounds.

New heteroaryl nitrones with spin trap properties: Identification of a 4-furoxanyl derivative with excellent properties to be used in biological systems

A new series of heteroaryl nitrones, 1-7, bearing furoxanyl and thiadiazolyl moieties, were evaluated for their free radical-trapping properties. The physicochemical characterization by electron paramagnetic resonance (EPR) demonstrated its capability to trap and stabilize oxygen-, carbon-, sulfur-, and nitrogen-centered free radicals. The 4-furoxanyl nitrone 3 (FxBN), alpha(Z)-(3-methylfuroxan-4-yl)-N-tert-butylnitrone, showed appropriate solubility in aqueous solution and taking into account that this physicochemical property is very important for biological applications, we studied it deeply in terms of its trapping and kinetic behaviors. For this, kinetic studies of the hydroxyl adduct decay gave rate constants k(ST) of 1.22x10(10)dm(3)mol(-1)s(-1) and half-live up to 7200s at physiological pH, without any artifactual signals. The ability of FxBN to directly traps and stabilizes superoxide free radical, with a half-life of 1620s at physiological pH, was also demonstrated. Besides, FxBN-hydroxyl and -superoxide adducts exhibited distinct and characteristic EPR spectral patterns. Finally, we confirmed the ability of FxBN to act as spin trap in a specific biological system, that is, in the free radical production of experimental anti-trypanosomatid drugs using Trypanosoma cruzi microsomes as biological system. Moreover, previous observations of low FxBN toxicity transform it in a good candidate for in vivo spin trapping.

Anti-trypanosomatid benzofuroxans and deoxygenated analogues: Synthesis using polymer-supported triphenylphosphine, biological evaluation and mechanism of action studies

Hybrid vinylthio-, vinylsulfinyl-, vinylsulfonyl- and vinylketo-benzofuroxans developed as anti-trypanosomatid agents, against Trypanosoma cruzi and Leishmania spp., have showed low micromolar IC(50) values. The synthetic route to access to these derivatives was an efficient Wittig reaction performed in mild conditions with polymer-supported triphenylphosphine (PS-TPP). Additionally, the benzofurozan analogues, deoxygenated benzofuroxans, were prepared using PS-TPP as reductive reagent in excellent yields. The trypanosomicidal and leishmanocidal activities of the benzofuroxan derivatives were measured and also some aspects of their mechanism of action studied. In this sense, inhibition of mitochondrial dehydrogenases activities, production of intra-parasite free radicals and cruzipain inhibition were studied as biological target for the anti-trypanosomatid identified compounds. The trypanosomicidal activity could be the result of both the parasite-mitochondrion function interference and production of oxidative stress into the parasite.

Preparation of phenazine N5,N10-dioxides: Effects of benzofuroxan substituents in the outcome of their expansion reaction with phenolates

Os efeitos mesomericos do substituinte benzofuroxano, na preparacao de N5,N10-dioxidos de fenazina sao descritos. As caracteristicas eletronicas do substituinte na posicao 5 dos benzofuroxanos determinam a proporcao dos isomeros 7 e 8 dos N5,N10-dioxidos de fenazina, quando fenois substituidos sao usados.

Biological evaluation of glucose and deoxyglucose derivatives radiolabeled with [99mTc(CO)3(H2O)3]+ core as potential melanoma imaging agents.

Glucose 9 and 2-deoxyglucose 10 were successfully synthesized and radiolabeled with [(99m)Tc(CO)(3)(H(2)0)(3)](+) intermediate in high yield. The complexes were characterized by HPLC and its stability with histidine over time was challenged. Cell uptake and biodistribution studies in melanoma-bearing C57BL/6 mice were performed. Both compounds showed accumulation in tumor tissue with high tumor-to-muscle ratios. Thus, D-glucose- and D-2-deoxyglucose-(99m)Tc complex could be considered as agents for melanoma diagnosis.