Juliano A. Roehrs

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles: Versatile Access to 2-Chalcogen-benzo[b]furans

An efficient synthesis of 2-chalcogen-3-substituted-benzo[b]furan compounds has been accomplished via electrophilic cyclization reaction of 2-chalcogenealkynyl anisoles using I(2), ICl, Br(2), and PhSeBr as electrophile sources. The product distributions were strongly dependent on the nature of substituents in the aromatic ring of anisole and on the chalcogen atom directly bonded to the triple bond. The 2-chalcogen-3-iodo-benzo[b]furans obtained smoothly underwent conversion to more complex structures of benzo[b]furan derivatives via palladium- or copper-catalyzed cross-coupling reaction with thiols, diphenyl diselenides, and zincates.

Involvement of the serotonergic system in the anxiolytic-like effect caused by m-trifluoromethyl-diphenyl diselenide in mice

The organoselenium compound diphenyl diselenide (PhSe)(2) has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented some toxic effects. m-Trifluoromethyl-diphenyl diselenide (m-CF(3)-C(6)H(4)Se)(2), a structural analog of (PhSe)(2), has proven to be antipsychotic and antioxidant in mice. The present study was designed to investigate the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2) in female mice, employing light/dark box and elevated plus-maze (EPM) tests. The involvement of 5-hydroxytryptamine (5-HT) receptors and monoamine oxidase (MAO) activity in the anxiolytic-like effect was also evaluated. (m-CF(3)-C(6)H(4)Se)(2) (0.1, 10 and 100 mg/kg, p.o.) did not affect locomotor activity as evaluated in the open-field test (OFT). (m-CF(3)-C(6)H(4)Se)(2) at the dose of 100 mg/kg produced an anxiolytic-like action, both in light-dark box and the EPM tests. To evaluate the role of 5-HT receptors in the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2), a selective 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg/kg, s.c.), a non-selective 5-HT(2A/2C) receptor antagonist, ritanserin (2 mg/kg, i.p.) and a selective 5-HT(3) receptor antagonist, ondansetron (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2). (m-CF(3)-C(6)H(4)Se)(2), at the dose of 100 mg/kg, inhibited the MAO-A activity in mice brain. Taken together these data demonstrated that the anxiolytic-like effect caused by (m-CF(3)-C(6)H(4)Se)(2) seems to be mediated by the involvement of the serotonergic system.

Evidence for the involvement of μ-opioid and δ-opioid receptors in the antinociceptive effect caused by oral administration of m-trifluoromethyl-diphenyl diselenide in mice.

Pain is one of the most prevalent conditions, which limits productivity and diminishes quality of life. This study examined the antinociceptive effects of m-trifluoromethyl-diphenyl diselenide [(m-CF3–C6H4Se)2] on behavioral models of pain in mice. The involvement of opioid receptors in (m-CF3–C6H4Se)2-induced antinociception was evaluated in the tail-immersion test. (m-CF3–C6H4Se)2 exhibited significant inhibition of nociception induced by capsaicin (1.6 μg/paw, intraplantarly) (10–100 mg/kg, orally), and acetic acid (1.6%, 10 ml/kg, intraperitoneally) (1–100 mg/kg, orally), and in tail-immersion (50–100 mg/kg) and hot-plate (10–100 mg/kg) tests. The antinociception caused by (m-CF3–C6H4Se)2 in the tail-immersion test was significantly attenuated by naloxone (a nonselective opioid antagonist, 1 mg/kg, subcutaneously), naloxonazine (a selective μ-opioid receptor antagonist, 35 mg/kg, subcutaneously), or naltrindole (a selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneally). In contrast, (m-CF3–C6H4Se)2-induced antinociception was not affected by treatment with nor-binaltorphimine (a selective κ-opioid receptor antagonist, 10 mg/kg, subcutaneously) or naloxone methiodide (a peripherally restricted opioid antagonist, 1 mg/kg, subcutaneously). These results indicate that (m-CF3–C6H4Se)2-elicited antinociception in different models of pain through mechanisms that seem to involve an interaction with the central opioid system, more specifically μ-opioid and δ-opioid receptors.

Bis(phenylimidazoselenazolyl) diselenide: a compound with antinociceptive properties in mice.

The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25–100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25–100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10–50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10–50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.

Diorganyl Dichalcogenides-Promoted Nucleophilic Closure of 1,4-Diyn-3-ols: Synthesis of 2-Benzoyl Chalcogenophenes.

We report here the preparation of chalcogenophene derivatives via cyclization reactions of diynols promoted by diorganyl dichalcogenides and a halogen source. Different chalcogenophenes, such as 4-halo-selenophenes, 4-butylselenyl-selenophenes, halo-thiophenes, and 4-methylthio-thiophenes, were selectively prepared in good yields from the same starting materials. The results revealed that the halogen source had a significant effect on the proportion of 4-bromo-selenophenes and 4-butylselenyl-selenophenes. The best yields of 4-iodo-selenophenes were obtained with iodine as a halogen source, while the use of NBS gave exclusively the 4-butylselenyl-selenophenes. The experiments also revealed that the cyclization reaction to form 4-halo-thiophene derivatives can also be controlled changing the ratios of reagents. The 4-iodo-thiophenes were exclusively obtained by using dimethyl disulfide (2.0 equiv) and iodine (1.5 equiv), while the 4-bromo-thiophenes were obtained when the reaction was carried out with a 1.5 molar ratio of dimethyl disulfide and a halogen source. In addition, the reaction of diynols with an excess of dimethyl disulfide in the presence of NBS gave the 4-methylthio-thiophenes as sole products. We also studied the application of chalcogenophenes obtained as starting materials in the Suzuki, Sonogashira, and Ullmann cross-coupling reactions.

Hyperthermic seizures enhance responsiveness to pentylenetetrazole and induce cognitive dysfunction: Protective effect of 3-alkynyl selenophene

AIMS In this study we investigated the effect of pre-treatment with 3-alkynyl selenophene (3-ASP) against the increase in responsiveness to pentylenetetrazole [PTZ seizure threshold] and cognitive dysfunction induced by experimental febrile seizures (FS). The effects of 3-ASP were compared to those of diazepam (DZP). MAIN METHODS Young rats, at postnatal day 21, developed seizures after exposure to a stream of heated air to approximately 41°C. A non-spatial long-term memory and PTZ seizure threshold were determined 30 days after FS. The behavioural seizures were stereotyped followed by facial automatisms, often followed by body flexion. Young rats were pre-treated with 3-ASP (50 and 100mg/kg; per oral route), DZP (1 and 5mg/kg; intraperitoneally) or vehicle. KEY FINDINGS 3-ASP and DZP pre-treatments were not effective in protecting against seizures induced by FS. 3-ASP pre-treatment protected against the increase in responsiveness to PTZ and cognitive dysfunction induced by FS. DZP pre-treatment was effective in protecting against the increase in responsiveness to PTZ, but not, against the impaired memory induced by FS. SIGNIFICANCE 3-ASP pre-treatment protected against impairment of memory performance in the step-down passive avoidance task and the increase in the susceptibility to seizures caused by FS early in life of rats.

Bis(phenylimidazoselenazolyl) diselenide as an antioxidant compound: An in vitro and in vivo study.

The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 μM, respectively). BPIS also presented dehydroascorbate reductase-like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited δ-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 μM, respectively). In vivo, brains of mice treated with SNP (0.335 μmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound.

Ultrasound-promoted organocatalytic enamine–azide [3 + 2] cycloaddition reactions for the synthesis of ((arylselanyl)phenyl-1H-1,2,3-triazol-4-yl)ketones

The use of sonochemistry is described in the organocatalytic enamine–azide [3 + 2] cycloaddition between 1,3-diketones and aryl azidophenyl selenides. These sonochemically promoted reactions were found to be amenable to a range of 1,3-diketones or aryl azidophenyl selenides, providing an efficient access to new ((arylselanyl)phenyl-1H-1,2,3-triazol-4-yl)ketones in good to excellent yields and short reaction times. In addition, this protocol was extended to β-keto esters, β-keto amides and α-cyano ketones. Selanyltriazoyl carboxylates, carboxamides and carbonitriles were synthesized in high yields at short times of reaction under very mild reaction conditions.

Iodine-mediated regioselective 5-endo-dig electrophilic cyclization reaction of selenoenynes: synthesis of selenophene derivatives

Selenoenynes underwent electrophilic cyclization reactions with iodine in the presence of an appropriate nucleophile to give 3-iodo-selenophenes and 3-organoselenyl-selenophenes. The selection of the appropriate reaction conditions allowed the cyclization process, which involves the initial formation of an iodonium intermediate, followed by a regioselective 5-endo-dig intramolecular selenium nucleophilic attack to the carbon–carbon triple bond. The key step for the preparation of the desired selenophenes was the trap of an allylic cation intermediate by N- and O-nucleophiles. The generality and limitations of the reactions with regard to each of the substituents at the starting materials were evaluated and addressed. The resulting 3-iodo-selenophenes were further functionalized by Sonogashira and Suzuki cross-coupling reactions.

Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model

Bis(phenylimidazoselenazolyl) diselenide (BPIS) is an organoselenium with acute antinociceptive and antioxidant properties.