Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential.

Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.

A comparative study between Cu(INA)2-MOF and [Cu(INA)2(H2O)4] complex for a click reaction and the Biginelli reaction under solvent-free conditions.

The catalytic activity of metal-organic framework Cu(INA)2 (INA = isonicotinate ion) and the complex [Cu(INA)2(H2O)4] were studied in the Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC) and Biginelli reaction under solvent-free reaction conditions. The robust, efficient and eco-friendly new method allowed the preparation of a variety of 1,2,3-triazole compounds in good to excellent yields and high selectivity for the 1,4-disubstituted triazole. Moreover, for the Biginelli reaction between aldehydes, ethyl acetoacetate and urea, the corresponding dihydropyrimidinones (DHPMs) were also obtained in satisfactory yields under mild reaction conditions for both catalysts. The comparative study between Cu(INA)2-MOF and [Cu(INA)2(H2O)4] complex demonstrated better results for the Cu-MOF, for both the yields and the regioselectivity of the products. Furthermore, no change in the heterogeneous catalyst structure was observed after the reaction, allowing them to be recovered and reused without any loss of activity.

Stereo- and regioselective cu-catalyzed hydroboration of alkynyl chalcogenoethers

A mild stereo- and regioselective Cu-catalyzed hydroboration method for the synthesis of (Z)-seleno-alkenyl boronates and (Z)-thio-alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N-heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give a -chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen-containing molecules.

Stereo- and regioselective cu-catalyzed hydroboration of alkynyl chalcogenoethers

A mild stereo- and regioselective Cu-catalyzed hydroboration method for the synthesis of (Z)-seleno-alkenyl boronates and (Z)-thio-alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N-heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give a -chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen-containing molecules.

Iron (III)-promoted synthesis of substituted 4H-Chalcogenochromenes and chemoselective functionalization

The iron(III)-promoted synthesis of densely-substituted 4H-chalcogenchromene from organochalcogen propargylamines in the presence of diaryl dichalcogenides is reported. Subsequent C2-functionalization with electrophiles and potassium trifluoroborate salts via Suzuki-Miyaura coupling reaction are also presented. A plausible mechanism based on HRMS experiments is proposed and discussed.

Iron (III)-promoted synthesis of substituted 4H-Chalcogenochromenes and chemoselective functionalization

The iron(III)-promoted synthesis of densely-substituted 4H-chalcogenchromene from organochalcogen propargylamines in the presence of diaryl dichalcogenides is reported. Subsequent C2-functionalization with electrophiles and potassium trifluoroborate salts via Suzuki-Miyaura coupling reaction are also presented. A plausible mechanism based on HRMS experiments is proposed and discussed.

In silico study toward the identification of new and safe potential inhibitors of photosynthetic electron transport.

To address the rising global demand for food, it is necessary to search for new herbicides that can control resistant weeds. We performed a 2D-quantitative structure-activity relationship (QSAR) study to predict compounds with photosynthesis-inhibitory activity. A data set of 44 compounds (quinolines and naphthalenes), which are described as photosynthetic electron transport (PET) inhibitors, was used. The obtained model was approved in internal and external validation tests. 2D Similarity-based virtual screening was performed and 64 compounds were selected from the ZINC database. By using the VEGA QSAR software, 48 compounds were shown to have potential toxic effects (mutagenicity and carcinogenicity). Therefore, the model was also tested using a set of 16 molecules obtained by a similarity search of the ZINC database. Six compounds showed good predicted inhibition of PET. The obtained model shows potential utility in the design of new PET inhibitors, and the hit compounds found by virtual screening are novel bicyclic scaffolds of this class.

Ytterbium-catalyzed formal [4+2] cycloaddition: synthesis of chalcogen-quinolines 3-unsubstituted

A regioselective ytterbium-catalyzed annulation reaction between ethylglyoxalate, anilines and silyl-alkynes bearing selenyl- and telluryl-moieties for the formation of poly-substituted quinolones is described. A series of examples formed under mild conditions are presented, including a scaled-up reaction and a study on catalyst recyclability.

Copper(I)/succinic acid cooperatively catalyzed one-pot synthesis of organoselenium-propargylamines via A3-coupling

Selenium propargylamines were synthesized via an A(3)-coupling approach using piperidine, p-methoxybenzaldehyde, and trimethylsilyl selenium-acetylene, catalyzed by copper(i) chloride and succinic acid as an additive, in good to excellent yields. This method is advantageous in that desilylation of the trimethylsilyl selenium-acetylene occurs in situ. The reaction time was monitored by FTIR studies and a probable mechanism is described. Scale-up was also performed in satisfactory yield. These selenium propargylamines could be hydrohalogenated to synthesize halovinyl selenides. The stereochemistry was determined by treatment with n-butyllithium and the coupling constant (J) values in H-1 NMR spectra. The vinyl selenides were employed in Sonogashira cross-coupling reactions to produce the corresponding enynes, with yields ranging from moderate to good.

Ytterbium-catalyzed formal [4+2] cycloaddition: synthesis of chalcogen-quinolines 3-unsubstituted

A regioselective ytterbium-catalyzed annulation reaction between ethylglyoxalate, anilines and silyl-alkynes bearing selenyl- and telluryl-moieties for the formation of poly-substituted quinolones is described. A series of examples formed under mild conditions are presented, including a scaled-up reaction and a study on catalyst recyclability.

Copper(I)/succinic acid cooperatively catalyzed one-pot synthesis of organoselenium-propargylamines via A3-coupling

Selenium propargylamines were synthesized via an A(3)-coupling approach using piperidine, p-methoxybenzaldehyde, and trimethylsilyl selenium-acetylene, catalyzed by copper(i) chloride and succinic acid as an additive, in good to excellent yields. This method is advantageous in that desilylation of the trimethylsilyl selenium-acetylene occurs in situ. The reaction time was monitored by FTIR studies and a probable mechanism is described. Scale-up was also performed in satisfactory yield. These selenium propargylamines could be hydrohalogenated to synthesize halovinyl selenides. The stereochemistry was determined by treatment with n-butyllithium and the coupling constant (J) values in H-1 NMR spectra. The vinyl selenides were employed in Sonogashira cross-coupling reactions to produce the corresponding enynes, with yields ranging from moderate to good.

Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)-coumarin derivatives: effect on inducible nitric oxide synthase.

A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-α secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that π···π interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored.

Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress.

Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/FOXO signaling and attenuating oxidative stress.

Hepatoprotective activity of a vinylic telluride against acute exposure to acetaminophen.

Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis and suicides attempts. Notably, oxidative stress plays a central role in the hepatic damage caused by APAP and antioxidants have been tested as alternative treatment against APAP toxicity. In the present study, we observed the hepatoprotector activity of the diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP), an organotellurium compound with low toxicity and high antioxidant potential. When the dose of 200 mg/kg of APAP was used, we observed that all used doses of DPTVP were able to restore the -SH levels that were depleted by APAP. Furthermore, the increase in thiobarbituric acid reactive substances levels and in the seric alanine aminotransferase (ALT) activity and the histopathological alterations caused by APAP were restored to control levels by DPTVP (30, 50 and 100 µmol/kg). On the other hand, when the 300 mg/kg dose of APAP was used, DPTVP restored the non-proteic -SH levels and repaired the normal liver morphology of the intoxicated mice only at 50 µmol/kg. Our in vitro results point out to a scavenging activity of DPTVP against several reactive species, action that is attributed to its chemical structure. Taken together, our results demonstrate that the pharmacological action of DPTVP as a hepatoprotector is probably due to its scavenging activity related to its chemical structure.

FeCl(3)-Diorganyl dichalcogenides promoted cyclization of 2-alkynylanisoles to 3-chalcogen benzo[b]furans.

A general synthesis of 3-chalcogen benzo[b]furans from the readily available 2-alkynylanisoles, via FeCl(3)/diorganyl dichalcogenides intramolecular cyclization, has been developed. Aryl and alkyl groups directly bonded to the chalcogen atom were used as cycling agents. The results revealed that the reaction significantly depends on the electronic effects of substituents in the aromatic ring bonded to the selenium atom of the diselenide species. We observed that the pathway of reaction was not sensitive to the nature of substituents in the aromatic ring of anisole since both the electron-donating and the electron-withdrawing groups delivered the products in similar yields. In addition, the obtained heterocycles were readily transformed to more complex products by using a chalcogen/lithium exchange reaction with n-BuLi followed by trapping of the lithium intermediate with aldehydes, furnishing the desired secondary alcohols in good yields.

A possible neuroprotective action of a vinylic telluride against Mn-induced neurotoxicity.

Manganese (Mn) is a metal required by biological systems. However, environmental or occupational exposure to high levels of Mn can produce a neurological disorder called manganism, which has similarities to Parkinson's disease. Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with a high antioxidant activity, especially in the brain. The present study was designed to investigate the effects of long-term low-dose exposure to Mn in drinking water on behavioral and biochemical parameters in rats and to determine the effectiveness of vinylic telluride in attenuating the effects of Mn. After 4 months of treatment with MnCl(2) (13.7 mg/kg), rats exhibited clear signs of neurobehavioral toxicity, including a decrease in the number of rearings in the open field and altered motor performance in rotarod. The administration of DPTVP (0.150 micromol/kg, ip, 2 weeks) improved the motor performance of Mn-treated rats, indicating that the compound could be reverting Mn neurotoxicity. Ex vivo, we observed that Mn concentrations in the Mn-treated group were highest in the striatum, consistent with a statistically significant decrease in mitochondrial viability and [(3)H]glutamate uptake, and increased lipid peroxidation. Mn levels in the hippocampus and cortex were indistinguishable from controls, and no significant differences were noted in the ex vivo assays in these areas. Treatment with DPTVP fully reversed the biochemical parameters altered by Mn. Furthermore, DPTVP treatment was also associated with a reduction in striatal Mn levels. Our results demonstrate that DPTVP has neuroprotective activity against Mn-induced neurotoxicity, which may be attributed to its antioxidant activity and/or its effect on striatal Mn transport.

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.

Repeated administration of diphenyl diselenide to pregnant rats induces adverse effects on embryonic/fetal development.

The present study was carried out to investigate the effects of diphenyl diselenide, (PhSe)(2), on embryo-fetal development. Dams were treated subcutaneously with 1.5, 3.0 and 6.0 mg/kg (PhSe)(2) from days 6 to 15 of pregnancy. After cesarean section at gestation day (GD) 20, external and skeletal abnormalities were evaluated. A decrease in maternal body weight gain was found in (PhSe)(2) groups, indicating maternal toxicity. There was a reduction in the fetal weight and in crown-rump (CR) length of fetuses at three doses tested. The occipito-nasal length decreased in fetuses from dams exposed to 3.0 mg/kg (PhSe)(2). Signs of delayed ossification in the skull, sternebrae and limbs were observed in all (PhSe)(2) groups, revealing a relation between morphological alterations and growth retardation in fetuses, but none of the changes appeared to be dose-dependent. Exposure of dams to (PhSe)(2) resulted in altered placental morphology that may have contributed to adverse reproductive outcomes. We concluded that (PhSe)(2) is toxic to dams and induces developmental delay of the fetal skeleton, but does not cause externally visible malformations in rat fetuses, in this experimental procedure.