Mechanistic investigation of enolate/stabilized vinylogous carbanion-mediated organocatalytic azide (3 + 2) cycloaddition reactions for the synthesis of 1,2,3-triazoles.

Herein, we report a fully detailed mechanistic study involving an organocatalyzed 1,3-dipolar cycloaddition via enolate or stabilized vinylogous carbanion intermediates and azide for the synthesis of 1,2,3-triazoles. A detailed investigation of the elementary steps, intermediates, and transition states of the two organocatalyzed metal-free click reactions is supported by DFT calculations and 1H NMR monitoring experiments, providing detailed profiles for both reaction mechanisms. Distortion-interaction activation-strain (DIAS) analysis was also employed to further elucidate the regioselectivity in both reactions.

Stereoselective Multicomponent Reactions in the Synthesis or Transformations of Epoxides and Aziridines.

Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with the advantages of environmentally benign synthetic procedures, multicomponent reactions (MCRs) have been explored in the synthesis and ring opening of these heterocyclic units. In this review, the recent advances in MCRs involving the synthesis and applications of epoxides and aziridines to the preparation of other heterocycles are discussed emphasizing the stereoselectivity of the reactions.

Visible-Light-Induced Synthesis of 1,2-Dicarboxyl Compounds from Carbon Dioxide, Carbamoyl-dihydropyridine, and Styrene.

ß-Amidated carboxylic acids, or succinamic acid derivatives, constitute a valuable chemical scaffold with broad applications in pharmaceuticals, agrochemicals, and polymer sciences. Herein, we report a redox-neutral multicomponent reaction for the synthesis of succinamic acid derivatives in good yields. This protocol involves styrene, CO2 and 1,4-carbamoyl-dihydropyridine as radical precursors. The method exhibits a broad substrate scope under mild reaction conditions, including late-stage functionalization. Moreover, by employing 13CO2, the method enables the synthesis of labeled 1,2-dicarboxylic compounds.

Synthesis, antioxidant activity, antimicrobial efficacy and molecular docking studies of 4-chloro-2-(1-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazol-2-yl)phenol and its transition metal complexes.

Herein, a one-pot synthesis of tetra-substituted imidazole, 4-chloro-2-(1-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazol-2-yl)phenol (HL), is reported by the reaction of benzil, 5-bromosalicylaldehyde, ammonium acetate and anisidine. The synthesized imidazole was reacted with salts of 1st row transition metals (Co(ii), Ni(ii), Cu(ii), Mn(ii) and Zn(ii)) to obtain metal complexes. The structure of the compounds was confirmed using various spectroscopic and analytical techniques. HL, which is crystalline, was characterized by SC-XRD. Subsequently, the synthesized compounds were evaluated for their antioxidant and antimicrobial activities. Antimicrobial studies revealed the more noxious nature of metal complexes compared to ligand against various strains of bacteria and fungi. Molecular docking results based on the binding energy values also supported the experimental results of the antioxidant activities of the compounds. HL was found to be a better antioxidant than metal complexes. For a better insight into the structure, computational studies of the compounds were also carried out. A clear intra-molecular charge transfer was perceived in the ligand and its metal complexes. The transfer integral values for holes (36.48 meV) were found to be higher than the electron transfer integrals (24.76 meV), which indicated that the ligand would be a better hole transporter. According to the frontier molecular orbitals of the dimer, the charge transfer within the molecule is found from monomer 1 to 2.

Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini reaction under eco-friendly reaction conditions.

An eco-friendly synthesis of highly functionalized epoxides and their incorporation into an organocatalytic multicomponent approach are reported. For this, a modified class of diarylprolinol silyl ethers was designed to enable high catalytic activity in an environmentally benign solvent system. The one-pot procedure showed great efficiency in promoting stereoselective multicomponent transformations in a tandem, 'green' fashion. Because of its non-residual, efficient and selective character, this synthetic design shows promise for large-scale applications in both diversity and target-oriented syntheses.

Decoding the Role of Melatonin Structure on Plasmodium falciparum Human Malaria Parasites Synchronization Using 2-Sulfenylindoles Derivatives.

Melatonin acts to synchronize the parasite's intraerythrocytic cycle by triggering the phospholipase C-inositol 1,4,5-trisphosphate (PLC-IP3) signaling cascade. Compounds with an indole scaffold impair in vitro proliferation of blood-stage malaria parasites, indicating that this class of compounds is potentially emerging antiplasmodial drugs. Therefore, we aimed to study the role of the alkyl and aryl thiol moieties of 14 synthetic indole compounds against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum. Four compounds (3, 26, 18, 21) inhibited the growth of P. falciparum (3D7) by 50% at concentrations below 20 µM. A set of 2-sulfenylindoles also showed activity against Dd2 parasites. Our data suggest that Dd2 parasites are more susceptible to compounds 20 and 28 than 3D7 parasites. These data show that 2-sulfenylindoles are promising antimalarials against chloroquine-resistant parasite strains. We also evaluated the effects of the 14 compounds on the parasitemia of the 3D7 strain and their ability to interfere with the effect of 100 nM melatonin on the parasitemia of the 3D7 strain. Our results showed that compounds 3, 7, 8, 10, 14, 16, 17, and 20 slightly increased the effect of melatonin by increasing parasitemia by 8-20% compared with that of melatonin-only-treated 3D7 parasites. Moreover, we found that melatonin modulates the expression of kinase-related signaling components giving additional evidence to investigate inhibitors that can block melatonin signaling.

Asymmetric organocatalysis with sulfones.

Asymmetric organocatalysis has become a powerful tool for the synthesis of optically active compounds. Whereas early research mainly focused on combining simple reagents as a proof-of-concept for asymmetric organocatalysis, recent investigations are directed towards extending the concept to more target- and diversity-oriented synthesis. As a result of the many transformation possibilities and their ability to generate both nucleophilic and electrophilic reaction partners, sulfones have become especially important substrates in the field of organocatalysis.

Photoinduced deaminative strategies: Katritzky salts as alkyl radical precursors.

Primary amines are one of the most predominant functional groups found in organic molecules. These entities help form the chemical architecture of natural products, bioactive molecules, synthetic building blocks and catalysts. Due to their ubiquitous presence, the development of strategies for the construction of C-C or C-X bonds through deaminative processes is of high importance. Deaminative methods offer new possibilities on the retrosynthetic rationale, and enable late-stage-functionalization of complex structures. As a result of the recent development of photoinduced processes, a variety of photo-mediated deaminative protocols employing 2,4,6-triphenyl-pyridinium salts - Katritzky Salts - as activating agents have been recently realized. This review covers the most recent developments of deaminative strategies by using Katritzky Salts as alkyl radical reservoirs, with particular concern on photoinduced processes applied to organic synthesis.

Design of a Helical-Stabilized, Cyclic, and Nontoxic Analogue of the Peptide Cm-p5 with Improved Antifungal Activity.

Following the information obtained by a rational design study, a cyclic and helical-stabilized analogue of the peptide Cm-p5 was synthetized. The cyclic monomer showed an increased activity in vitro against Candida albicans and Candida parapsilosis, compared to Cm-p5. Initially, 14 mutants of Cm-p5 were synthesized following a rational design to improve the antifungal activity and pharmacological properties. Antimicrobial testing showed that the activity was lost in each of these 14 analogues, suggesting, as a main conclusion, that a Glu-His salt bridge could stabilize Cm-p5 helical conformation during the interaction with the plasma membrane. A derivative, obtained by substitution of Glu and His for Cys, was synthesized and oxidized with the generation of a cyclic monomer with improved antifungal activity. In addition, two dimers were generated during the oxidation procedure, a parallel and antiparallel one. The dimers showed a helical secondary structure in water, whereas the cyclic monomer only showed this conformation in SDS. Molecular dynamic simulations confirmed the helical stabilizations for all of them, therefore indicating the possible essential role of the Glu-His salt bridge. In addition, the antiparallel dimer showed a moderate activity against Pseudomonas aeruginosa and a significant activity against Listeria monocytogenes. Neither the cyclic monomer nor the dimers were toxic against macrophages or THP-1 human cells. Due to its increased capacity for fungal control compared to fluconazole, its low cytotoxicity, together with a stabilized α-helix and disulfide bridges, that may advance its metabolic stability, and in vivo activity, the new cyclic Cm-p5 monomer represents a potential systemic antifungal therapeutic candidate.

Oxalate modulates thiobarbituric acid reactive species (TBARS) production in supernatants of homogenates from rat brain, liver and kidney: effect of diphenyl diselenide and diphenyl ditelluride.

The aim of this paper was to investigate the mechanism(s) involved in the sodium oxalate pro-oxidative activity in vitro and the potential protection by diphenyl diselenide ((PhSe)(2)) and diphenyl ditelluride ((PhTe)(2)) using supernatants of homogenates from brain, liver and kidney. Oxalate causes a significant increase in the TBARS (thiobarbituric acid reactive species) production up to 4mmol/l and it had antioxidant activity from 8 to 16mmol/l in the brain and liver. Oxalate had no effect in kidney homogenates. The difference among tissues may be related to the formation of insoluble crystal of oxalate in kidney, but not in liver and brain homogenates. (PhSe)(2) and (PhTe)(2) reduced both basal and oxalate-induced TBARS in rat brain homogenates, whereas in liver homogenates they were antioxidant only on oxalate-induced TBARS production. (PhSe)(2) showed a modest effect on renal TBARS production, whereas (PhTe)(2) did not modulate TBARS in kidney preparations. Oxalate at 2mmol/l did not change deoxyribose degradation induced by Fe(2+) plus H(2)O(2), whereas at 20mmol/l it significantly prevents its degradation. Oxalate (up to 4mmol/l) did not alter iron (10micromol/l)-induced TBARS production in the brain preparations, whereas at 8mmol/l onwards it prevents iron effect. In liver preparations, oxalate amplifies iron pro-oxidant activity up to 4mmol/l, preventing iron-induced TBARS production at 16mmol/l onwards. These results support the antioxidant effect of organochalcogens against oxalate-induced TBARS production. In addition, our results suggest that oxalate pro- and antioxidant activity in vitro could be related to its interactions with iron ions.

Low toxicity of diphenyl diselenide in rabbits: a long-term study.

Selenium compounds, like diphenyl diselenide (Ph(2)Se(2)), possess glutathione peroxidase (GSHPx)-like activities and other antioxidant properties. The aim of this study was to evaluate the effects of a long-term oral supplementation with Ph(2)Se(2) on various toxicological parameters in rabbits. Adult New Zealand male rabbits were divided into four groups: Group I served as control; Groups II, III and IV received 0.3, 3.0 and 30 p.p.m. of Ph(2)Se(2) pulverized in the chow for 8 months. A number of toxicological parameters were examined in liver, kidney, cerebral cortex and hippocampus, such as delta-aminolaevulinic acid dehydratase (delta-ALA-D), catalase (CAT), GSHPx activities, non-protein thiol (-SH), lipid peroxidation and ascorbic acid levels. The results indicated that supplementation 30 p.p.m. Ph(2)Se(2 )significantly increased delta-ALA-D activity in liver and in cerebral cortex. Non-protein -SH levels were significantly increased in liver but not in kidney, cerebral cortex and hippocampus of rabbits. Ascorbic acid content was significantly lower in the liver and cerebral cortex after supplementation with 30 p.p.m. Ph(2)Se(2). Conversely, no alterations in GSHPx and CAT activities, nor in thiobarbituric acid reactive substances levels were observed in rabbit tissues. These results indicate that oral supplementation with Ph(2)Se(2) is relatively secure in rabbits after 8 months of exposure. The findings encourage further experiments on the potential therapeutic effects of such compound.

Changes in biochemical parameters in rabbits blood after oral exposure to diphenyl diselenide for long periods.

The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. The present study was conducted to evaluate the potential toxicity of long time oral exposure to diphenyl diselenide (PhSe)2 in rabbits. Male adult New Zealand rabbits were divided into four groups, group I served as control; groups II, III and IV received 0.3, 3.0 and 30 ppm of (PhSe)2 pulverized in the chow for 8 months. A number of parameters were examined in blood as indicators of toxicity, including delta-aminolevulinate dehydratase (delta-ALA-D), catalase, glutathione peroxidase (GPx), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine, TBARS, non-protein-SH, ascorbic acid and selenium. The results demonstrated that 6 and 8 months of 30 ppm (PhSe)2 intake caused a significant increase in blood delta-ALA-D activity. Erythrocyte non-protein thiol levels were significantly increased after 2 months of 30 ppm (PhSe)2 intake and then return to control levels after prolonged periods of intake. Ingestion of 3.0 ppm of (PhSe)2 for 8 months significantly increased catalase activity in erythrocytes. Conversely, no alterations in GPx, ALT, AST, TBARS and selenium levels were observed in rabbit serum, conversely, selenium levels in peri-renal adipose tissue were significantly increased after 8 months of 30 ppm (PhSe)2 intake, indicating its great lipophylicity. The present results suggest that diphenyl diselenide was not hepato- or renotoxic for rabbits, but caused some biochemical alterations that can be related to some pro-oxidant activity of the compound (particularly the reduction in Vitamin C).

Effect of ebselen and organochalcogenides on excitotoxicity induced by glutamate in isolated chick retina.

In this study, we evaluated the effects of three simple organochalcogenides (diphenyl diselenide, diphenyl ditelluride and diphenyl telluride) and ebselen on the glutamate-driven 45Ca2+ influx into chick embryonic retinal cells, as well as their effects on the excitotoxic injury in retina cells. None of the compounds tested interfered with basal 45Ca2+ uptake. Diphenyl diselenide and diphenyl ditelluride had no effects on glutamate-driven 45Ca2+ influx. Diphenyl telluride (100-400 microM) decreased and ebselen (100-400 microM) completely blocked the glutamate-driven 45Ca2+ influx (P < 0.01) into chick retinal explants. The assessment of neural injury was made spectrophotometrically by quantification of cellularly reduced MTT (3(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) 24 h after the beginning of glutamate exposure (8 h). Ebselen had no effects on retinal MTT reduction when co-incubated with glutamate for 8 h. However, when ebselen (100 and 400 microM) was co-incubated for 8 h with glutamate and remained in the incubation media until MTT evaluation (24 h after the beginning of incubation), it protected retinal cells against the decrease in MTT reduction induced by glutamate. These data indicate that besides its capacity of interacting with Ca2+ channels, other mechanisms are involved in the neuroprotection afforded by ebselen in this work, possibly its antioxidant properties.

Basic-functionalized recyclable ionic liquid catalyst: A solvent-free approach for Michael addition of 1,3-dicarbonyl compounds to nitroalkenes under ultrasound irradiation.

A task-specific ionic liquid (TSIL) has been introduced as a recyclable catalyst in Michael addition. A series of nitroalkenes and various C-based nucleophiles were reacted in the presence of 30mol% of recyclable basic-functionalized ionic liquid. Good to excellent yields were obtained in 30min under ultrasound irradiation.