Diastereoselective Synthesis of Highly Functionalized γ-Lactams via Ugi Reaction/Michael Addition.

The γ-lactam ring is a prominent feature in medicinal chemistry, and its synthesis has garnered significant interest due to its valuable properties. Among the γ-lactams, 2-oxopyrrolidine-3-carbonitrile derivatives stand out as versatile synthons that can be readily transformed into a variety of other functional groups. In this work, we successfully synthesized highly functionalized 3-cyano-2-pyrrolidinones with moderate to good overall yields using the Ugi reaction followed by intramolecular Michael addition. The process demonstrated excellent diastereoselectivity and showed good tolerance to a range of isonitriles and carbonyl compounds.

A Sonochemical and Mechanochemical One-Pot Multicomponent/Click Coupling Strategy for the Sustainable Synthesis of Bis-heterocyclic Drug Scaffolds.

Bis-heterocycles were synthesized via a consecutive one-pot process by a Groebke-Blackburn-Bienaymé reaction (GBB-3CR) followed by Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) assisted by alternative sustainable energies (ASE) such as ultrasound irradiation (USI) and mechanical. These efficient and convergent strategies allowed the in situ generation of complex azides functionalized with imidazo[1,2-a]pyridines (IMPs), which was used as a synthetic platform. The target molecules contain two privileged scaffolds in medicinal chemistry: IMPs and the heterocyclic bioisostere of trans-amide bond, the 1,4-disubstituted 1H-1,2,3-triazoles (1,4-DS-1,2,3-Ts).

Development of a "turn off" fluorescent molecularly imprinted nanoparticle-based sensor for selective captopril quantification in synthetic urine and wastewater samples.

The combination of silica nanoparticles with fluorescent molecularly imprinted polymers (Si-FMIPs) prepared by a one-pot sol-gel synthesis method to act as chemical sensors for the selective and sensitive determination of captopril is described. Several analytical parameters were optimized, including reagent ratio, solvent, concentration of Si-FMIP solutions, and contact time. Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and the ninhydrin assay were used for characterization. The selectivity was evaluated against molecules belonging to other drug classes, such as fluoroquinolones, nonacid nonopioids, benzothiadiazine, alpha amino acids, and nitroimidazoles. Under optimized conditions, the Si-FMIP-based sensor exhibited a working range of 1-15 µM, with a limit of detection (LOD) of 0.7 µM, repeatability of 6.4% (n = 10), and suitable recovery values at three concentration levels (98.5% (1.5 µM), 99.9% (3.5 µM), and 99.2% (7.5 µM)) for wastewater samples. The sensor provided a working range of 0.5-15 µM for synthetic urine samples, with an LOD of 0.4 µM and a repeatability of 7.4% (n = 10) and recovery values of 93.7%, 92.9%, and 98.0% for 1.0 µM, 3.5 µM, and 10 µM, respectively. In conclusion, our single-vessel synthesis approach for Si-FMIPs proved to be highly effective for the selective determination of captopril in wastewater and synthetic urine samples.

Silver Nanoparticle-Embedded Carbon Nitride: Antifungal Activity on Candida albicans and Toxicity toward Animal Cells.

The development of engineered nanomaterials has been considered a promising strategy to control oral infections. In this study, silver-embedded carbon nitrides (Ag@g-CN) were synthesized and tested against Candida albicans, investigating their antifungal action and biocompatibility in animal cells. Ag@g-CN was synthesized by a simple one-pot thermal polymerization technique and characterized by various analytical techniques. X-ray diffraction (XRD) analysis revealed slight alterations in the crystal structure of g-CN upon the incorporation of Ag. Fourier transform infrared (FT-IR) spectroscopy confirmed the presence of Ag-N bonds, indicating successful silver incorporation and potential interactions with g-CN's amino groups. UV-vis spectroscopy demonstrated a red shift in the absorption edge of Ag@g-CN compared with g-CN, attributed to the surface plasmon resonance effect of silver nanoparticles. Field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) confirmed the 2D layered sheet like morphology of both materials. The Ag 3d peaks found in X-ray photoelectron spectroscopy (XPS) confirmed the presence of metallic Ag0 nanoparticles in Ag@g-CN. The Ag@g-CN materials exhibited high antifungal activity against reference and oral clinical strains of C. albicans, with minimal inhibitory concentration (MIC) ranges between 16-256 µg/mL. The mechanism of Ag@g-CN on C. albicans was attributed to the disruption of the membrane integrity and disturbance of the biofilm. In addition, the Ag@g-CN material showed good biocompatibility in the fibroblastic cell line and in Galleria mellonella, with no apparent cytotoxicity observed at a concentration up to 1000 µg/mL. These findings demonstrate the potential of the Ag@g-CN material as an effective and safe antifungal agent for the treatment of oral fungal infections.

Enantioselective Synthesis of Dihydrobenzofurans, Dihydrobenzosulfones, and Dihydroindoles by Merging One-pot Intramolecular Heck-Matsuda Reactions from Anilines with Redox-Relay Process.

A one-pot tandem process was developed aiming at the concise and expeditious enantioselective synthesis of dihydrobenzofuran, dihydrobenzosulfone, and dihydroindole scaffolds under mild, and open-flask conditions. This process combines the in situ generation of aryldiazonium salt directly from the anilines in methanol telescoped to an intramolecular Heck-Matsuda reaction linked to a redox relay process to provide the final products as the dimethyl acetals. These Heck products were smoothly converted into the corresponding primary alcohols or esters. The robustness and the efficiency of the protocol are demonstrated by the synthesis of 24 enantioenriched dihydrobenzofurans, dihydrobenzosulfones, and dihydroindoles in overall yields up to 78 % in enantiomeric ratios up to 99 : 1 by a sequential 5-step protocol.

One-Pot Synthesis and Surfactant Removal from MCM-41 Using Microwave Irradiation.

This research pioneers the application of microwave irradiation as an innovative strategy for one-pot synthesis and surfactant elimination (cetyltrimethylammonium bromide-CTAB) from MCM-41, introducing a rapid and efficient methodology. MCM-41 silica is widely utilized in various applications due to its unique textural and structural properties. Nonetheless, the presence of residual surfactants after synthesis poses a challenge to its effective application. MCM-41 synthesis, conducted in a microwave reactor at 60 °C, provided a result within 0.5 to 1 h. Comprehensive analyses of structural, chemical, morphological, and surface characteristics were undertaken, with a focus on the impact of synthesis time on these properties. Surfactant extraction involved the use of ethanol as a solvent at 120 °C for 6 min within the microwave reactor. The acquired particles, coupled with the properties of textural and structural features, affirmed the efficacy of the synthesis process, resulting in the synthesis of MCM-41 within 36 min. This study presents the first instance of one-pot synthesis and surfactant removal from MCM-41 using a microwave reactor. The proposed method not only addresses the surfactant removal challenge, but also substantially accelerates the synthesis process, thereby enhancing the potential for MCM-41's application in diverse fields.

Supercritical transesterification of vegetable oil and ethanol: temperature and residence time effects on phase formation and water content

Supercritical transesterification has emerged as a readily available alternative for biodiesel production since no catalyst is required, thereby generating fewer waste products. In this research, the supercritical transesterification of refined vegetable oil and aqueous ethanol was carried out at temperatures 400 to 480 °C and a 12:1 ethanol to oil molar ratio, to assess the effect of temperature and residence time in the formation of a homogeneous phase, effluent appearance and increased water content derived from glycerol etherification. The results showed that water was produced at temperatures higher than 400 °C, as expected from the occurrence of glycerol etherification, and that prolonged times resulted in gas and soot formation, indicating esters decomposition. Through water mass balances, it was possible to identify the set of operation conditions in which the water formed from glycerol etherification matched with the maximum expected according to the proposed reaction scheme.

La transesterificación supercrítica se ha propuesto como una alternativa para la producción de biodiesel ya que no requiere catalizador de esta manera se generan menos residuos. En esta investigación, la transesterificación supercrítica de aceite vegetal refinado y etanol acuoso se llevó a cabo a temperaturas en el rango 400 a 480 °C y relación molar etanol a aceite de 12:1, para evaluar el efecto de la temperatura y el tiempo de residencia en la formación de una fase homogénea, apariencia del efluente e incremento del contenido de agua resultado de las reacciones de eterificación del glicerol. Los resultados mostraron que se produjo agua a temperaturas mayores a 400°C, atribuida a la eterificación del glicerol, y que tiempos de residencia prolongados resultaron en formación de gas y hollín, indicativo de reacciones de descomposición de esteres. A través de balances de masa, fue posible identificar el conjunto de condiciones de operación a las cuales el agua formada por la eterificación del glicerol coincide con el valor máximo esperado de acuerdo con el esquema de reacción propuesto.

A transesterificação supercrítica foi proposta como uma alternativa para a produção de biodiesel porque não requer catalisador e, dessa forma, gera menos resíduos. Nesta pesquisa, a transesterificação supercrítica de aceite vegetal refinado e etanol acuoso foi conduzida a temperaturas entre 400 e 480 °C e uma relação molar de etanol e aceite de 12: 1, para avaliar o efeito da temperatura e do tempo de residência na formação de uma fase homogênea, apariência do efluente e aumento do conteúdo de água resultante das reações de eterificação do glicerol. Os resultados mostraram que se produziu água a temperaturas maiores que 400°C, atribuída à eterificação do glicerol, e que os tempos de residência prolongados resultaram na formação de gás e hollín, indicativo de reações de decomposição de ésteres. Por meio de balanças de massa, foi possível identificar o conjunto de condições de operação em que a água formada pela eterificação do glicerol coincide com o valor máximo esperado de acordo com o esquema de reação proposto.

One-Pot, Optimized Microwave-Assisted Synthesis of Difunctionalized and B-N Co-Doped Carbon Dots: Structural Characterization.

In this work, we employed a novel microwave-assisted synthesis method to produce nitrogen and boron co-doped carbon dots (B-N co-doped CDs). To achieve optimal synthesis, we conducted a comprehensive parameter modulation approach, combining various synthesis temperatures, times, and precursor concentrations, while keeping the power constant at 150 W and pH 5. Using maximum fluorescence emission as our response variable, the best conditions were identified as 120 °C, 3 min, and a precursor concentration of 1 mg/mL. Characterization using field emission scanning electron microscopy revealed these CDs to have a spherical morphology with an average size of 10.9 ± 3.38 nm. Further high-resolution transmission electron microscopy showed an interplanar distance of 0.23 nm, which is in line with prior findings of CDs that present a 0.21 nm distance corresponding to the (100) plane of graphite. Optical properties were ascertained through UV-vis absorption, identifying distinct π-π* and n-π* transitions. Fluorescence spectroscopy highlighted an emission peak at 375 nm when excited at 295 nm, achieving a quantum yield of 56.7%. Fourier-transform infrared spectroscopy and Raman spectroscopy analyses confirmed the boronic acid and amine groups' presence, underscoring the graphitic nature of the core and the co-doping of boron and nitrogen. These empirical observations were compared with theoretical investigations through simulated Raman spectra, proposing a potential structure for the CDs. X-ray photoelectron spectroscopy further endorsed the co-doping of nitrogen and boron, along with the detection of the specified functional groups. All these characteristics could lend this nanomaterial to different types of applications such as fluorescent probes for a broad range of analytes and for fluorescent cell imaging.

Multicomponent Reactions Applied to Total Synthesis of Biologically Active Molecules: A Short Review.

Multicomponent reactions (MCRs) are processes in which three or more starting materials are combined in the same reaction vessel, forming an adduct that contains all or most of the atoms of the starting materials. MCRs are one-pot processes that provide attractive advantages for the total synthesis of target molecules. These reactions allow rapid access to structurally complex adducts from particularly simple starting materials. Moreover, MCRs are generally intrinsically associated with principles of green syntheses, such as atom economy, minimization of isolation, and purification of synthetic intermediates, leading to large solvent economies and avoiding the production of large amounts of reaction waste. Thus, synthetic routes employing multicomponent reactions are generally more convergent, economical and often allow higher overall yields. In total synthesis, the use of MCRs has been mainly applied in the preparation of key advanced intermediates. Progress in the use of MCRs in total synthesis has been described over the last decades, including not only classical MCRs reactions (e.g. isocyanide-based transformations), but also non-traditional multicomponent reactions. Furthermore, reports concerning stereoselective multicomponent transformations are still scarce and present further development opportunities. This review aims to provide a general overview of the application of MCRs as key steps in the rapid preparation of structurally complex derivatives and fine chemicals. In special, some selected examples have been successfully applied for medicinal purposes. Finally, in some representative cases, either key intermediates formed during the reaction vessel or corresponding transition states have been disclosed in order to provide insights into the reaction mechanisms.

Polyhydroxy Fullerenes Enhance Antibacterial and Electrocatalytic Activity of Silver Nanoparticles.

Silver nanoparticles (AgNPs) are known and widely used for their antibacterial properties. However, the ever-increasing resistance of microorganisms compels the design of novel nanomaterials which are able to surpass their capabilities. Herein, we synthesized silver nanoparticles using, for the first time, polyhydroxy fullerene (PHF) as a reducing and capping agent, through a one-pot synthesis method. The resulting nanoparticles (PHF-AgNPs) were compared to AgNPs that were synthesized using sodium citrate (citrate-AgNPs). They were characterized using high-resolution transmission electron microscopy (HR-TEM), dynamic light scattering, and UV-visible spectroscopy. Our results showed that PHF-AgNPs have a smaller size and a narrower size distribution than citrate-AgNPs, which suggests that PHF may be a better capping agent than citrate. Antibacterial assays using E. coli showed enhanced antimicrobial activity for PHF-AgNPs compared to citrate-AgNPs. The electrocatalytic activity of nanoparticles towards oxygen evolution and reduction reaction (OER and ORR, respectively) was tested through cyclic voltammetry. Both nanoparticles are found to promote OER and ORR, but PHF-AgNPs showed a significant increase in activity with respect to citrate-AgNPs. Thus, our results demonstrate that the properties of forming nanoparticles can be tuned by choosing the appropriate reducing/capping agent. Specifically, this suggests that PHF-AgNPs can find potential applications for both catalytic and biomedical applications.

Development of an eco-friendly acetosolv protocol for tuning the acetylation of coconut shell lignin: Structural, antioxidant, solubility and UV-blocking properties.

The optimization of the parameters involved in lignin extraction is crucial for obtaining a lignin with specific structural features for its further valorization. The aim of this work was to develop an eco-friendly organosolv protocol for tuning the acetylation degree of coconut shell lignins (CSLs) by using MgCl2 and HCl as catalyst and co-catalyst, respectively. CSLs were obtained by mixing coconut shell powder with 90% v/v acetic acid combined to no catalyst, 2% v/v HCl and 2% w/v MgCl2 (1, 2 and 3 h) and 2% w/v MgCl2 combined to 0.1, 0.25 and 0.5% v/v HCl (2 h) at 110 °C. CSLs were characterized by FTIR, 1H NMR, GPC and TGA. The effects of the acetylation degree were evaluated on their antioxidant activity (DPPH assay) and UV-blocking capacity in sunscreen formulations. The results have shown that the use of HCl as co-catalyst increased the lignin yield (from 21.4 to 48.8%) and the acetylation degree (from 0.81 to 1.58 mmol g-1), which positively affected thermal (200 < Tonset < 226 °C), antioxidant (46.6 < IC50 < 67.5 µg mL-1) and UV-blocking capacities of CSLs. It can be concluded that the design of the organosolv process was capable of generating lignins with peculiar functionalities and properties through an eco-friendly protocol.

Ready-to-use room temperature one-pot synthesis of surface-decorated gold nanoparticles with targeting attributes.

Gold nanoparticles (AuNPs) can be used in diagnostic and therapeutic applications. The development of facile and fast synthetic approaches is accordingly desirable towards ready-to-use biomedical materials. We report a practical one-pot method for the synthesis in aqueous media and room temperature of surface-decorated AuNPs with enhanced biological responses. The gold ions could be reduced using only polyethyleneimine (PEI) derivatives containing sugar and-or alkyl chains acting simultaneously as reducing and stabilizing agent, without the aid of any other mediator. The process is possibly potentialized by the presence of the amino groups in the polymer chains which further confer colloidal stability. The kinetics of AuNPs nucleation and growth depends on the chemical nature of the polymer chains. Particularly, the presence of lactose moieties conjugated to the PEI chains conducted to surface-decorated AuNPs with low cytotoxicity that are remarkably faster uptaken by HepG2 cells. These cells overexpress asialoglycoprotein (ASGP-R), a galactose receptor. These findings may kick off significant advances towards the practical and ready-to-use manufacturing of functionalized AuNPs towards cell-targeting since the methodology is applicable for a large variety of other ligands that can be conjugated to the same polymer chains.

Multicomponent Reactions (MCRs) with o-Quinone Methides.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho-quinone methide intermediates (o-QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron-rich dienophiles in inverse-electron demand hetero-Diels-Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

2-Aminoselenazoles and 2-aminothiazoles: One-pot synthesis and control of the fungus Colletotrichum lindemuthianum in common beans.

BACKGROUND: Anthracnose, caused by the fungus Colletotrichum lindemuthianum, increases losses in the production of common beans. As 1,3-diazoles can act against fungi by inhibiting the enzyme squalene epoxidase (SE), 2-aminoselenazoles and 2-aminothiazoles were synthesized and subjected to tests with the fungus. In addition, the interactions of the most promising substances with the enzyme SE were investigated in silico. RESULTS: Seventeen compounds (eight new) were prepared by a one-pot methodology. In vitro antifungal activities of these compounds against C. lindemuthianum were determined by the minimum inhibitory concentration (MIC) method. Most treatments differed from the control (water), and six azoles with the lowest MIC values underwent an assay employing common bean plants inoculated with the fungus. Among the best results were those from 2-(3-fluorophenyl)amino-4-phenyl-1,3-thiazole (16; 2857 µg mL-1 ), which reduced the severity of anthracnose in common beans to values statistically comparable to the commercial fungicide thiophanate-methyl (700 µg mL-1 ). The in silico affinity of compound 16 for SE was statistically equal to those calculated for several inhibitors of this enzyme. CONCLUSIONS: The results suggested that 2-(3-fluorophenyl)amino-4-phenyl-1,3-thiazole (16) could be considered a potential fungicidal lead compound for further structural optimization, which according to the in silico study acts via SE inhibition. © 2022 Society of Chemical Industry.

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles.

An efficient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cyclization of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H activation. In a single-step approach, a variety of 2-substituted indoles were also generated via a Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes. The arylacetylenes proved to be more effective than the alkyl derivatives.

Synthesis by spray pyrolysis of gold nano species confined in iron oxide nanospheres effective in the reduction of 4-nitrophenol to 4-aminophenol.

The highly effective Au/Fe2O3-@Au/Fe2O3nanoreactors for the 4-nitrophenol (4-NP) reduction are successfully obtained by one-pot synthesis using the spray pyrolysis (SP) technique. The Au/Fe2O3-@Au/Fe2O3nanoreactors manifest superior catalytic activity in the reduction of 4-NP in the presence of sodium borohydride (NaBH4) compared to gold-iron oxide nanoreactors prepared via a colloidal approach. The negative effect of the reaction product accumulation, the 4-aminophenol (4-AP), on the catalytic reduction of 4-NP over Au/Fe2O3-@Au/Fe2O3is examined by a direct pre-injection of 4-AP to the reaction media. To the best of our knowledge, it is the first experimental evidence of gold active sites blocking by 4-AP. All obtained samples are characterized by the yolk-shell spherical hollow structure mainly consisted of two embedded hollow nanospheres. The reduction of iron oxide precursor concentration diminishes the diameter of final iron oxide nanospheres. According to STEM-EDS analysis and STEM, Au nano species are uniformly dispersed on both iron oxide nanospheres. The SP technique presently used to synthesize Au/Fe2O3-@Au/Fe2O3nanoreactors manifests high potential for the one-pot fabrication of a large variety of nanoreactors with various active materials applied as heterogeneous catalysts in numerous catalytic processes.

One-Pot Hydrothermal Synthesis of Victoria Green (Ca3Cr2Si3O12) Nanoparticles in Alkaline Fluids and Its Colour Hue Characterisation.

One-pot hydrothermal preparation of Ca3Cr2Si3O12 uvarovite nanoparticles under alkaline conditions was investigated for the first time. The experimental parameters selected for the study considered the concentration of the KOH solvent solution (0.01 to 5.0 M), the agitation of the autoclave (50 rpm), and the nominal content of Si4+ (2.2-3.0 mole). Fine uvarovite particles were synthesised at 200 °C after a 3 h interval in a highly concentrated 5.0 M KOH solution. The crystallisation of single-phase Ca3Cr2Si3O12 particles proceeded free of by-products via a one-pot process involving a single-step reaction. KOH solutions below 2.5 M and water hindered the crystallisation of the Ca3Cr2Si3O12 particles. The hydrothermal treatments carried out with stirring (50 rpm) and non-stirring triggered the crystallisation of irregular anhedral particles with average sizes of 8.05 and 12.25 nm, respectively. These particles spontaneously assembled into popcorn-shaped agglomerates with sizes varying from 66 to 156 nm. All the powders prepared by the present method exhibited CIE-L*a*b* values that correspond to the Victoria green colour spectral space and have a high near infrared reflectance property. The particle size and structural crystallinity are factors affecting the Victoria pigment optical properties, such as CIE-L*a*b* values, green tonality, and near-infrared reflectance.

2,4-Thiazolidinedione as Precursor to the Synthesis of Compounds with Anti-glioma Activities in C6 and GL261 Cells.

BACKGROUND: Thiazolidinediones (TZDs) represent an important class of heterocyclic compounds that have versatile biological activities, including anticancer activity. Glioma is one of the most common primary brain tumors, and it is responsible for most of the deaths caused by primary brain tumors. In the present work, 2,4-thiazolidinediones were synthesized via a multicomponent microwave one-pot procedure. The cytotoxicity of compounds was analyzed in vitro using rat (C6) and mouse (GL261) glioblastoma cell lines and primary cultures of astrocytes. OBJECTIVE: This study aims to synthesize and characterize 2,4-thiazolidinediones and evaluate their antitumor activity. METHODS: TZDs were synthesized from three components: 2,4-thiazolidinedione, arene-aldehydes, and aryl chlorides. The reactions were carried out inside a microwave and monitored using thinlayer chromatography (TLC). Compounds were identified and characterized using gas chromatography coupled to mass spectrometry (CG-MS) and hydrogen (1H-NMR) and carbon nuclear magnetic resonance spectroscopy (13C-NMR). The antitumor activity was analyzed using the 3-(4,5- dimethyl)-2,5-diphenyltetrazolium bromide (MTT) reduction test, in which cell viability was verified in the primary cultures of astrocytes and in rat and mouse glioblastoma cells exposed to the synthesized compounds. The cytotoxicity of all derivatives was analyzed at the 100 µM concentration, both in astrocytes and in the mouse and rat glioblastoma cell lines. The compounds that showed the best results, 4CI and 4DI, were also tested at concentrations 25, 50, 100, 175, and 250 µM to obtain the IC50. RESULTS: Seventeen TZD derivatives were easily obtained through one-pot reactions in 40 minutes with yields ranging from 12% to 49%. All compounds were cytotoxic to both glioblastoma cell lines without being toxic to the astrocyte primary cell line at 100 µM, thus demonstrating a selective activity. Compounds 4CI and 4DI showed the best results in the C6 cells: IC50 of 28.51 µM and 54.26 µM, respectively. CONCLUSION: The compounds were not cytotoxic in astrocyte culture, demonstrating selectivity for malignant cells. Changes in both rings are important for anti-glioma activity in the cell lines tested. TZD 4CI had the best anti-glioma activity.

Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer.

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 µM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.