Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Functionalizing Dendrimers for Targeted Delivery of Bioactive Molecules to Macrophages: A Potential Treatment for Mycobacterium tuberculosis Infection-A Review.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages.

Application of Synchrotron Radiation-Based Fourier-Transform Infrared Microspectroscopy for Thermal Imaging of Polymer Thin Films.

The thermal imaging of surfaces with microscale spatial resolution over micro-sized areas remains a challenging and time-consuming task. Surface thermal imaging is a very important characterization tool in mechanical engineering, microelectronics, chemical process engineering, optics, microfluidics, and biochemistry processing, among others. Within the realm of electronic circuits, this technique has significant potential for investigating hot spots, power densities, and monitoring heat distributions in complementary metal-oxide-semiconductor (CMOS) platforms. We present a new technique for remote non-invasive, contactless thermal field mapping using synchrotron radiation-based Fourier-transform infrared microspectroscopy. We demonstrate a spatial resolution better than 10 um over areas on the order of 12,000 um2 measured in a polymeric thin film on top of CaF2 substrates. Thermal images were obtained from infrared spectra of poly(methyl methacrylate) thin films heated with a wire. The temperature dependence of the collected infrared spectra was analyzed via linear regression and machine learning algorithms, namely random forest and k-nearest neighbor algorithms. This approach speeds up signal analysis and allows for the generation of hyperspectral temperature maps. The results here highlight the potential of infrared absorbance to serve as a remote method for the quantitative determination of heat distribution, thermal properties, and the existence of hot spots, with implications in CMOS technologies and other electronic devices.

In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities: 3D-QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies.

Glycogen synthase kinase 3 (GSK-3) is involved in different diseases, such as manic-depressive illness, Alzheimer's disease and cancer. Studies have shown that insulin inhibits GSK-3 to keep glycogen synthase active. Inhibiting GSK-3 may have an indirect pro-insulin effect by favouring glycogen synthesis. Therefore, the development of GSK-3 inhibitors can be a useful alternative for the treatment of type II diabetes. Aminopyrimidine derivatives already proved to be interesting GSK-3 inhibitors. In the current study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have been performed on a series of 122 aminopyrimidine derivatives in order to generate a robust model for the rational design of new compounds with promising antidiabetic activity. The q2 values obtained for the best CoMFA and CoMSIA models have been 0.563 and 0.598, respectively. In addition, the r2 values have been 0.823 and 0.925 for CoMFA and CoMSIA, respectively. The models were statistically validated, and from the contour maps analysis, a proposal of 10 new compounds has been generated, with predicted pIC50 higher than 9. The final contribution of our work is that: (a) we provide an extensive structure-activity relationship for GSK-3 inhibitory pyrimidines; and (b) these models may speed up the discovery of GSK-3 inhibitors based on the aminopyrimidine scaffold. Finally, we carried out docking and molecular dynamics studies of the two best candidates, which were shown to establish halogen-bond interactions with the enzyme.Communicated by Ramaswamy H. Sarma.

Structure, controlled release mechanisms and health benefits of pectins as an encapsulation material for bioactive food components.

Encapsulation of food and feed ingredients is commonly applied to avoid the loss of functionality of bioactive food ingredients. Components that are encapsulated are usually sensitive to light, pH, oxygen or highly volatile. Also, encapsulation is also applied for ingredients that might influence taste. Many polymers from natural sources have been tested for encapsulation of foods. In the past few years, pectins have been proposed as emerging broadly applicable encapsulation materials. The reasons are that pectins are versatile and inexpensive, can be tailored to meet specific demands and provide health benefits. Emerging new insight into the chemical structure and related health benefits of pectins opens new avenues to use pectins in food and feed. To provide insight into their application potential, we review the current knowledge on the structural features of different pectins, their production and tailoring process for use in microencapsulation and gelation, and the impact of the pectin structure on health benefits and release properties in the gut, as well as processing technologies for pectin-based encapsulation systems with tailor-made functionalities. This is reviewed in view of application of pectins for microencapsulation of different sensitive food components. Although some critical factors such as tuning of controlled release of cargo in the intestine and the impact of the pectin production process on the molecular structure of pectin still need more study, current insight is that pectins provide many advantages for encapsulation of bioactive food and feed ingredients and are cost-effective.

Synthesis, antitumor activity, 3D-QSAR and molecular docking studies of new iodinated 4-(3H)-quinazolinones 3N-substituted.

A novel series of 6-iodo-2-methylquinazolin-4-(3H)-one derivatives, 3a-n, were synthesized and evaluated for their in vitro cytotoxic activity. Compounds 3a, 3b, 3d, 3e, and 3h showed remarkable cytotoxic activity on specific human cancer cell lines when compared to the anti-cancer drug, paclitaxel. Compound 3a was found to be particularly effective on promyelocytic leukaemia HL60 and non-Hodgkin lymphoma U937, with IC50 values of 21 and 30 µM, respectively. Compound 3d showed significant activity against cervical cancer HeLa (IC50 = 10 µM). The compounds 3e and 3h were strongly active against glioblastoma multiform tumour T98G, with IC50 values of 12 and 22 µM, respectively. These five compounds showed an interesting cytotoxic activity on four human cancer cell types of high incidence. The molecular docking results reveal a good correlation between experimental activity and calculated binding affinity on dihydrofolate reductase (DHFR). Docking studies proved 3d as the most potent compound. In addition, the three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis exhibited activities that may indicate the existence of electron-withdrawing and lipophilic groups at the para-position of the phenyl ring and hydrophobic interactions of the quinazolinic ring in the DHFR active site.

Cytotoxic Effects on Breast Cancer Cell Lines of Chalcones Derived from a Natural Precursor and Their Molecular Docking Analysis.

This study aimed to determine the in vitro cytotoxicity and understand possible cytotoxic mechanisms via an in silico study of eleven chalcones synthesized from two acetophenones. Five were synthesized from a prenylacetophenone isolated from a plant that grows in the Andean region of the Atacama Desert. The cytotoxic activity of all the synthesized chalcones was tested against breast cancer cell lines using an MTT cell proliferation assay. The results suggest that the prenyl group in the A-ring of the methoxy and hydroxyl substituents of the B-ring appear to be crucial for the cytotoxicity of these compounds. The chalcones 12 and 13 showed significant inhibitory effects against growth in MCF-7 cells (IC50 4.19 ± 1.04 µM and IC50 3.30 ± 0.92 µM), ZR-75-1 cells (IC50 9.40 ± 1.74 µM and IC50 8.75 ± 2.01µM), and MDA-MB-231 cells (IC50 6.12 ± 0.84 µM and IC50 18.10 ± 1.65 µM). Moreover, these chalcones showed differential activity between MCF-10F (IC50 95.76 ± 1.52 µM and IC50 95.11 ± 1.97 µM, respectively) and the tumor lines. The in vitro results agree with molecular coupling results, whose affinity energies and binding mode agree with the most active compounds. Thus, compounds 12 and 13 can be considered for further studies and are candidates for developing new antitumor agents. In conclusion, these observations give rise to a new hypothesis for designing chalcones with potential cytotoxicity with high potential for the pharmaceutical industry.

Lanthanide SMMs Based on Belt Macrocycles: Recent Advances and General Trends.

Enhancement of axial magnetic anisotropy is the central objective to push forward the performance of Single-Molecule Magnet (SMM) complexes. In the case of mononuclear lanthanide complexes, the chemical environment around the paramagnetic ion must be tuned to place strongly interacting ligands along either the axial positions or the equatorial plane, depending on the oblate or prolate preference of the selected lanthanide. One classical strategy to achieve a precise chemical environment for a metal centre is using highly structured, chelating ligands. A natural approach for axial-equatorial control is the employment of macrocycles acting in a belt conformation, providing the equatorial coordination environment, and leaving room for axial ligands. In this review, we present a survey of SMMs based on the macrocycle belt motif. Literature systems are divided in three families (crown ether, Schiff-base and metallacrown) and their general properties in terms of structural stability and SMM performance are briefly discussed.

Computational Study of the Stability of Pyrrolidine-Derived Iminium Ions: Exchange Equilibria between Iminium Ions and Carbonyl Compounds.

The tendency of carbonyl compounds to form iminium ions by reaction with pyrrolidine or chiral pyrrolidine derivatives (in other words, the relative stability to hydrolysis of these iminium ions) has been computationally examined, mainly using the M06-2X/6-311+G(d,p) method. We have thus obtained the equilibrium positions for R-CH=O + CH2=CH-CH=N+R2* → R-CH=N+R2* + CH2=CH-CH=O reactions and for related exchanges. In these exchanges, there is a transfer of a secondary amine between two carbonyl compounds. Their relative energies may be used to predict which iminium species can be predominantly formed when two or more carbonyl groups are present in a reaction medium. In the catalytic Michael additions of nucleophiles to iminium ions arising from conjugated enals, dienals, and trienals, if the formation of the new Nu-C bond is favorable, the chances of amino-catalyzed reactions to efficiently proceed, with high conversions, depend on the calculated energy values for these exchange equilibria, where the iminium tetrafluoroborates of the adducts (final iminium intermediates) must be more prone to hydrolysis than the initial iminium tetrafluoroborates. The density functional theory (DFT) calculations indicate that the MacMillan catalysts and related oxazolidinones are especially suitable in this regard.

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia.

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 µM for BTK) and 5b (IC50 = 0.38 µM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs.

Substituted Purines as High-Affinity Histamine H3 Receptor Ligands.

Continuing with our program to obtain new histamine H3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are designed from the isosteric replacement of the scaffold presented in our previous ligand, pyrrolo[2,3-d]pyrimidine ring, by a purine core. This design also considers maintaining the fragment of bipiperidine at C-4 and aromatic rings with electron-withdrawing groups at N-9, as these fragments are part of the proposed pharmacophore. The in vitro screening results show that two purine derivatives, 3d and 3h, elicit high affinities to the H3R (Ki values of 2.91 and 5.51 nM, respectively). Both compounds are more potent than the reference drug pitolisant (Ki 6.09 nM) and show low toxicity with in vitro models (IC50 > 30 µM on HEK-293, SH-SY5Y and HepG2 cell lines). Subsequently, binding modes of these ligands are obtained using a model of H3R by docking and molecular dynamics studies, thus determining the importance of the purine ring in enhancing affinity due to the hydrogen bonding of Tyr374 to the N-7 of this heterocycle. Finally, in silico ADME properties are predicted, which indicate a promising future for these molecules in terms of their physical−chemical properties, absorption, oral bioavailability and penetration in the CNS.

Spectroscopic and Thermal Characterization of Extra Virgin Olive Oil Adulterated with Edible Oils.

The substitution of extra virgin olive oil with other edible oils is the primary method for fraud in the olive-oil industry. Developing inexpensive analytical methods for confirming the quality and authenticity of olive oils is a major strategy towards combatting food fraud. Current methods used to detect such adulterations require complicated time- and resource-intensive preparation steps. In this work, a comparative study incorporating Raman and infrared spectroscopies, photoluminescence, and thermal-conductivity measurements of different sets of adulterated olive oils is presented. The potential of each characterization technique to detect traces of adulteration in extra virgin olive oils is evaluated. Concentrations of adulterant on the order of 5% can be detected in the Raman, infrared, and photoluminescence spectra. Small changes in thermal conductivity were also found for varying amounts of adulterants. While each of these techniques may individually be unable to identify impurity adulterants, the combination of these techniques together provides a holistic approach to validate the purity and authenticity of olive oils.

Review on Sol-Gel Synthesis of Perovskite and Oxide Nanomaterials.

Sol-Gel is a low cost, well-established and flexible synthetic route to produce a wide range of micro- and nanostructures. Small variations in pH, temperature, precursors, time, pressure, atmosphere, among others, can lead to a wide family of compounds that share the same molecular structures. In this work, we present a general review of the synthesis of LaMnO3, SrTiO3, BaTiO3 perovskites and zinc vanadium oxides nanostructures based on Sol-Gel method. We discuss how small changes in the parameters of the synthesis can modify the morphology, shape, size, homogeneity, aggregation, among others, of the products. We also discuss the different precursors, solvents, working temperature, reaction times used throughout the synthesis. In the last section, we present novel uses of Sol-Gel with organic materials with emphasis on carbon-based compounds. All with a perspective to improve the method for future applications in different technological fields.

Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies.

Alzheimer's disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures' field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209-9.417 for force-field QSAR and 9.111-9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists.

Amino-Catalyzed Reactions of Aldehydes with Chiral Nitroalkenes.

Chiral nitroalkenes are used for the first time in Michael additions of aldehydes, catalyzed by pyrrolidine derivatives. They yield the same major stereoisomer with either (S)-proline or (R)-proline, but this asymmetric induction does not overcome the effect of sterically more congested catalysts. Nitrocyclobutane intermediates are often formed, which are more stable than those from (E)-1-nitro-2-phenylethene. The cyclobutanes and final products were characterized by 2D NMR and chemical correlations.

NMR and Computational Studies on the Reactions of Enamines with Nitroalkenes That May Pass through Cyclobutanes.

The addition of aldehyde enamines to nitroalkenes affords cyclobutanes in all solvents, with all of the pyrrolidine and proline derivatives tested by us and with all of the substrates we have examined. Depending on the temperature, concentration of water, solvent polarity, and other factors, the opening and hydrolysis of such a four-membered ring may take place rapidly or last for several days, producing the final Michael-like adducts (4-nitrobutanals). Thirteen new cyclobutanes have now been characterized by NMR spectroscopy. As could be expected, s-trans-enamine conformers give rise to all-trans-(4S)-4-nitrocyclobutylpyrrolidines, while s-cis-enamine conformers afford all-trans-(4R)-4-nitrocyclobutylpyrrolidines. These four-membered rings can isomerize to adduct enamines, which should be hydrolyzed via their iminium ions. MP2 and M06-2X calculations predict that one iminium ion is more stable than the other iminium species, so that protonation of the adduct enamines can be quite stereoselective; in the presence of water, the so-called syn adducts (e.g., OCH-*CHR-*CHPh-CH2NO2, with R and Ph syn) eventually become the major products. Why one syn adduct is obtained with aldehydes, whereas cyclic ketones (the predicted ring-fused cyclobutanes of which isomerize to their enamines more easily) produce the other syn adduct, is also explained by means of molecular orbital calculations. Nitro-Michael reactions of aldehyde enamines that "stop" at the nitrocyclobutane stage and final enamine stage do not work catalytically, as known, but those of cyclic ketone enamines that do not work stop at the final enamine stage (if their hydrolysis to the corresponding nitroethylketones is less favorable than expected). These and other facts are accounted for, and the proposals of the groups led by Seebach and Hayashi, Blackmond, and Pihko and Papai are reconciled.

Further Insight into the Interactions of the Cytotoxic Macrolides Laulimalide and Peloruside A with Their Common Binding Site.

The binding site of the macrolides laulimalide and peloruside A, which is different from that of the clinically useful drugs paclitaxel/taxol and ixabepilone (tax site), is known to be between two adjacent ß-tubulin units (ext site). Here, we report our study of the binding of these molecules to an α1ß1/α2ß2-tubulin "tetramer" model. AutoDock 4.2.6//AutoDock Vina dockings predicted that the affinities of laulimalide and peloruside A for the tax site are quite similar to those for the ext site. However, molecular dynamics (MD) simulations indicated that only when these two ligands are located at the ext site, there are contacts that help stabilize the system, favoring the ß1/ß2 interactions. The binding affinity of laulimalide for this site is stronger than that of peloruside A, but this is compensated for by additional ß1/ß2 contacts that are induced by peloruside A. MD studies also suggested that epothilones at the tax site and either laulimalide or peloruside A at the ext site cause similar stabilizing effects (mainly linking the M-loop of ß1 and loop H1-B2 of ß2). In a "hexamer" model (3 units of αß-tubulin), the effects are confirmed. Metadynamics simulations of laulimalide and peloruside A, which are reported for the first time, suggest that peloruside A produces a stronger change in the M-loop, which explains the stabilization of the ß1/ß2 interaction.

The Performance of Several Docking Programs at Reproducing Protein-Macrolide-Like Crystal Structures.

The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0-10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

Importance of the Electron Correlation and Dispersion Corrections in Calculations Involving Enamines, Hemiaminals, and Aminals. Comparison of B3LYP, M06-2X, MP2, and CCSD Results with Experimental Data.

While B3LYP, M06-2X, and MP2 calculations predict the ΔG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford ΔG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol).