Assessing the Potential of 1,2,3-Triazole-Dihydropyrimidinone Hybrids Against Cholinesterases: In Silico, In Vitro, and In Vivo Studies.

Combining the pharmacological properties of the 1,2,3-triazole and dihydropyrimidinone classes of compounds, two small families of mono- and di(1,2,3-triazole)-dihydropyrimidinone hybrids, A and B, were previously synthesized. The main objective of this work was to investigate the potential anti-Alzheimer effects of these hybrids. The inhibitory activities of cholinesterases (AChE and BuChE), antioxidant activity, and the inhibitory mechanism through in silico (molecular docking) and in solution (STD-NMR) experiments were evaluated. The 1,2,3-triazole-dihydropyrimidinone hybrids (A and B) showed moderate in vitro inhibitory activity on eqBuChE (IC50 values between 1 and 58.4 µM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC50 of 1 ± 0.1 µM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC50 of 12 ± 2 µM, similar to that of galantamine. Molecular docking and STD-NMR experiments revealed the key binding interactions of these promising inhibitors with BuChE. Hybrids A and B did not display Artemia salina toxicity below 100 µM.

Asymmetric Additions Empowered by OrganoCatalysts, Metal Catalysts, and Deep Natural Eutectic Solvents (NADES).

This article is a history of an industrial-academic partnership that started almost two decades ago and details the evolution of a relationship between a small academic research group and a spin-out company located in Portugal. Their activities have ranged from the development of new metal-based catalytic systems for asymmetric epoxidations, allylic alkylations, and arylations to the development of novel cinchona-based organocatalysts for asymmetric hydrosilylations and Michael additions. Current common interests are centered on the development of novel chiral Natural Deep Eutectic Solvent systems, which they are investigating in different types of reaction systems.

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs.

A sequential strategy to access 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones (DBDAPs) is disclosed in this article through a palladium and copper-catalyzed amination (Buchwald-Hartwig (B-H) or Chan-Lam (C-L)) followed by a palladium-catalyzed intramolecular aminocarbonylation with Mo(CO)6 as CO surrogate (to avoid toxic CO handling) of readily available o-phenylenediamines and either 1,2-dibromobenzene or 2-bromophenylboronic acid. The 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinone could be synthezised in good yield using a sequential catalytic procedure, using both C-L and B-H approaches. Gratifingly, the use of the C-L reaction was more impressive, and afforded the dibenzodiazepinones in good yields (up to 45%; 2 steps) and much milder conditions using copper as the catalyst. The synthetic utility of this novel strategy was showcased by demonstrating a formal synthesis for the antipsychotic drug clozapine and to an anticancer triazole-DBDAP hybrid.

Early pharmacological profiling of isatin derivatives as potent and selective cytotoxic agents.

Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds' mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines.

What is the future of click chemistry in drug discovery and development?

INTRODUCTION: The concept of click chemistry was introduced in 2001 as an effective, efficient, and sustainable approach to making functional groups harnessing the thermodynamic properties of a set of known chemical reactions that are based on nature. Some of the most common examples include reactions that produce 1,2,3-triazoles, which have been used with great success in drug discovery and development, and in chemical biology. The reactions unite two molecules quickly and irreversibly, and the reactions can be performed inside living cells, without harming the cell. AREAS COVERED: The main focus of this perspective is the future of click chemistry in drug discovery and development, exemplified by novel click chemistry approaches and other aspects of the drug development enterprise, like SPAAC and analogous techniques, PROTACs, as well as diversity-oriented click chemistry. EXPERT OPINION: Drug discovery and development has benefited enormously from the amazing advances that have been made in the field of click chemistry since 2001. The methods most likely to have the most future applications include metal-catalyzed azide-alkyne cycloadditions giving 1,2,3-triazoles, SPAAC for medical diagnostics and vaccine development, other congeners, Sulfur-Fluoride Exchange (SuFEx) and Diversity-Oriented Clicking (DOC), a concept with diverse molecular methodology with the potential for obtaining extensive molecular diversity.

Quercetin-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer's Agents.

The number of patients with Alzheimer's disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. Herein, we report the evaluation of a library of quercetin-1,2,3-triazole hybrids (I-IV) in antioxidant, hydrogen peroxide-induced oxidative stress protection, and cholinesterases (AChE and BuChE) inhibitory activities. Hybrids IIf and IVa-d showed potent in vitro inhibitory activity on eqBuChE (IC50 values between 11.2 and 65.7 µM). Hybrid IIf, the best inhibitor, was stronger than galantamine, displaying an IC50 value of 11.2 µM for eqBuChE, and is also a competitive inhibitor. Moreover, toxicity evaluation for the most promising hybrids was performed using the Artemia salina toxicity assay, showing low toxicity. Hybrids IIf, IVb, and IVd did not affect viability at 12.5 µM and also displayed a protective effect against oxidative stress induced by hydrogen peroxide in cell damage in MCF-7 cells. Hybrids IIf, IVb, and IVd act as multifunctional ligands in AD pathologies.

Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients.

INTRODUCTION: Over the last 20 years, it has become clear that organocatalysis is the third pillar of catalysis. The low reactivity in the early days of organocatalysis has been overcome with the invention of more efficient catalysts, and by harnessing enabling technologies like continuous-flow chemistry and photo-redox catalysis. AREAS COVERED: The main focus of this review is on the development over the last 10-15 years of key APIs using asymmetric organocatalysis. Due to significant engineering advances, and also due to the need for continuous manufacturing, flow and photo-redox approaches are becoming more widespread. EXPERT OPINION: Over the last 20 years, organocatalysis has been used on various occasions for accessing chiral drugs. The great advantage of using these catalysts is that the final active pharmaceutical ingredient (API) is metal-free. Also due to their inherent stability in air and water, they are very amenable to recovery via attachment to appropriate solid supports and also application in continuous flow systems. In recent years, more efficient organocatalysts have been developed, which includes the photoredox types, with much potential for chiral API synthesis.

N-1,2,3-Triazole-isatin derivatives: anti-proliferation effects and target identification in solid tumour cell lines.

Molecular hybridization approaches have become an important strategy in medicinal chemistry, and to this end, we have developed a series of novel N-1,2,3-triazole-isatin hybrids that are promising as tumour anti-proliferative agents. Our isatin hybrids presented high cytotoxic activity against colon cancer cell line SW480, lung adenocarcinoma cell line A549, as well as breast cancer cell lines MCF7 and MDA-MB-231. All tested compounds demonstrated better anti-proliferation (to 1-order of magnitude) than the cis-platin (CDDP) benchmark. In order to explore potential biological targets for these compounds, we used information from previous screenings and identified as putative targets the histone acetyltransferase P-300 (EP300) and the acyl-protein thioesterase 2 (LYPLA2), both known to be involved in epigenetic regulation. Advantageous pharmacological properties were predicted for these compounds such as good total surface area of binding to aromatic and hydrophobic units in the enzyme active site. In addition, we found down-regulation of LYPLA2 and EP300 in both the MCF7 and MDA-MB-231 breast cancer cells treated with our inhibitors, but no significant effect was detected in normal breast cells MCF10A. We also observed upregulation of EP300 mRNA expression in the MCF10A cell line for some of these compounds and the same effect for LYPLA2 mRNA in MCF7 for one of our compounds. These results suggest an effect at the transcriptional regulation level and associated with oncological contexts.

Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease.

The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 µM) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 µM. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.

Recent Advances in Asymmetric Hydrogenation Catalysis Utilizing Spiro and Other Rigid C-Stereogenic Phosphine Ligands.

Transition-metal-catalyzed asymmetric reactions have been a powerful tool in organic synthesis for many years. The design of chiral ligands with the right configuration is fundamental to induce high regio- and stereoselectivity to catalytic reactions and to achieve high turnover numbers and high yields. A challenge is the control of prochiral centers with similar electronic properties in a similar steric environment within the same molecule. Over the last 10 years, a range of novel rigid C-stereogenic chiral phosphine ligands has been developed and successfully applied in various types of asymmetric transformations. Many of these ligands are of a di-, tri-, or multidentate nature. The purpose of this Perspective is to highlight recent synthetic achievements (since 2010) with spiro-phosphines and other rigid phosphines and discuss some mechanistic aspects of the catalytic reactions.

Ugi Reaction Synthesis of Oxindole-Lactam Hybrids as Selective Butyrylcholinesterase Inhibitors.

Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole-lactam hybrids, under catalyst-free conditions. The resulting oxindole-ß-lactam and oxindole-γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole-lactam hybrids as new potential agents for the treatment of Alzheimer's disease.

Seeking a Fast Screening Method of the Varietal Origin of Olive Oil: The Usefulness of an NMR-Based Approach.

This work encompasses the use of 1D multinuclear NMR spectroscopy, namely, 1H NMR and 13C NMR DEPT 45, combined with a multivariate statistical analysis to characterize olive oils produced from nine different varieties: Galega Vulgar, Cobrançosa, Cordovil de Serpa, Blanqueta, Madural, Verdeal Alentejana, Arbequina, Picual and Carrasquenha. Thus, the suitability of an NMR-based spectroscopic tool to discriminate olive oils according to their varietal origin is addressed. The results obtained show that the model based on 13C NMR DEPT 45 data has a stronger performance than the model based on 1H NMR data, proving to be promising in the discrimination of the olive oils under study based on their varietal origin, being particularly relevant for olive oils of the Galega Vulgar variety.

Stereoselective benzilic acid rearrangements: new advances on an old story.

The benzilic acid rearrangement (BAR) is the oldest rearrangement on record. It is a powerful synthetic tool for accessing significant biologically active molecules. The reaction is both catalytic (generally Lewis acid) and stereoselective, recently the first catalytic asymmetric version was reported with astonshing results (ees of up to 97%) to give chiral tartronic esters. In this unique highlight, we look at the progress made over the last 10 years on the stereoseletive aspects of this synthetic transformation, showing interesting examples of this rearrangment in both acyclic and cyclic systems (like for instance its importance in the stereoselective synthesis of syn and anti-hydroxy-iso-evoninic acids, α-hydroxy-α-perfluoroalkyl esters, a selective nonsteroidal mineralocorticoid receptor antagonist, Geldanamycin type polyketides and (-)-isatisine A, etc.) and the differnces in stereoselectivity encountered which culminated recently in the conquest of the first catalytic asymmetric example on record.

Engaging Isatins in Multicomponent Reactions (MCRs) - Easy Access to Structural Diversity.

Multicomponent reactions (MCRs) are a valuable tool in diversity-oriented synthesis. Its application to privileged structures is gaining relevance in the fields of organic and medicinal chemistry. Isatin, due to its unique reactivity, can undergo different MCRs, affording multiple interesting scaffolds, namely oxindole-derivatives (including spirooxindoles, bis-oxindoles and 3,3-disubstituted oxindoles) and even, under certain conditions, ring-opening reactions occur that leads to other heterocyclic compounds. Over the past few years, new methodologies have been described for the application of this important and easily available starting material in MCRs. In this review, we explore these novelties, displaying them according to the structure of the final products obtained.

The application of isatin-based multicomponent-reactions in the quest for new bioactive and druglike molecules.

Oxindole derivatives are known for their great interest in the field of Medicinal Chemistry, as they display vast biological activities. Recent efforts concerning the preparation of oxindole derivatives using isatin-based multicomponent reactions (MCRs) constitute a great advance in generating druglike libraries fast and with wide scaffold diversity. In this review, we address those recent developments, exploring the synthetic pathways and biological activities described for these compounds, namely antitumor, antibacterial, antifungal, antiparasitic, antiviral, antioxidant, anti-inflammatory and central nervous system (CNS) pathologies. To add new depth to this work, we used a well-established web-based free tool (SwissADME) to evaluate the most promising scaffolds in what concerns their druglike properties, namely by evaluating their compliance with some of the most valuable rules applied by medicinal chemists in both academia and industrial settings (Lipinski, Ghose, Veber, Egan, Muegge). The aim of this review is to endorse isatin-based MCRs as a valuable synthetic approach to attain new hit compounds bearing the oxindole privileged structure, while critically exploring these scaffolds' druglike properties.

Ambipolar pentacyclic diamides with interesting electrochemical and optoelectronic properties.

Developing organic semiconductors for organic thin film transistors (OTFT) and optoelectronic applications is a challenge. We developed highly crystalline pentacyclic diimides (3) and (4) which showed good OTFT and OLED potential and energy gaps of 2.60 eV and 2.54 eV. They exhibited interesting photo and eletroluminescence activity. Both compounds showed good quantum yields (0.56 for (3) and 0.60 for (4)).

N-1,2,3-triazole-isatin derivatives for cholinesterase and ß-amyloid aggregation inhibition: A comprehensive bioassay study.

Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and ß-amyloid (Aß) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 µM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aß anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.

In silico, NMR and pharmacological evaluation of an hydroxyoxindole cholinesterase inhibitor.

From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 µM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer's disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies. Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min-1.mg-1) than donepezil (0.112 µmol.min-1.mg-1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min-1.mg-1).

A photoswitchable "host-guest" approach for the selective enrichment of dimethoate from olive oil.

This work describes the development of a new selective photocontrollable molecularly imprinted-based sorbent for the selective enrichment/pre-concentration of dimethoate from spiked olive oil samples. To achieve this goal an improved molecularly imprinted strategy relying on the embedding of a functional monomer containing an azobenzene chromophore as light-responsive element, on the crosslinked tridimensional molecular imprinted network, has been assessed. To address the mechanisms underlying template recognition and uptake/release of the analyte from the functional imprinted material, computational studies using a quantum chemical approach, have been explored. This new functional sorbent provides a straightforward controllable uptake/release of the target template using light as the stimuli tool, which is highly advantageous due to light manipulation characteristics, such as superior clean, precision and remote controllable properties. In general, this work will contribute to the implementation of a photoswitchable analytical methodology that proves to be suitable for the selective isolation and further quantification of dimethoate from olive oil matrices at levels similar to the maximum residues limits imposed by the legislation. The limits of detection, calculated based on 3σ, was 1.6 mgL-1 and the limit of quantification, based on 10σ, was 5.2 mgL-1. The implemented sample preparation shows high reproducibility and recoveries (93.3 ±â€¯0.4%).

A magnetic controllable tool for the selective enrichment of dimethoate from olive oil samples: A responsive molecular imprinting-based approach.

Aiming to develop a straightforward magnetic-based sample preparation methodology for the selective extraction of dimethoate from olive oil, the synthesis of dimethoate-imprinted polymer on the surface of modified magnetic nanoparticles has been attempted. Molecular recognition assays have proven their suitability for the selective pre-concentration of dimethoate. Mechanistic basis for template selective recognition has been explored using a quantum chemical approach, providing new insights about the mechanisms underlying template recognition. Thus, a magnetic molecularly imprinted solid-phase extraction method was developed allowing the extraction of dimethoate from spiked olive oil samples, at levels similar to the maximum residue limits imposed by legislation, followed by the quantification of their levels by high-performance liquid chromatography with diode-array detection. Recoveries of 94.55% were obtained, with relative standard deviations lower than 0.53% (n = 3). The developed sample preparation technique enables a selective pre-concentration/enrichment of dimethoate from olive oil matrix with minimum handling and less solvent consumption.