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.

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.

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.

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.

Assessment of Dimethoate in Olive Oil Samples Using a Dual Responsive Molecularly Imprinting-Based Approach.

A new generation of advanced materials developed by molecular imprinting technology showing a stimuli-responsive functionality are emerging. The switchable ability to control the uptake/release of the target analyte by action of external stimulus combined with a remarkable selectivity and specificity, makes these functional materials very attractive for sample preparation purposes. In this work, the usefulness of a sample preparation tool for the selective enrichment/pre-concentration of dimethoate from olive oil spiked samples based on "tailor-made" dual responsive magnetic and photonic molecularly imprinted polymers as sorbents is explored. To achieve this goal, a smart molecularly imprinted polymer (MIP) possessing magnetic and photonic responsiveness was successfully synthesized, and its physico-chemical and morphological characterization was assessed. Further, the trace analysis of dimethoate in spiked olive oil samples was validated and successfully implemented using smart-MIPs as sorbents in the sample preparation step, with high recoveries (83.5 ± 0.3%) and low detection limit (0.03µg·mL-1).

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.

Dual-layer solid-phase extraction based on molecular imprinting technology: Seeking a route to enhance selectivity for trace analysis of pesticide residues in olive oil.

Aiming to introduce a multiresidue analysis for the trace detection of pesticide residues belonging to organophosphorus and triazine classes from olive oil samples, a new sample preparation methodology comprising the use of a dual layer of "tailor-made" molecularly imprinted polymers (MIPs) SPE for the simultaneous extraction of both pesticides in a single procedure has been attempted. This work has focused on the implementation of a dual MIP-layer SPE procedure (DL-MISPE) encompassing the use of two MIP layers as specific sorbents. In order to achieve higher recovery rates, the amount of MIP layers has been optimized as well as the influence of MIP packaging order. The optimized DL-MISPE approach has been used in the preconcentration of spiked organic olive oil samples with concentrations of dimethoate and terbuthylazine similar to the maximum residue limits and further quantification by HPLC. High recovery rates for dimethoate (95%) and terbuthylazine (94%) have been achieved with good accuracy and precision. Overall, this work constitutes the first attempt on the development of a dual pesticide residue methodology for the trace analysis of pesticide residues based on molecular imprinting technology. Thus, DL-MISPE constitutes a reliable, robust, and sensitive sample preparation methodology that enables preconcentration of the target pesticides in complex olive oil samples, even at levels similar to the maximum residue limits enforced by the legislation.

Novel hydroxyamides and amides containing D-glucopyranose or D-fructose units: Biological assays in MCF-7 and MDST8 cell lines.

A novel library of 15 compounds, hydroxyamides and amides containing a ß-D-glucopyranose (D-Gluc) or a ß-D-fructose (D-Fruc) units was designed and synthesized for antiproliferative assays in breast (MCF-7) and colon (MDST8) cancer cell lines. Twelve of them were hydroxyamides and were successfully synthesized from ß-D-glucuronic acid (D-GluA). Six of these hydroxyamides which were acetylated hydroxy-ß-D-glucopyranuronamide 2a-2f (1st Family) and the other six were their respective isomers, that is, hydroxy-ß-D-fructuronamide 3a-3f (2nd Family), obtained by acid-base catalyzed isomerization. These compounds have the general structure, D-Gluc-C=ONH-CHR-(CH2)n-OH and D-Fruc-C=ONH-CHR-(CH2)n-OH, where R=an aromatic, alkyl or a hydrogen substituent, with n=0 or 1. Eight of these contained a chiral aminoalcohol group. Three compounds were amides containing a D-glucopyranose unit (3rd Family). SAR studies were conducted with these compounds. Antiproliferative studies showed that compound 4a, the bromo-amide containing the ß-D-glucopyranose ring, potently inhibits the proliferation of the MDST8 cells. Five compounds (2e, 2f, 3d, 3e, and 3f) were shown to potently selectively inhibit the proliferation of the MCF-7 cells. Compound 4b was the only one showing inhibition in both cell lines. In general, the more active compounds were the amides and hydroxyamides containing the ß-D-fructose moiety, and containing an alkyl group or hydrogen. Half-inhibitory concentrations (IC50) of between 0.01 and 10 µM, were observed.

Design and development of molecularly imprinted polymers for the selective extraction of deltamethrin in olive oil: An integrated computational-assisted approach.

This work firstly addresses the design and development of molecularly imprinted systems selective for deltamethrin aiming to provide a suitable sorbent for solid phase (SPE) extraction that will be further used for the implementation of an analytical methodology for the trace analysis of the target pesticide in spiked olive oil samples. To achieve this goal, a preliminary evaluation of the molecular recognition and selectivity of the molecularly imprinted polymers has been performed. In order to investigate the complexity of the mechanistic basis for template selective recognition in these polymeric matrices, the use of a quantum chemical approach has been attempted providing new insights about the mechanisms underlying template recognition, and in particular the crucial role of the crosslinker agent and the solvent used. Thus, DFT calculations corroborate the results obtained by experimental molecular recognition assays enabling one to select the most suitable imprinting system for MISPE extraction technique which encompasses acrylamide as functional monomer and ethylene glycol dimethacrylate as crosslinker. Furthermore, an analytical methodology comprising a sample preparation step based on solid phase extraction has been implemented using this "tailor made" imprinting system as sorbent, for the selective isolation/pre-concentration of deltamethrin from olive oil samples. Molecularly imprinted solid phase extraction (MISPE) methodology was successfully applied for the clean-up of spiked olive oil samples, with recovery rates up to 94%.

Development of a selective sorbent for the solid-phase extraction of terbuthylazine in olive oil samples: a molecular imprinting strategy.

Aiming to implement an analytical methodology that is highly selective for the extraction and quantification of terbuthylazine from olive oil, we successfully achieved: (i) the development of a molecularly imprinted polymer by bulk polymerization using terbuthylazine as template molecule, methacrylic acid as functional monomer, ethylene glycol dimethacrylate as cross-linker, and dichloromethane as porogen; (ii) characterization of the imprinting material using Fourier transform infrared spectroscopy, thermogravimetric analysis, nitrogen adsorption at 77 K, and scanning electron microscopy; (iii) their molecular recognition for the template molecule using high-performance liquid chromatography, and (iv) optimization of a solid-phase extraction procedure using as sorbent the synthesized molecularly imprinted polymer for the selective extraction and clean-up of terbuthylazine from spiked organic olive oil and further quantification of the pesticide levels by high-performance liquid chromatography. The suitability of the implemented analytical methodology was demonstrated, as concentrations of terbuthylazine below the tolerated maximum residue limits in the spiked organic olive oil samples could be satisfactorily analyzed with good precision/accuracy with high recovery rates (96%). Overall, the implemented methodology has proven to be reliable and robust and is highly promising in the field of sample preparation, particularly for the isolation/preconcentration of terbuthylazine in complex food samples.

3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase.

Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97±0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ∼90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.

Five-membered iminocyclitol α-glucosidase inhibitors: synthetic, biological screening and in silico studies.

The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent α-glucosidase inhibitors in the series. Docking studies performed with an homology model of α-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a' occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.