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.

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.

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.

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.

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 stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin.

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

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.

Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR).

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5µM for EeAChE and 153.8µM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4µM (EeAChE) and 277.8µM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Stereoselective Reduction of Imines with Trichlorosilane Using Solid-Supported Chiral Picolinamides.

The stereoselective reduction of imines with trichlorosilane catalyzed by chiral Lewis bases is a well-established procedure for the synthesis of enantio-enriched amines. Five supported cinchona-based picolinamides have been prepared and their activity tested in a model reaction. The comparison of different supporting materials revealed that polystyrene gave better results than silica in terms of stereoselectivity. The applicability of the solid-supported catalyst of choice to the reduction of different imines was also demonstrated. Additionally, for the first time, a catalytic reactor containing a polymer-immobilized chiral picolinamide has been employed for the stereoselective reduction of imines with trichlorosilane under continuous flow conditions.

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.

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.

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.

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 phosphinoamidoester-derived Pd catalysts in the asymmetric allylic alkylation reaction: theoretical studies and mechanistic insights.

Two simple hemilabile P,O-coordinating phosphinoamidoester ligands 6a and 6b were synthesized and studied in the Pd(0)-catalyzed asymmetric allylic alkylation of rac-1,3-diphenylpropenyl acetate affording a highest ee of 83% ee with 6a. To gain an insight into the actual mechanism of this catalytic reactions, which had previously been investigated with a first generation family of P,O-coordinating phosphinoamido-alcohol ligands-4a and 4b-a semiempirical computational study was carried out with the Pd-allyl complexes formed from both 4a and 6a including Hitchcock's phosphinoamido-alcohol ligand 5 (R(1)= H, R(2)= Ph). The results of this study substantiate a working model that has previously been proposed for this reaction using hemilabile P,O-coordinating phosphinoamido-type ligands.