J. Carlos Menendez

Complutense University of Madrid | UCM · Department of Organic Chemistry and Pharmaceutical

Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahy...

Brain amyloid depositions are the main hallmarks of Alzheimer's and other protein misfolding diseases. Since they are believed to precede clinical symptoms by several years, imaging of such fibrillar aggregates is particularly suitable to diagnose the onset of the disease in its early stage and monitor its progression. In this context, near infrare...

The InCl3-catalyzed sequential multicomponent reaction between 2-furfurylamine, β-dicarbonyl compounds and α,β-unsaturated aldehydes in ethanol, followed by microwave irradiation in solvent-free conditions, afforded good to excellent yields of highly substituted pyridines, with loss of a 2-furylmethyl side chain. The method was also adapted to the...

C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved CaV1.3/CaV1.2 selectivity in comparison with nifedipine. Furthermore, they were able...

Medicinal Chemistry of Anticancer Drugs, Second Edition, provides an updated treatment from the point of view of medicinal chemistry and drug design, focusing on the mechanism of action of antitumor drugs from the molecular level, and on the relationship between chemical structure and chemical and biochemical reactivity of antitumor agents. Antitum...

The first achievement of the 2022 Chemistry Nobel Prize awardees, Sharpless in particular, was of a conceptual nature and consisted in the proposal of the click chemistry concept, together with its placement in a broader theoretical frame. In a second phase, both Sharpless and Meldal established the copper(I)-catalyzed conditions that allowed the H...

The isoquinoline nucleus is the fundamental structure of many natural and synthetic biologically active substances. This scaffold is found in a variety of compounds, including antihypertensive agents, anesthetics, and vasodilators. In the present work, the synthesis and antibacterial activity of novel 3-amino-1,2-dihydroisoquinoline derivatives hav...

Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC co...

The solvent-free preparation of unsymmetrical N-aryl-5,6-unsubstituted-1,4-dihydropyridines (DHPs) by ball-milling was investigated. Three different mechanochemical domino reactions (one-pot/one step or stepwise) were studied, the process parameters underlying any mechanochemical process were modulated and the differences with solution-based mechan...

Many aspects of gene transcription, protein translation, signaling, and cellular growth and repair depend on protein-protein interactions (PPIs). Therefore, the design of specific inhibitors of aberrant PPIs to realign systems toward homeostasis is a highly relevant goal in anticancer drug discovery. This chapter critically summarizes from the drug...

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like mole...

Mechanochemistry is a powerful tool to develop environmentally benign syntheses of active pharmaceutical ingredients. In this context, we report here the synthesis of the anti-epileptic agent rufinamide through a one-pot sequential multi-component approach, which was fully carried out applying a ball milling method. This solid-state synthesis of ru...

Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthe...

2,5‐Diketopiperazine is the simplest cyclic peptide. It is a structural fragment of many natural products and synthetic bioactive molecules. Furthermore, 2,5‐diketopiperazines introduce structural diversity at four positions and contain up to two stereogenic centers. For this reason, they have been widely employed as chiral templates to build enant...

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecu...

Three chiral pyrazoline derivatives were synthesized by a flavanone ring‐opening reaction followed by cyclocondensation with hydrazine hydrate to give better yields. Their enantiomeric resolution was achieved using polysaccharide chiral stationary phase columns consisting of cellulose (Chiralcel®OD‐RH, Chiralcel®OZ‐3) and amylose (Chiralpak®IA) by...

Brain's metals accumulation is associated with toxic proteins, like amyloid-proteins (Aβ), formation, accumulation, and aggregation, leading to neurodegeneration. Metals downregulate the correct folding, disaggregation, or degradation mechanisms of toxic proteins, as heat shock proteins (HSPs) and proteasome. The 7-amino-phenanthridin-6(5H)-one der...

A five-step route to a ring-contracted analogue of the oxicam derivative propoxicam from thiosalicylic acid, sarcosine and N,N-dimethyl-1,3-propanediamine is described. The route has as key steps the base-promoted cross-Claissen coupling of protected sarcosine and thiosalicylic acid derivatives, the installation of a β-ketoamide moiety and a final...

Organocatalysis, i.e. the acceleration of chemical reactions by substoichiometric amounts of organic molecules, is steadily gaining importance in organic synthesis, and in particular enantioselective organocatalysis is highly promising for target‐oriented synthesis and for the construction of structurally diverse chiral heterocyclic libraries. The...

The environmental presence of anions of natural origin or anthropogenic origin is gradually increasing. As a tool to tackle this problem, carbazole derivatives are an attractive gateway to the development of luminescent chemosensors. Considering the different mechanisms proposed for anion recognition, the fluorescence properties and anion-binding r...

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral pro...

Any advanced society requires new molecules and materials to be used as drugs, agrochemicals, energy production and storage and countless other applications. This, in turn, requires the development of new methods for synthesis. The 2021 Nobel Prize in Chemistry was awarded to Professors Benjamin List and David MacMillan “for the development of asym...

Catalytic asymmetric Povarov protocols have undergone an explosive growth, especially in the last ten years, since the first example was published in 1996. The use of chiral Lewis and Brønsted acids and dual strategies based on their combination with catalysts acting by hydrogen bond formation, as well as covalent aminocatalysis, are reviewed. More...

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na + /Ca 2+ exchanger antagonist , and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by u...

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of pip...

The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydrox...

Ball milling of aromatic, heteroaromatic, vinylic, and aliphatic esters with ethanol and calcium nitride afforded the corresponding primary amides in a transformation that was compatible with a variety of functional groups and maintained the integrity of a stereocenter α to carbonyl. This methodology was applied to α-amino esters and N-BOC dipeptid...

A series of 4‐unsubstituted fused quinoline derivatives, including the biologically significant 5‐deazaflavin analogs and 6H‐chromeno[4,3‐b]quinolin‐6‐ones, were synthesized from easily accessible N‐(2‐aminobenzylidene)‐4‐methylanilines and heterocyclic 1,3‐dicarbonyl compounds. The reaction was carried out in water in the absence of any catalyst t...

Neurodegenerative diseases have been associated with brain metal accumulation, which produces oxidative stress (OS), matrix metalloproteinases (MMPs) induction, and neuronal cell death. Several metals have been reported to downregulate both the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the antioxidant enzymes regulated by it, m...

Bis‐indolylquinones are fungal natural products endowed with interesting pharmacological properties. Most of the previously described methodologies in solution for the construction of the bis‐indolylquinone framework show disadvantages associated with long reaction times and difficult, waste‐generating purifications. We describe a one‐pot mechanoch...

Synaptic spine morphology is controlled by the activity of Rac1, Cdc42 and RhoA, which need to be finely balanced, and in particular RhoA/ROCK prevents the formation of new protrusions by stabilizing actin formation. These processes are crucial to the maturation process, slowing the de novo generation of new spines. The RhoA/ROCK also influences pl...

PurposeA number of tetrahydropyrimidines and their bioisosteric dihydropyridines bearing chloro substituent at various positions of phenyl ring in C4 of main scaffolds were designed, synthesized and evaluated for antileishmanial activity.Methods The antileishmanial activity of the synthesized compounds was evaluated against promastigote and amastig...

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones...

The Povarov reaction of p-anisidine, cinnamaldehyde and methacrolein dimethylhydrazone afforded a 1,2,3,4-tetrahydroquinoline derivative bearing 2-styryl, 4-methyl and 4-dimethylhydrazono substituents in a fully diastereoselective fashion. This is the first example of the combination of a type I aza-vinylogous Povarov reaction and a type II vinylog...

Treatment of a N-2-pyridyl-β-ketoamide precursor with bromine afforded the first example of the 3-aryl(α-hydroxy)methylenelimidazo[1,2-a]pyridin-2(3H)-one framework. This transformation proceeded through a domino process comprising an initial bromination, cyclization via an intramolecular SN reaction, and a final keto-enol tautomerism, and allows g...

Solid-state synthetic chemistry has some potential advantages that include the absence of solubility issues and solvation phenomena, together with increased environmental friendliness. Mechanochemical synthesis, in particular, has undergone an exponential growth in recent years and has led to the improvement of many previously known transformations...

The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated dimethylhydrazones was carried out in a sequential three-component fashion under mechanochemical conditions. Following extensive optimization work, the reaction was performed on a vibratory ball mill operating at 20 Hz and using zircon...

Pancreatic β cells are essential in the maintenance of glucose homeostasis during the progression to type 2 Diabetes Mellitus (T2DM), generating compensatory hyperinsulinemia to counteract insulin resistance. It is well known, that throughout the process there is an increased mTORC1 signaling pathway, with an impairment in different quality control...

Matrix metalloproteinases (MMPs) are zinc-dependent hydrolytic enzymes of great biological relevance, and some of them are key to the neuroinflammatory events and the brain damage associated to stroke. Non-zinc binding ligands are an emerging trend in drug discovery programs in this area due to their lower tendency to show off-target effects. 7-Ami...

A three‐component, [3 + 2]‐cycloaddition/annulation domino protocol is described for the synthesis in excellent yield of a polycyclic cage‐like heterocyclic hybrid (PCHH) that comprises various advantaged structural units viz., α,β‐unsaturated ketone moiety, 4‐pyridinone and pyrroloisoquinoline in a cage‐like framework. The antitumor activity of PC...

A Ce(IV)-catalyzed three-component reaction between chalcones, anilines and β-ketoesters followed by a microwave-assisted thermal cyclization afforded 1,3-diaryl-1,2-dihydroacridin-9(10H)-ones. Their microwave irradiation in nitrobenzene, acting both as solvent and oxidant, afforded fully unsaturated 1,3-diarylacridin-9(10H)-ones, which combine acr...

A step- and atom-economical protocol is described allowing the synthesis of 1,4-diazepanes, and also tetrahydro- and decahydro-1,5-benzodiazepines. The method proceeds from very simple starting materials such as 1,2-diamines and alkyl 3-oxohex-5-enoates and can be performed under solvent-free conditions in many instances. The key event was the in s...

Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the form...

One interesting aspect of antioxidant organic molecules is their use as probes for the detection and quantitation of biologically relevant reactive oxidant species (ROS). In this context, a small library of dihydroterphenyl derivatives has been synthesised and studied as fluorescent chemodosimeters for detecting reactive oxygen species and hypochlo...

NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and...

Water is not flammable, has no smell, is nontoxic and is easily separated from the products of organic reactions. Furthermore, when used as a reaction medium it often enhances the rate and selectivities of many organic reactions or leads to alternative reaction modes. Due to these features, stereoselective organocatalysis in water has attracted muc...

A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human co...

Two multitarget hybrids, derived from an aza‐analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were designed in order to combine in a single molecule the antioxidant and Nrf2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The hybrid derivatives showed Nrf2 induction and radical s...

An investigation was reported concerning the chiral analysis of some Imino-4-Hesperetin and the impact of different factors on their chiral high-performance liquid chromatographic separation. Using Schiff bases reactions, new Imino-4-Hesperetin derivatives had been elaborated by the reaction of Hesperetin with various diamines differ only in their...

An investigation was reported concerning the chiral analysis of some Imino-4-Hesperetin and the impact of different factors on their chiral high-performance liquid chromatographic separation. Using Schiff bases reactions, new Imino-4-Hesperetin derivatives had been elaborated by the reaction of Hesperetin with various diamines differ only in their...

An oxidant-free three-component synthesis of biologically significant 7-amino-6H-benzo[c]chromen-6-ones was established involving a Sc(OTf)3 catalyzed three-component reaction between primary amines, β-ketoesters and 2-hydroxychalcones under green conditions. In this strategy, both the B and C rings of 6H-benzo[c]chromen-6-ones were constructed sim...

The Front Cover shows a rearrangement reaction, which is represented by the final stage in the resolution of the Rubik‐s cube that finally clicks all elements of the puzzle into place. In this particular case, the rearrangement of a 4,4‐disubstituted tetrahydroquinoline into the corresponding aromatic quinoline was achieved, where a functional grou...

Several types of C4‐functionalized 4‐alkyl‐2‐aryl‐1,2,3,4‐tetrahydroquinolines underwent rearrangement of their functional groups to C3, with concomitant aromatization, by simple reflux in 1,2‐dichlorobenzene. The functional groups that were shown to undergo the C4 to C3 migration were –CH=CH‐Z (where Z = CO2Et, CN, NO2, COCH3, CH2OH) and –CH=C(Y)‐...

Proline is a non‐toxic and inexpensive natural amino acid that is readily available in both enantiomeric forms and was one of the very first compounds to be studied as an organocatalyst. Proline can engage in several modes of organocatalysis, as it can behave both as Brønsted acid or base, and it can also easily generate the iminium or enamine inte...

The principles of Green Chemistry aim to improve the sustainability of chemical processes and reduce the generation of hazardous substances. There has been great growth in the field over the past few years and the number of research groups working in this area is still increasing. Now one of the biggest challenges is to embed the Green Chemistry id...

An efficient green protocol for the synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine and coumarin/pyrazole moieties was established, involving an intramolecular [4+2] hetero Diels-Alder reaction as the key step. The biologically significant 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones and 6,10-dihydro-5H-b...

A small library of A- and D-ring modified luotonin-inspired heterocyclic systems have been synthesised in moderate to good yields following a six-step route that starts from phenylalanine and has the final key stage an intramolecular Povarov reaction of imines obtained from a tetrahydroquinoline-derived alkynyl aldehyde and various arylamines.

Tetrahydroquinoline is one of the most important simple nitrogen heterocycles, being widespread in nature and present in a broad variety of pharmacologically active compounds. This Review summarizes the progress achieved in the chemistry of tetrahydroquinolines, with emphasis on their synthesis, during the period from the mid-2010s to early 2018.

A small library of spirooxindole-pyrrolidine hybrids have been synthesized for the first time in an ionic liquid, [bmim]Br in good to excellent yields employing a new class of non-stabilized azomethine ylides derived from isatin and tyrosine, a combination that has been rarely employed for the in situ generation of azomethine ylides using [3+2] cyc...

A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its...

The build/couple/pair strategy was applied to the generation of 18 structurally diverse scaffolds built around pyrrole cores. The couple phase, involving the first application of a mechanochemical multicomponent reaction for this purpose, afforded pyrrole derivatives that were transformed into some unusual fused heterocyclic systems using a domino...

A series of structurally intriguing novel pyrrolo[3,2-c]quinolinone heterocyclic hybrids have been synthesized for the first time via a one-pot multicomponent domino reaction sequence that involves a 1,3-dipolar cycloaddition and two subsequent annulation steps. Baylis-Hillman adducts derived from various substituted benzaldehyde and methyl acrylat...

Novel spiropyrrolidine heterocyclic hybrids were synthesized for the first time in a sustainable fashion employing a 1,3-dipolar cycloaddition strategy to form a new class of azomethine ylides generated from tyrosine and acenaphthenequinone. Following their synthesis and characterization, these heterocyclic hybrids were tested for their anticancer...

Pyrrole is one of the most important one-ring heterocycles because of its widespread presence in natural products and unnatural bioactive compounds and drugs in clinical use. The preparation of pyrroles by reaction between primary amines, β-dicarbonyl compounds, and α-halo ketones, known as the Hantzsch pyrrole synthesis, is reviewed here for the f...

The three-component reaction between alkyl- or arylamines, β-ketoesters and chalcones in refluxing ethanol containing a catalytic amount of Ce(IV) ammonium nitrate allowed the construction of a large library of highly substituted dihydro-m-terphenyl derivatives containing β-alkylamino- or β-arylamino ester moieties. This process generates three new...

Background: Spiropyrrolidine tethered piperidone heterocyclic hybrids were synthesized with complete regio- and stereoselectively in excellent yield via a tandem three-component 1,3-dipolar cycloaddition and subsequent enamine reaction in [bmim]Br. The synthesized compounds were evaluated for their anticancer activity against FaDu hypopharyngeal t...