Leonor Y. Vargas Méndez

Recent Progress in the Synthesis of Quinolines

New developments in the chemistry of quinoline derivatives are reviewed. Two general synthetic routes based on the utilization of mono-substituted or ortho-substituted anilines are discussed. Their major methods and modifications are analyzed. syntheses. These classical syntheses are well-known and still frequently used for the preparation of pharmaceutical agents, ligands and functional materials bearing a quinoline backbone. However, current methods for quinoline synthesis often do not allow for adequate diversity and substitution on the quinoline ring system (19). Recent developments in the chemistry of quinoline derivatives have demonstrated that new metal-catalyzed coupling cyclizations or acid catalyzed cycloaddition of appropriate precursors could compete with classical syntheses in the efficacy and rapidity of the quinoline construction. These new developments have prompted us to review and analyze their major methods and modifications.

Antiparasitic properties of homoallylamines and related compounds

A study of some antiparasitic properties of several homoallylamines and related tetrahydroquinolines and quinolines, previously described, was carried out using in vitro activity assays against the epimastigote form of Trypanosoma cruzi and against Trichomonas vaginalis. Unspecific cytotoxicity against murine macrophages was also studied. Although the antichagasic and trichomonacidal activities are not comparable to those of the standard drugs, nifurtimox and metronidazole, some of the compounds exhibit an interesting specific antiparasitic activity.

Improved Trolox® Equivalent Antioxidant Capacity Assay for Efficient and Fast Search of New Antioxidant Agents

Abstract An improvement of the the Trolox® equivalent antioxidant capacity (TEAC) assay, using the ABTS+. radical-cation discoloration method, produced a highly efficient method for the exploration of the natural and/or synthetic product antioxidant capacity (AOC). The improved method was developed in a Versamax 96-well microplate reader with data acquisition software, SoftMax® Pro-software. The proposed method incorporated three modifications: areaction-time increase to near completion; an assay miniaturization using 96-well multiplate reader, and TEAC value determination of the relationship between the 50 % inhibitory concentrations (IC50) of the tested substances and Trolox®, under equilibrium. The modifications led to a substantial decrease of: 1. 1. assay sample amounts (from 10–500 mg to 0.08–20 mg, range of reading); 2. 2. solvent volumes (from 1–3 mL to 200 μL, per sample in each reading); 3. 3. reading error (blank for each used plate-column) (% RSD <_ 5 %); and, 4. 4. TEAC value underestimation for the tested molecules (close-to-equilibrium conditions at 30 min). This methodology provides efficient and fast processing of a great number of samples (3 samples with 12 dilutions, by duplicate, with their blanks, in 30 min) as well as friendly data management.

An Efficient Synthesis of Hexahydro Oxaisoindolo(2,1-a)Quinoline Derivatives via the Diels-Alder Reactions

The straightforward synthesis of new carboxylic acids with hexahydro-oxaisoindolo(2,1- a)quinoline core from the 2,4-disustituted 1,2,3,4-tetrahydroquinolines bearing a furan fragment via the intramolecular Diels-Alder reaction has been proposed. It was demonstrated that synthesis of key precursors can be realized with excellent level of diastereoselectivity either by imino-Diels-Alder reaction or multi- component condensation approach. The chemistry of tetrahydroquinoline derivatives has long been an area of intense for organic chemists due to the presence of these scaffolds within the framework of numerous biologically interesting natural products and pharmaceutical agents. Many new methods for the synthesis of tetrahydroquinoline derivatives have been developed (1, 2). The most attractive strategy for these derivatives is the acid-promoted imino-Diels-Alder reaction between N- arylaldimines and electron-rich alkenes that has been a topic of continuing interest for forty years (3, 4). The synthesis of such compounds by the three-component-reaction of substituted anilines, an aryl aldehydes, and an electron-rich olefins in the presence of different Lewis acid catalysts has also been reported recently (5). On the other hand, the intramolecular Diels-Alder reaction with furan as the diene partner is a powerful synthetic tool for constructing rigid tricyclic nitrogen heterocycles (6). With these facts in mind and taking into consideration that the 2-furyl-1,2,3,4- tetrahydroquinoline synthesis and its chemistry have been poorly explored, we consider that tetrahydroquinolines with furan moiety show interesting features that make them attractive for synthetic and pharmacological use. As part of our ongoing research program aiming at the search of bioactive polyheterocycles containing nitrogen atom from accessible aldimines (7), we were interested in an efficient synthesis of isoindolo(2,1-a)quinoline derivatives. Herein, we wish to report the straightforward synthesis of 1,3-

Synthesis of new 4-methyl-2-(4-pyridyl)-1,2,3,4-tetrahydroquinolines as potent antifungal compounds

Synthesis, spectral characterization and biological results of new series of 2-(4-pyridyl)-1,2,3,4-tetrahydroquinolines and their closer precursors, -N-aryl-N-[1-(4-pyridyl)but-3-enyl]amines are reported. It was found that both γ-pyridyl substituted precursors and final products, tetrahydroquinolines, showed very good antifungal activities against Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Microsporum gypseun, Trichophyton rubrum and Trichophyton mentagrophytes.

Efficient synthesis and free-radical scavenging capacity of new 2,4-substituted tetrahydroquinolines prepared via BiCl3-catalyzed three-component Povarov reaction, using N-vinylamides

Efficient synthesis of new structurally different 2-(het)aryl-4-amidyl-substituted tetrahydroquinolines 8–29 is reported. The synthesis based on BiCl3-catalyzed three-component Povarov reaction between anilines, (het)aryl aldehydes and enamides offers a fast, safe, and cheap way for efficient tetrahydroquinoline libraries construction. Using N-vinylamides (N-vinylpyrrolidin-2-one and N-vinylacetamide) in this reaction, it was possible to obtain two series of different cis tetrahydroquinolines with antioxidant properties. Among 14 tested compounds, 7 tetrahydroquinolines revealed a prominent anti-radical capacity, equal or higher than that of the commercial antioxidants. Being the most active molecule, the N-[2-(α-furanyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-4-yl] acetamide 21 was ca. 2.2-fold more potent than the well-known antioxidant, vitamin E (α-tocopherol).

The study of metal-free and palladium-catalysed synthesis of benzochromenes via direct C–H arylation using unactivated aryl benzyl ethers derived from essential oils as raw materials

The synthesis of 6H-benzo[c]chromenes from unactivated 2-bromo aryl benzyl ethers was studied through two approaches: (i) the transition-metal-free intramolecular dehydrohalide coupling via intramolecular homolytic aromatic substitution; and (ii) the intramolecular cyclization via direct C–H arylation catalysed by PdCl2(MeCN)2. Having developed the most efficient method, a 17-membered chromene library was prepared in good yields and in shorter reaction times starting from commercially available phenol derivatives and phenol-rich essential oils (Eugenia caryophyllys and Plectranthus amboinicus) as raw materials, proving how sustainable and eco-friendly our protocol is. Additionally, the ruggedness of the optimized reaction conditions was evaluated with N-benzylanilines, giving the respective phenanthridone as an unexpected product, while the metal-free oxidation of the obtained 6H-benzo[c]chromenes was also performed to furnish the benzocoumarins.

Intramolecular N to N acyl migration in conformationally mobile 1′-acyl-1-benzyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinoline] systems promoted by debenzylation conditions (HCOONH4/Pd/C)

AbstractWe report an efficient and useful synthesis of new attractive spiropiperdine scaffolds 4 based on an intramolecular acyl transfer process in 1′-acyl-1-benzyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinolines] 3 using simple and mild debenzylation reaction conditions (HCOONH4/Pd/C). The compounds 3 were prepared by acylating 1-benzyl-4′-methyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinolines] 2 that are easily available from 1-benzyl-4-piperidone 1. The intramolecular character of this process was proven primarily through a crossover experiment technique. Through an examination of all spectroscopic information (1H, 13C NMR, VT-1H NMR, and 2D NMR) it was possible to correctly predict amide configurations and piperidine ring conformations of starting and final spiropiperidine compounds.

Ce(SO4)2-catalysed the highly diastereoselective synthesis of tetrahydroquinolines via an imino Diels Alder ABB′ type reaction and their in vivo toxicity and imaging in zebrafish embryos

An efficient and practical approach has been developed for the synthesis of N-(tetrahydroquinolinyl-4) amides 3a–l in good yield with high diastereoselectivity. The strategy comprises the domino type ABB′ imino Diels Alder reaction catalysed by a cerium(IV) salt between anilines and N-vinyl amides for the preparation of a 12-membered library of tetrahydroquinolines that were tested for their in vivo toxicity against zebrafish embryos. Upon determining their LC50 values, N-(8-methoxy-2-methyl-tetrahydroquinolinyl-4) acetamide 3k was identified as the most toxic derivative with an LC50 below 95 μM (24 mg L−1). Finally, the phenotypes induced, at concentrations below their LC50, were analyzed at 48, 72 and 96 hours post fertilization, wherein the treated embryos manifested diverse visual phenotypes, such as big yolk sacs (3b, 3h, 3j), pericaldial edemas (3a, 3i) and red blood cells in the liver region (3b, 3l), in comparison to the morphology of the control embryos, the phenotypes could be associated with specific biological targets.

Coumarin-Based Molecules as Suitable Models for Developing New Neuroprotective Agents Through Structural Modification

The recent developments in the use of natural coumarin products and synthetic coumarin-based molecules as therapeutic agents for Alzheimer disease (AD) and Parkinson disease (PD) as well as the current methods for their synthesis and isolation are reviewed. Classic and modern syntheses of coumarin derivatives are discussed providing novel reaction conditions for Pechmann synthesis and Perkin and Knoevenagel condensations. Novel synthetic routes to accessing coumarins with diverse kinds of substituents from intermolecular or intramolecular reactions are classified and discussed. Lipinskis parameters and in silico study are also briefly mentioned and applied to some coumarins active against acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase (MAO). This chapter focuses on medicinal chemistry research with natural and synthetic coumarin molecules as cholinesterase inhibitors and/or MAO inhibitors and also as antioxidant agents. Carefully selected examples are discussed to underline the progress made in the development of natural and synthetic coumarins for potential therapeutic applications in AD and PD.