Tetrahydroquinoline Derivatives Research Articles

Ytterbium Triflate-Catalyzed Intramolecular Arylative Ring Opening of Arylaminomethyl-Substituted Donor-Acceptor Cyclopropanes: Access to Tetrahydroquinolines.

The treatment of arylaminomethyl-substituted donor-acceptor cyclopropanes with a catalytic amount of Yb(OTf)3 provides expedient access to tetrahydroquinoline derivatives. The transformation proceeds through an intramolecular SN2-type attack of the aminomethyl-containing aryl ring on the cyclopropane ring, leading to the formation of the products as single diastereomers.

Organocatalytic Approaches Towards the Synthesis of Asymmetric Tetrahydroquinoline (THQ) Derivatives

Abstract1,2,3,4-Tetrahydroquinolines (THQs) are present in molecules with significant biological importance and pharmaceuticals with diverse biological activities. Various synthetic routes have been developed to tetrahydroquinolines, such as the hydrogenation of quinolines, domino reactions, intramolecular cyclization, and notably, the Povarov reaction. Organocatalysts are small, chiral organic molecules that can successfully catalyze organic transformations. This review examines the use of organocatalysts in the asymmetric synthesis of tetrahydroquinoline derivatives using aminocatalysis, NHC catalysis, and H-bonding catalysis covering the literature between 2000 and early 2024.1 Introduction2 Aminocatalysis3 NHC Catalysis4 H-Bonding Catalysis5 Miscellaneous6 Conclusion

Reaction under Ball-Milling: Solvent- and Metal-Free One-Pot Diastereoselective Synthesis of Tetrahydroquinoline Derivatives as Potential Antibacterial and Anticancer Agents

AbstractA mild and efficient one-pot, three-component ball-mill-assisted reaction of aldehydes, anilines, and dihydrofuran (or dihydropyran and cyclohexenone) has been described for the first time in the presence of the catalytic amount of aqueous perchloric acid (8 mol%) at room temperature under organic solvent- and metal-free conditions. The reactions are fast (1 h), providing the products with excellent yields and high diastereoselectivity. This procedure endows a simple, efficient, and cost-effective method for the diastereoselective synthesis of furano- and pyrano-tetrahydroquinolines and phenanthridinone derivatives, which are important biological compounds. The diastereomers with cis configuration were isolated as major products. The H–H COSY, NOESY experiments and X-ray crystallographic analysis of selected compounds were performed to confirm the cis isomer. The synthesized tetrahydroquinolines have been evaluated in vitro for their antibacterial and anticancer activities, and it was found that both the prepared compounds showed significant antibacterial and anticancer properties.

Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells

Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 μM and 40.6 μM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

Designing of target‐specific N‐substituted tetrahydroquinoline derivatives as potent mTOR inhibitors via integrated structure‐guided computational approaches

AbstractThere is a need to develop innovative, safe, and more effective treatment methods for lung cancer due to obstacles including resistance, side effects, and low bioavailability, among others related to present medicines. Our previous research findings gave some promising results of tetrahydroquinoline (THQ) derivatives as mTOR inhibitors for the treatment of lung cancer. The current research has employed certain integrated computational techniques to enhance the effectiveness of THQ derivatives. Various computational methods, like the generation of the pharmacophore model, virtual screening, and QSAR modeling were employed to achieve the goal, and their results were connected to develop novel THQ analogues. This study revealed that among 48 newly designed THQ derivatives, the compound UC_1 indicated the XP Gscore of −9.378 kcal/mol and also showed the key amino acid interactions with the mTOR protein viz. Gln2167, Val2240. Interestingly, compound UC_1 showed a better binding affinity with the mTOR protein compared to the clinical trial molecules viz. AZD‐8055 and AZD‐2014. The molecular dynamics simulations (100 ns) along with each output give a shred of strong evidence that the designed THQ derivative (UC_1) has all the required features in terms of inhibiting mTOR protein for the treatment of lung cancer.

Synthesis of tetrahydroquinoline derivatives via electrochemical hydrocyanomethylation or hydrogenation of quinolines with MeCN

Electrochemical hydrocyanomethylation of quinoline skeletons employing acetonitrile as both a hydrogen resource and a cyanomethyl precursor has been described.

Influence of the structure of quinoline derivatives on their sorption on hypercrosslinked polystyrene

The article is devoted to the study of the chromatographic behaviour of quinoline and tetrahydroquinoline derivatives. The purpose of the study was to investigate the patterns of sorption of these compounds from aqueous-acetonitrile solutions on hyper-cross-linked polystyrene using reverse-phase high-performance liquid chromatography. The volume, polarizability, lipophilicity, and dipole moment of molecules of quinoline derivatives were calculated, which significantly depended on the nature and position of functional groups and substituents in the main nucleus. It has been established that the appearance of functional groups and substituents leads to an increase in the volume and polarizability of the molecules of quinoline derivatives compared to unsubstituted quinoline and methylquinoline, while the lipophilicity and dipole moment change depending on the nature of the substituent and its position in the main fragment. The dependences of sorption characteristics on the structure and physicochemical properties of sorbates were obtained. It has been shown that, in accordance with the laws of the reversed-phase version of liquid chromatography, the retention of substances changes symbatically with the change in the characteristics of the molecules responsible for dispersion interactions. In this case, the presence in the molecules of halogen atoms, phenyl radicals and other substituents capable of π-interactions with the surface of hyper-cross-linked polystyrene led to a significant increase in retention, and the presence of a carboxyl group or carboxyalkyls prone to interaction with the polar eluent significantly weakens retention. The appearance of an ester group in sorbate molecules generally significantly increased the volume, polarizability and lipophilicity of the corresponding derivatives, but had virtually no effect on retention, and therefore it was suggested that the presence of a carbonyl oxygen atom, capable of interacting with the polar components of the eluent, neutralizes the effect of physical-chemical factors that determine the sorption of these substances due to dispersion interactions. Thus, despite the symmetry in changes in the physicochemical parameters of the studied compounds and their retention, there was no strict proportionality, since, on the one hand, the retention of sorbates was carried out in accordance with the change in their physicochemical parameters, and on the other hand, it was determined by the tendency molecules of these compounds to competitive interactions with the components of the mobile phase. The presented results of the study can be useful in the development and optimization of methods for analysing compounds with similar structures, as well as for developing the theory of sorption of polyfunctional compounds from multicomponent solutions and establishing the relationship between sorption characteristics, other physicochemical parameters and the structure of molecules.

A mild catalyzed imino Diels-Alder reaction for the synthesis of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide derivatives as regulators of Quorum Sensing in Pseudomonas aeruginosa

Bacterial resistance is one of the major global public health problems. In addition, virulence factors promoted multiple drug resistance through cell-to-cell communications by molecules within microbial communities, denominated Quorum Sensing (QS). The regulation of QS by small molecules appears as a therapeutic alternative through the use of synthetic analogs of agonists. The present work developed the construction of a series of derivatives of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl) formamide (1a-h) via Povarov-type sequential reactions to deliver the tetrahydroquinoline (THQ) derivatives in moderate to good yields (24–78%). To evaluate the potential in molecular diversity of THQ-type autoinducers, a study of these agents as potential inhibitors of bacterial growth and virulence factors involved in QS systems on P. aeruginosa was carried out both as antibacterial evaluation on E. coli strain. THQs showed significant activity values for molecules with halogen substituents at the C-6 position (-F, -Cl, and I), revealing at a concentration of 75 µg/mL a percentage inhibition between 27 and 40%. Furthermore, autoinducers with halogen substitutes in phenotypic studies on P. aeruginosa showed good results. Also, they exhibited weak formation of both biofilm and low pyocyanin formation, which are indicators of virulence in P. aeruginosa. Overall, the results suggest that compound N-(6-fluor-2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide (1a) stands out as the most representative within this series of THQ derivatives.

O-70 - Optimization of the automated radiosynthesis of an 18F-labeled tetrahydroquinoline derivative for brain HDAC6 imaging

O-70 - Optimization of the automated radiosynthesis of an 18F-labeled tetrahydroquinoline derivative for brain HDAC6 imaging

Ligand-Controlled Diastereodivergency in Propargylic Alkylation of Vinylogous Aza-Enamines: Construction of 1,3-Stereocenters.

The first diastereodivergent propargylic alkylation reaction is developed. This Cu(I)-catalyzed formal decarboxylative [4+2] cycloaddition between ethynyl benzoxazinanone and vinylogous aza-enamine delivers each diastereomer of tetrahydroquinoline derivatives, bearing 1,3-stereocenters, using either i-Pr-Pybox or BINAP as the ligand under otherwise identical reaction conditions. This is the first application of vinylogous aza-enamines in a transition metal-catalyzed transformation and the first example of the creation of 1,3-stereocenters in a propargylic substitution reaction.

Photoinduced electron transfer reaction for synthesis of tetrahydroquinoline derivatives with conjugated structure using chlorophyll b‐modified magnetic titanium dioxide photocatalyst

Photocatalytic conversion of organic compounds has recently emerged as a cost‐effective, safe, and easy‐to‐operate procedure to synthesize value‐added materials. In this study, the magnetic titanium dioxide‐based (Fe3O4/SiO2/TiO2) photocatalyst was designed to synthesize conjugated derivatives of tetrahydroquinoline through a photoinduced electron transfer (PET) reaction. Chlorophyll b was immobilized on the surface of magnetic titanium dioxide, as a natural visible‐light‐sensitive compound using 3‐aminopropyltriethoxysilane (APTES) as a coupling agent containing terminal amine (Fe3O4/SiO2/TiO2‐NH2‐Chb) to improve light harvesting ability. Fourier transform infrared (FT‐IR), powder X‐ray diffraction (PXRD), thermogravimetric analysis (TGA), energy‐dispersive X‐ray spectrometer (EDS), and vibrating sample magnetometer (VSM) results confirmed the successful synthesis of Fe3O4/SiO2/TiO2‐NH2‐Chb. Scanning electron microscope (SEM) and transmission electron microscope (TEM) images displayed the preserved spherical morphology of Fe3O4/SiO2/TiO2‐NH2‐Chb. Chlorophyll b‐modified magnetic titanium dioxide was highly active under visible‐light irradiation toward the cyclization of (E)‐3‐[4‐(dimethylamino)phenyl)]‐1‐arylprop‐2‐en‐1‐one with 1‐aryl‐1H‐pyrrole‐2,5‐dione to achieve new tetrahydroquinoline derivatives with conjugated structure in high yields at ambient temperature, in air. The incorporation of chlorophyll b in the photocatalyst plays an important role in the photocatalytic mechanism, facilitating photoinduced electron transfer to the conduction band of TiO2. Moreover, the magnetic property enabled easy recovery of the photocatalyst and improved its reusability up to three runs. The characteristics of tetrahydroquinoline derivatives were studied by FT‐IR, CHN, 1H NMR, and 13C NMR analyses.

The povarov reaction in the synthesis of <i>N</i>-polycyclic compounds with a tetrahydroquinoline fragment

The review is devoted to the analysis of the data synthesized biologically active tetrahydroquinoline derivatives based on the Povarov reaction and its three-component modification over the past 8 years.

Chlorophyll b-modified TiO2 nanoparticles for visible-light-induced photocatalytic synthesis of new tetrahydroquinoline derivatives

The exploitation of visible light to drive organic reactions has recently gained great attention as a sustainable technology for the synthesis of organic compounds. In this study, chlorophyll b (Chb) extracted from spinach was immobilized on the surface of TiO2 nanoparticles using 3-aminopropyltriethoxysilane (APTES) as a coupling agent. The absorption of TiO2 nanoparticles modified by magnesium-containing chlorophyll was broadened from UV light to visible light region by dye-sensitization. The prepared photocatalyst (Chb/APTES/TiO2) was characterized by FT-IR, XRD, FE-SEM, UV–Vis, TGA, PL, EDX, and XPS. Chb/APTES/TiO2 exhibited high efficiency and reusability for the single electron transfer (SET) reaction in the direct cyclization of N,N-dimethylaniline and 4‑bromo-N,N-dimethylaniline with 1-(4-alkoxyphenyl)-1H-pyrrole-2,5‑dione derivatives under visible light irradiation to achieve new tetrahydroquinoline framework in high yields at ambient temperature. The synthesized tetrahydroquinoline derivatives were characterized using 1HNMR, 13CNMR, FT-IR, and CHN analyses. This work reveals a significant improvement in the SET reaction between tertiary anilines and maleimides using visible-light sensitive Chb/APTES/TiO2 photocatalyst by adjusting the bandgap of TiO2.

Development of a copper-chelated ZIF-67 framework to effectively catalyse oxidative coupling between N-arylmaleimides and N,N-dimethylanilines

BackgroundProducing bioactive skeletons through direct oxidative coupling of C(sp3)-H bonds adjacent to heteroatoms with C(sp2)-H alkenes bonds has become a topic of growing interest, in which catalysts play an important role. However, designing an effective and stable catalyst for these coupling reactions remains a great challenge. MethodThe Cu@ZIF-67 material, in which Cu(II) species were chelated into the 2-methylimidazole moiety of the ZIF-67 framework, was prepared and used as a catalyst in an oxidative coupling reaction between N-phenylmaleimide and 4,N,N-trimethylaniline. Cu@ZIF-67 was characterized using X-ray powder diffraction (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermal gravimetric analysis (TGA). Gas chromatography (GC), 1H NMR, and 13C NMR were employed to determine the yield and chemical structure of the product. Significance of findingsThe Cu@ZIF-67 material exhibited remarkable catalytic activity by increasing the product yield to 93% under optimal reaction conditions. In addition, various tetrahydroquinoline derivatives were produced using Cu@ZIF-67 as a catalyst. It was found that the high catalytic activity of Cu@ZIF-67 resulted from the synergistic effect of the chelated Cu species and ZIF-67 structure. This work provides a promising catalyst for different organic syntheses.

Synthesis of Functionalized Tetrahydroquinoline Containing Indole Scaffold via Chemoselective Annulation of Aza-ortho-quinone Methide Precursor.

The chemoselective annulation of aza-ortho-quinone methide generated by in situ o-chloromethyl sulfonamide has been achieved with bifunctional acyclic olefin. This efficient approach provides access to the diastereoselective synthesis of functionalized tetrahydroquinoline derivatives containing indole scaffolds through the inverse-electron-demand aza-Diels-Alder reaction under mild reaction conditions with excellent results (up to 93% yield, > 20:1 dr). Moreover, this article realized the cyclization of α-halogeno hydrazone with electron-deficient alkene affording the tetrahydropyridazine derivatives, which had never been reported.

Rh(II)/Pd(0) Dual Catalysis: Interception of Ammonium Ylide with Allyl Palladium to Construct 2,2-Disubstituted Tetrahydroquinoline Derivatives.

New synthetic methods to construct 2,2-disubstituted tetrahydroquinoline derivatives are of significant value in pharmaceutical chemistry. Herein, a Rh(II)/Pd(0) dual-catalyzed diazo α-aminoallylation reaction has been developed between allylpalladium(II) and ammonium ylides derived from the Rh2(OAc)4-mediated intramolecular N-H bond insertion reaction of diazo compounds, affording various 2,2-disubstituted tetrahydroquinoline derivatives in good yields up to 93% with high chemoselectivities under mild reaction conditions. A substrate scope investigation reveals broad ester substituent tolerance, and control experiments provide the basis for a proposed reaction mechanism.

Contributions of nonconventional intramolecular hydrogen bond on the bioactivity of a series of substituted 6-amino, 4-phenyl, tetrahydroquinoline derivatives

Although intramolecular hydrogen bond formation/disruption is a critical tool in the drug absorption process, it is difficult to be determined due to its group-atom nature. We proposed a proper descriptor to reasonably correlate pIC50 of a series of 19 substituted 6-amino, 4-phenyl, tetrahydroquinoline (6A4PTHQ) derivatives with their non-conventional intramolecular hydrogen bond (nCIHB) using quantum chemical calculations at B3LYP/6-31++G (d,p) level of theory. Effects of the protic and aprotic solvents and water on the nCIHB were studied. Solvents, especially protic solvents, weaken nCIHB in all 6A4PTHQ derivatives. It was found that the nCIHB is preserved within the 6A4PTHQ derivatives when docked in the human follicle-stimulating hormone (FSH) receptor. However, Molecular dynamic simulations showed that nCIHB disruption occurs in the aqueous compartment of the two-layered membrane, which enhances the absorption process via entropy increasing mechanism. Our approach may lead to the clarification of the complex role of nCIHB in drug transport and absorption processes in further research.

Remote stereocontrol in the (4 + 2) cycloadditions of 1,7-zwitterions: Asymmetric synthesis of multifunctionalized tetrahydroquinoline derivatives

The scope of stereochemistry recognition usually occurs near the chiral scaffold of a ligand or catalyst. Remote stereocontrol, which can surpass the limits of stereorecognition of remote prochiral centers, has long been a challenging object of great interest in asymmetric catalysis. The current work realized the remote stereocontrol of 1,7-zwitterion intermediates formed from Huang's o-amino aryl MBH carbonates. With simple and easily accessible β-ICD as the bifunctional catalyst, multifunctionalized tetrahydroquinoline derivatives could be synthesized via (4 + 2) cycloadditions with excellent enantioselectivity and diastereoselectivity under mild conditions. The strategy possesses broad substrate scope, and three types of electron-deficient enones are successfully applied. Mechanistic studies disclosed the Lewis base-catalyzed reaction pathway, and H-bonding between the catalyst and enones is crucial for long-range stereocontrol. Scale-up reaction and transformations of the tetrahydroquinoline products demonstrated the potential of this strategy.

Green synthesis of some tetrahydroquinoline derivatives and evaluation as anticancer agents

This study demonstrates the design and synthesis of heterocyclic compounds with diverse biological effects. Using an ionic liquid catalyst, a sonosynthetic approach for the assembly of bis-arylidene cycloalkanone derivatives (bis-chalcones) has been reported. Three cancer cell lines Hepatocellular carcinoma cells (HepG-2), Breast carcinoma cells (MCF-7), and Lung carcinoma cells (A-549) were utilized to investigate the antiproliferative effects of some selected samples. Many evaluated drugs exhibited good to moderate cytotoxicity against the examined cell lines. Notably, the IC50 values for the S-alkyl derivatives ranged from 2.86 to 13.14 µg/mL.

Quantitative Structure-Activity relationship, Molecular Docking and ADMET Screening of Tetrahydroquinoline Derivatives as Anti-Small Cell Lung Cancer Agents

Lung carcinoma (LC) is responsible for almost one-third of all cancer fatalities worldwide. Tetrahydroquinoline is an organic molecule that is the semi-hydrogenated derivative of quinoline and could be found in several naturally occurring compounds such as flindersine, oricine etc. Some tetrahydroquinoline derivatives with pyrazole and hydrazide moieties were evaluated in silico against A549 (human lung cancer cell lines). The quantitative structural-activity relationship (QSAR) model created was statistically significant with validation metrics of R2 (0.9525), R2adj (0.9314), and CV.R (0.9719). The molecular docking analysis revealed that compound C14 demonstrated the best binding affinity towards the studied protein with binding affinity value of –10.1 kcal mol–1 (4LRM). This is in accordance with the experimental result (IC50 = 0.69). The factors observed for ADME&T correlated well with the factors observed for the referenced drug. This study indicates that compounds C1 and C9 can be further developed as anti-epidermal growth factor receptor (EGFR) compounds. Thus, our findings may open door for the design and development of library of efficient Tetrahydroquinoline-based drug-like compounds as potential anti-LC agents.