Tetrahydroisoquinoline Derivatives Research Articles

Chalcogen‐Bonding Catalyzed in situ Trityl Cation Activation for C‐C Bond Forming Reactions

In this work, the use of chalcogen‐bonding for the catalytic activation of trityl cation by chloride abstraction from bench stable trityl chloride and further application in C‐C bond forming reactions is reported. In particular, telluronium salts bearing non‐coordinative counteranions such as BArF24 proved highly efficient. Thus, low catalyst loading of 1 mol% allows for the trapping of the in situ generated trityl cation in a Friedel‐Crafts reaction, as well as its use as catalyst in the carbonyl‐ene cyclization of citronellal or as hydride‐type oxidant in diastereoselective C‐H functionalization/cyclization of tetrahydroisoquinoline derivatives. A new family of chiral chalcogen‐triazolium salts presenting the chirality in the central backbone was also designed and employed in the C‐H functionalization reaction, slightly outperforming hydrogen and halogen bonding activation. Although no appreciable chirality transfer was achieved so far, those simple and modular structures might open new possibilities towards enantioselective chalcogen catalysis.

Discovery and Development of HDAC Inhibitors: Approaches for the Treatment of Cancer a Mini-review.

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Design, synthesis, and mechanism study of novel tetrahydroisoquinoline derivatives as antifungal agents.

In screening for natural-derived fungicides, a series of 32 novel tetrahydroisoquinoline derivatives were designed and synthesized based on tetrahydroisoquinoline alkaloids. Their structures were verified by 1H NMR, 13C NMR, HRMS, and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50mg/L. Interestingly, compounds A13 and A25 with EC50 values of 2.375 and 2.251mg/L against A. alternate were similar to boscalid (EC50 = 1.195mg/L). The in vivo experiments revealed that A13 presented 51.61 and 70.97% protection activities against A. alternate at the dosage of 50 and 100mg/L, respectively, which were equal to that of boscalid (64.52 and 77.42%). SDH enzyme assays and molecular docking studies indicated that compound A13 may act on SDH. In addition, the SEM analysis showed that compound A13 could strongly damage the mycelium morphology. These results revealed that A13 may be a promising lead compound for the development of natural-derived fungicides.

Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/β-catenin signaling inhibitors to suppress colorectal cancer

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/β-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of β-catenin, thereby suppressing the Wnt/β-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/β-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease.

More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of Aβ aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.

Design, synthesis, and biological antitumor evaluation of tetrahydroisoquinoline derivatives

Cancer, as a public health issue, is the leading cause of death worldwide. Tetrahydroisoquinoline derivatives have effective biological activities and can be used as potential therapeutic agents for antitumor drugs. In this work, we designed and synthesized a series of novel tetrahydroisoquinoline compounds and evaluated their antitumor activity in vitro on several representative human cancer cell lines. The results showed that the vast majority of compounds showed good inhibitory activities against the cancer cell lines of HCT116, MDA-MB-231, HepG2, and A375.

New tetrahydro-isoquinoline derivatives as cholinesterase and α-glycosidase inhibitors: Synthesis, characterization, molecular docking & dynamics, ADME prediction, in vitro cytotoxicity and enzyme inhibition studies

In the presented work, it was reported about the synthesis procedure of new isoquinoline derivatives starting from chalcones and acetoacetanilide, a multi-step synthesis pathway yielded four isoquinoline derivatives (5a-d). At the first stage of our research, corresponding cyclohexanone derivatives are synthesized from the Michael addition reaction of chalcones with acetoacetanilide. After that, on the based cyclohexanone derivative was obtained novel isoquinoline derivatives. According to the structures, a plausible reaction mechanism was suggested. The structure of the synthesized compounds was confirmed by NMR spectroscopy method and X-Ray analysis. Additionally, to determine cholinesterase and α-glycosidase inhibition activity compounds 5(a-d) were tested against AChE, BChE and α-Gly as in vitro. In this work, the novel isoquinoline derivatives 5(a-d) demonstrated encouraging inhibitory action against α-glucosidase, as seen by their IC50 values ranging from 9.95 to 19.25 nM. This indicates that they were approximately 1–3 times more active than acarbose (IC50 = 23.07 nM). Also, the molecular docking IFD XP Gscores, dynamics simulations and MM-GBSA ΔG binding free energies of the isoquinoline derivatives on hAChE, hBChE and α-Gly are determined. The molecular dynamics (MD) simulations conducted in this study provided valuable insights into the dynamic behaviors, stabilities, and interaction profiles of ligand–protein complexes involving the R and S isomers of compounds 5c-hAChE, 5c-hBChE, and 5a-αGly. The MD simulations were crucial for understanding the complex stabilities and dynamic mechanisms of the ligand–protein interactions, shedding light on the potential inhibitory roles of these compounds..

Rhodium(II)-Catalyzed Denitrogenative Annulation for the Synthesis of Substituted Tetrahydroisoquinolines.

Tetrahydroisoquinoline (THIQ) derivatives stand out as a promising class of compounds due to their diverse range of biological activities, making them particularly valuable in drug discovery. To enhance their structural diversity, an Rh-catalyzed denitrogenative annulation method has been introduced for synthesizing these derivatives. An intriguing aspect of this method is the ability of the Brønsted acid to prevent further annulation while facilitating the production of the desired THIQ derivatives, achieving impressive yields of up to 86%. This synthetic approach was subsequently leveraged to create an analogue of cyclocelabenzine, a compound showing potential as an anti-inflammatory agent.

Direct Dearomatization of Quinoline/Isoquinoline Ammonium Halides to Construct N‐Substituted Tetrahydroquinolines and Tetrahydroisoquinolines

AbstractDearomatization of quinoline/isoquinoline quaternary ammonium salts to synthesize valuable tetrahydroquinolines was firstly reported. Under this method, we used phenylsilane as a reducing agent to prepare a series of tetrahydroquinoline and tetrahydroisoquinoline derivatives conveniently and quickly in moderate to good yields. This method showed good functional group tolerance, wide substrate range, mild reaction conditions and simple operation.

Efficient and scalable synthesis of 3,4-dihydroisoquinolin-1(2H)-ones by benzylic oxidation of tetrahydroisoquinoline derivatives using cerium ammonium nitrate (CAN).

An efficient and scalable method for the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones through benzylic oxidation of tetrahydroisoquinoline derivatives using a catalytic amount of cerium ammonium nitrate (CAN) and a stoichiometric amount of NaBrO3 as oxidants was developed. The reaction is significantly influenced by the substituent groups on the phenyl ring. While electron-withdrawing groups on the phenyl ring can lower the reactivities of the substrates, electron-donating groups on the phenyl ring can dramatically promote the oxidation rate.

Selective electrochemical acceptorless dehydrogenation reactions of tetrahydroisoquinoline derivatives.

Selective dehydrogenation reactions of tetrahydroisoquinoline derivatives through electrochemical oxidation are disclosed. In the presence of nitric acid, the selective partial dehydrogenation of tetrahydroisoquinolines to form 3,4-dihydroisoquinolines was achieved via anodic oxidation. The results of CV (Cyclic Voltammograms) experiments and DFT calculations showed the 3,4-dihydroisoquinolines protonated by an external Brønsted acid to be less prone than their unprotonated counterparts to oxidation under electrochemical conditions, thus avoiding their further dehydrogenation. Moreover, a TEMPO-mediated electrochemical oxidation enabled a complete dehydrogenation to yield fully aromatized isoquinolines. Thus, tunable processes involving electrochemical dehydrogenation of tetrahydroisoquinolines could be used to selectively produce various 3,4-dihydroisoquinolines and isoquinoline derivatives.

Synthesis, structural and X-ray analysis evaluations and computational studies of newly tetrahydroisoquinoline derivatives as potent against microsomal prostaglandin E synthase 1

Tetrahydroisoquinolines (THIQs) are a significant class within the broad range of natural compounds known as isoquinoline alkaloids. Natural and manmade drugs based on THIQ have a variety of biological effects that protect against different infectious pathogens and neurological diseases. In this study, two new THIQ derivatives were synthesized and characterized using by X-ray crystallographic analysis. The performed Hirshfeld analysis shows the intermolecular interactions and reactive sites of compounds. The 2D fingerprints reveal dominants H···C interactions up to 8.8% in 3a while 43% H···H elemental interactions are observed in compound 3b. In studied compound 3a, the repulsion energies (k-rep) dominate the other energies where the highest amount of 63.8 kJ/mol is obtained whereas 3b has a significant contribution from E-dis to the total energy of the molecule from the energy framework study. Moreover, the density functional theory study reveals better thermodynamic and electronic stabilities. These compounds have reduced HOMO-LUMO gaps (EH-L) ranging from 3.66 to 3.60 eV, indicating their remarkable conductive and electronic properties. The significant reduction in EH-L also guarantees our synthesized compounds’ soft nature and reactivity. Our studied compound’s NBO charges and MEPs analysis show electron-rich sites and donor–acceptor mechanism. Our synthesized compounds have remarkable polarizability (αo) and hyperpolarizability (βo) values (446.23 − 1312.73 au), which indicates their optical and nonlinear optical properties. The density of states spectra further illustrates their notable structural-electronic properties and reduced band gaps. Based on structural activity relationship studies, we found that these tetrahydro-isoquinolines derivatives are potent against microsomal prostaglandin E synthase 1(MPGES1), the docking analysis shows that studied compounds have a good binding affinity with MPGES1, and further ADME/T analysis was carried out for both compounds. In addtion to this molecular dynamics, studies were performed to understand the binding stability of both compounds in protien complex system during 100 ns simulation. Communicated by Ramaswamy H. Sarma

Design, synthesis, and biological evaluation of simplified tetrahydroisoquinoline analogs.

A series of tetrahydroisoquinoline derivatives were prepared and their antitumor activity was studied against several human carcinoma cell lines, including Ketr3, BEL-7402, BGC-823, KB, HCT-8, MCF-7, HeLa, A2780, A549, and HT-1080. Compound 20, an analog of phthalascidin 650, exhibited good broad-spectrum antitumor activity in vitro. However, compounds 19 and 21, in which the side chains at C-22 are simplified, showed no obvious antitumor activity, indicating that the C-22 side chain of this type of compound has a greater impact on its activity. The difference in the in vivo activity between compound 20 and phthalascidin 650 also shows a significant effect of the substituents on the skeleton structure on the in vivo activity.

Design, synthesis, and biological evaluation of THIQ as antidepressive agents

7-substituted tetrahydroisoquinolines derivatives were designed, synthesized, and evaluated for neuroprotective properties. We summarized the preliminary structure activity relationships (SAR). Compound 3i was screened as a hit compound and its antidepressant activity was evaluated by employing the forced swimming test, tail suspension test. Additionally, ADMET profile (absorption, distribution, metabolism, excretion and toxicity properties) of the compound 3i was predicted in order to evaluate their lead-like properties and safety. The interaction of compound 3i bound to MAO-A was explored using molecular docking and molecular dynamics simulation. Results of biological studies revealed that the compound 3i exhibited almost equal antidepressant activity compared with magnoflorine. Compound 3i is predicted to possess good drug like properties and safety based on ADMET profile predictions. This work provides ideas for the drugs discovery of antidepressant agents.

Electrochemically‐Driven Organocatalytic Enantioselective Oxidative Coupling of Tetrahydroisoquinolines and Acrylaldehyde

AbstractAn electrochemically‐driven organocatalytic enantioselective oxidative coupling of tetrahydroisoquinolines and acrylaldehyde was developed. Various chiral C1‐alkenyl tetrahydroisoquinolines derivatives were obtained with 69–86% yields and 93:7–96:4 er. Notable features of this reaction include asymmetric organocatalysis (5.0 mol% β‐ICD as catalyst), electricity as the oxidant, air atmosphere, and undivided cell. This synthetic route offers access to various optically active C1‐substituted tetrahydroisoquinolines derivatives.

Activation and Deactivation of Benzylic C−H Bonds Guided by Stereoelectronic Effects in Hydrogen Atom Transfer from Amides and Amines to Alkoxyl Radicals

AbstractKinetic and product studies on the reactions of tert‐alkoxyl radicals with secondary and tertiary alkanamides bearing benzylic α‐C−H bonds, isoindoline, tetrahydroisoquinoline and the corresponding N‐acetyl derivatives were carried out. Product studies on the reactions with the tert‐butoxyl radical (tBuO⋅) point toward exclusive HAT from the benzylic α‐C−H bonds. Comparison of the kH values measured for reaction with the cumyloxyl radical (CumO⋅) with those obtained previously for the corresponding reactions of N‐alkyl‐ and N,N‐dialkylalkanamides, are indicative of a lack of benzylic activation and the operation of steric and stereoelectronic effects. Compared to N‐methyl and N‐ethyl groups, the presence of N‐benzyl groups increases the barrier required to reach the optimal conformation for HAT, where the α‐C−H bond to be cleaved is perpendicular to the plane of the amide, precluding concurrent overlap with the phenyl π‐system. When the benzylic α‐C−H bonds are in a conformation that allows for optimal overlap with both the phenyl π‐system and the amide π‐system or amine nitrogen lone pair, as in the isoindoline and tetrahydroisoquinoline derivatives, increases in kH that exceed 2‐orders of magnitude were observed, highlighting the strong contribution provided by stereoelectronic activation to these HAT processes.

Synthesis, Crystal Growth, and Computational Investigation of New Tetrahydroisoquinoline Derivatives Potent against Molecule Nitric Oxide Synthases

In the present work, we describe the synthesis of new tetrahydroisoquinoline derivatives and the crystal structures of two of them. Density functional theory (DFT) investigations at the B3LYP/6-31+G(d,p) level provided their structural reactivity and nonlinear optical properties. The low HOMO-LUMO gaps (EH-L) suggest a soft nature and higher reactivity, while calculated global reactivity descriptors provide assessments of their reactivity and electronic stability. The calculated natural bonding molecular orbital (NBO) charges show excellent charge separation (charge transfer) and identify the donor and acceptor parts of the molecules. Density of states (DOS) analyses show the newly generated energy states and reduced band gaps, which impart higher conductive properties. For surface reactivity, 3D MESP surfaces are plotted and show electron-rich sites near the nitrogen atoms of the tetrahydroisoquinoline rings. Nonlinear optical (NLO) properties of the crystals are predicted from calculated polarizability (αo) and hyperpolarizability (βo) values. For IVb, the αo and βo values are 415.53 and 1003.44 au. The remarkable value (1003.44 au) of the hyperpolarizability (βo) shows IVb has excellent NLO properties. Structural activity relationship analysis suggests that nitric oxide synthases are better targets for both compounds, and they were further subjected to molecular docking simulations to understand the binding efficiency. In addition, ADMET analyses were carried out to understand the potential activity of the molecules as drug candidates.

Aminomethylation of Quercetin by Tetrahydroisoquinoline Derivatives and Their Biological Activity

Aminomethylation of Quercetin by Tetrahydroisoquinoline Derivatives and Their Biological Activity

Biological Activities of Tetrahydroisoquinolines Derivatives

1,2,3,4-Tetrahydroisoquinoline (THIQ) is a common scaffold of many alkaloids isolated from several plants and mammalian species. THIQ derivatives possess a broad spectrum of biological activities, including antitumor, antitubercular, antitrypanosomal, antibacterial, anti-HIV, anti-inflammatory, anti-Alzheimer, and anticonvulsant ones.Aim. To cover updated studies on the biological properties of THIQ derivatives, as well as their structure-activity relationship (SAR), in order to highlight the effect of diverse functional groups responsible for the manifestation of the desired activity.Results and discussion. We have presented the review on biological activities of THIQ. The SAR studies show that the electron-donating, electron-withdrawing and some heterocyclic functional groups on the backbone plays a vital role in modulating the biological potential of the compounds synthesized.Conclusions. This review will help pharmaceutical researchers to synthesize novel and potent compounds containing THIQ scaffold.

Aminomethylation of Uracil and 6-Methyluracil by 3,4-dimethoxyphenylethylamine and Tetrahydroisoquinoline Derivatives

Aminomethylation of Uracil and 6-Methyluracil by 3,4-dimethoxyphenylethylamine and Tetrahydroisoquinoline Derivatives