Tetralone Derivatives Research Articles

Synthesis of β-lactams and transformation to β-amino acid ethyl ester derivatives: Theoretical calculations

Because of the important biological properties of β-amino acids in the present work, two new β-amino acid ethyl ester derivatives were synthesized, and their mechanistic occurrence was investigated. The title compounds were synthesized from related tetralone derivatives containing bromine and methoxy groups. Tetralone derivatives were reduced to their benzyl alcohol derivatives with NaBH4, followed by elimination with p-toluenesulfonic acid (pTSA) to give the desired 1,2-dihydronaphthalene derivatives. The reactions of 1,2-dihydronaphthalenes with chlorosulfonyl isocyanate (CSI) afforded β-lactams. β-Amino acids were obtained from the reaction of β-lactams with EtOH in HCl. Computational studies are concerned with synthesizing four-membered lactams (β-lactam) formed by the reaction between 1,2-dihydronaphthalene derivatives and CSI. The mechanism of the formation of compounds has been elucidated using DFT at M06-2X.

In-Depth Structural Simplification of Celangulin V: Design, Synthesis, and Biological Activity.

Celangulin V is a novel botanical insecticide with significant bioactivity and a unique molecular target, but its complex polyol ester structure hinders its broader application in agriculture. To discover new analogues of celangulin V with a simpler structure and enhanced biological activities, we initiated a research project aimed at simplifying its structure and assessing insecticidal efficacy. In this study, a series of novel 1-tetralone derivatives were designed via a structure-based rational design approach and synthesized by a facile method. The biological activities of the target compounds were determined against Mythimna separata (M. separata), Plutella xylostella, and Rhopalosiphum padi. The results revealed that most of the synthesized compounds exhibited superior activities compared to celangulin V. Remarkably, the insecticidal activity of compound 6.16 demonstrated 102-fold greater stomach toxicity than celangulin V against M. separata. In addition, certain compounds showed significant contact toxicity against M. separata, a finding not reported previously in the structural optimization studies of celangulin V. Molecular docking analysis illustrated that the binding pocket of compound 6.16 with the H subunit of V-ATPase was the same as celangulin V. This study presents novel insights into the structural optimization of botanical pesticides.

Copper-catalyzed desymmetric silylative-cyclization of 1,6-diynes for synthesis of spirocyclic compounds

The silylative-cyclization desymmetrization of 1,6-diynes has been realized. This reaction enabled the construction of silyl-functionalized spirocyclic oxindoles, indanone, quinolinone, and tetralone derivatives from readily available 1,6-diynes.

A Diastereoselective Assembly of Tetralone Derivatives via a Tandem Michael Reaction and ipso-Substitution of the Nitro Group.

A highly diastereoselective tandem reaction of 2'-nitrochalcones is reported, involving Michael addition and a subsequent ipso-substitution of the nitro group to produce 1-tetralones with two contiguous chiral centers. A related annulation reaction of 2'-nitrochalcones with potassium cyanide affording 1-indanones with a C3-quaternary chiral center is also demonstrated.

Antioxidative Indenone and Benzophenone Derivatives from the Mangrove-Derived Fungus Cytospora heveae NSHSJ-2.

Seven new polyketides, including four indenone derivatives, cytoindenones A-C (1, 3-4), 3'-methoxycytoindenone A (2), a benzophenone derivative, cytorhizophin J (6), and a pair of tetralone enantiomers, (±)-4,6-dihydroxy-5-methoxy-α-tetralone (7), together with a known compound (5) were obtained from the endophytic fungus Cytospora heveae NSHSJ-2 isolated from the fresh stem of the mangrove plant Sonneratia caseolaris. Compound 3 represented the first natural indenone monomer substituted by two benzene moieties at C-2 and C-3. Their structures were determined by the analysis of 1D and 2D NMR, as well as mass spectroscopic data, and the absolute configurations of (±)-7 were determined on the basis of the observed specific rotation value compared with those of the tetralone derivatives previously reported. In bioactivity assays, compounds 1, 4-6 showed potent DPPH· scavenging activities, with EC50 values ranging from 9.5 to 16.6 µM, better than the positive control ascorbic acid (21.9 µM); compounds 2-3 also exhibited DPPH· scavenging activities comparable to ascorbic acid.

Divergent reactivity of sulfoxonium ylide with allyl carbonate and allyl carbamate.

A divergent reactivity of sulfoxonium ylide with allyl carbonates and allyl carbamates is demonstrated. Rh(III)-catalyzed C-H activation and cyclization of sulfoxonium ylide with ally esters leads to the formation of a cyclopropane-fused tetralone derivative by cascade C-H activation, (4+2) annulation, and cyclopropanation. A similar reaction of sulfoxonium ylide with allyl carbamates forms a C3-substituted indanone derivative via a rare and interesting domino C-H activation and (4+1) annulation in which allyl carbamate is acting as a C1-synthon.

Silver-catalyzed cyclization of α-imino-oxy acids to fused tetralone derivatives.

A silver-catalyzed intramolecular radical relay cyclization of α-imino-oxy acids under mild conditions has been described. This reaction offers facile access to a diverse range of fused tetralone derivatives with exquisite stereoselectivity in moderate to good yields (40-98%). Experimental studies show that the reaction undergoes a decarboxylation and acetone fragmentation/1,5-hydrogen atom transfer (HAT)/cyclization process.

Tridysoxyphenols A and B, two new trimeric sesquiterpene phenols from Dysoxylum parasiticum leaves

Two new sesquiterpene phenol trimers, tridysoxyphenols A ( 2 ) and B ( 3 ), along with two known compounds, namely a sesquiterpene phenol, (+)-7-hydroxycalamenene ( 1 ), and a tetralone derivative, 4-hydroxy-4,7-dimethyl- α -tetralone ( 4 ), were isolated from the leaves of Dysoxylum parasiticum (Osbeck) Kosterm. The structures of 2 and 3 were elucidated using nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV) spectroscopy, infrared (IR) spectroscopy, high-resolution electrospray ionization time-of-flight mass spectrometry (HR-ESI/TOF-MS), and time-dependent density functional theory (TDDFT) calculations of the electronic circular dichroism (ECD) spectroscopic data. No cytotoxic activity was observed for any of the isolated compounds at low concentrations, although compound 1 suppressed the viability of HL60 cells at 119.85 ± 10.03 μM. • The metabolites isolated from the leaves of Dysoxylum parasiticum were studied. • Tridysoxyphenols A and B represent the trimeric sesquiterpene phenols. • Their structures were elucidated on the basis of spectroscopic analyses.

Visible-Light-Promoted Multistep Tandem Reaction of Vinyl Azides toward the Formation of 1-Tetralones.

A visible-light-driven multistep tandem reaction between vinyl azides and alkyl bromides has been developed leading to the formation of tetralone skeletons under mild conditions, which can be easily scaled up to the gram scale. Various 1-tetralone derivatives are synthesized and transformed into desired products in good to high yields.

Eremophilane Sesquiterpenoids with Antibacterial and Anti-inflammatory Activities from the Endophytic Fungus Septoria rudbeckiae.

Fourteen eremophilane sesquiterpenoids (1-14), including nine new congeners, septoreremophilanes A-I (1-9), together with three known sesquiterpenes (15-17), two known tetralone derivatives (18, 19), and two known cholesterol analogues (20, 21), were isolated from the endophytic fungus Septoria rudbeckiae. Compounds 1-6 and 7a belong to the family of the highly oxygenated eremophilane sesquiterpenoids with a 6/6/5 tricyclic system and bearing a hemiacetal moiety. The inhibitions of all metabolites against eight bacteria were estimated in vitro, and nine new metabolites (1-9) were tested for antineuroinflammatory activity. Notably, the effects of 4 against Pseudomonas syringae pv. actinidae and 20 against Bacillus cereus displayed potent inhibitory, with the MIC values of 6.25 and 6.25 μM, respectively. Further, scanning electron microscopy analyses indicated that 4 and 20 were to change the outer configuration of bacterial cells, respectively, and the investigations demonstrated that 4 and 20 may act as potential structure templates for the development of the agrochemical bactericides. Additionally, compound 6 displayed potent inhibition of NO generation in lipopolysaccharide-induced BV-2 microglial cells (IC50 = 12.0 ± 0.32 μM), and the conceivable anti-inflammatory mechanisms implicated were also investigated by molecular docking. Thus, the bioactive metabolites of the strain S. rudbeckiae may serve as a novel resource to be developed.

Atropo‐Enantioselective Oxidation‐Enabled Iridium(III)‐Catalyzed C−H Arylations with Aryl Boronic Esters

AbstractAtropo‐enantioselective biaryl coupling through C−H bond functionalization is an emerging technology allowing direct construction of axially chiral molecules. This approach is largely limited to electrophilic coupling partners. We report a highly atropo‐enantioselective C−H arylation of tetralone derivatives paired with aryl boronic esters as nucleophilic components. The transformation is catalyzed by chiral cyclopentadienyl (Cpx) iridium(III) complexes and enabled by oxidatively enhanced reductive elimination from high‐valent cyclometalated Ir‐species.

Atropo-Enantioselective Oxidation-Enabled Iridium(III)-Catalyzed C-H Arylations with Aryl Boronic Esters.

Atropo‐enantioselective biaryl coupling through C−H bond functionalization is an emerging technology allowing direct construction of axially chiral molecules. This approach is largely limited to electrophilic coupling partners. We report a highly atropo‐enantioselective C−H arylation of tetralone derivatives paired with aryl boronic esters as nucleophilic components. The transformation is catalyzed by chiral cyclopentadienyl (Cpx) iridium(III) complexes and enabled by oxidatively enhanced reductive elimination from high‐valent cyclometalated Ir‐species.

The inhibition of catechol O-methyltransferase and monoamine oxidase by tetralone and indanone derivatives substituted with the nitrocatechol moiety

The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson’s disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.

Tetralone Derivatives From a Deep-Sea-Derived Fungus Cladosporium Sp. HDN17-58

One new tetralone derivative, named aladothalen (1), and one known biogenetically related compound, (3 S,4 S)−3,4,8-trihydroxy-3,4-dihydronaphthalen-1(2 hours)-one (2), were isolated from a deep-sea-derived-fungal Cladosporium sp. HDN17-58. Their structures, including absolute configurations, were elucidated by extensive NMR, MS, and ECD analyses. Compound 1 exhibited potent bacteriostatic activity against Bacillus cereus, Mycobacterium phlei and methicillin-resistant coagulase-negative Staphylococci, with a MIC value of 25 µM.

Tetralone Scaffolds and Their Potential Therapeutic Applications

Substituted tetralones have played a substantial role in organic synthesis due to their strong reactivity and suitability as a starting material for a range of synthetic heterocyclic compounds, pharmaceuticals along with biological activities as well as precursors of many natural products and their derivatives. Many α-tetralone derivatives are building blocks that have been used in the synthesis of therapeutically functional compounds like some antibiotics, antidepressants, acetylcholinesterase inhibitors effective for treating Alzheimer’s disease and alkaloids possessing antitumor activity. In this review, there has been an attempt to explore the small molecule library having an α-tetralone scaffold along with their diverse biological activities. Structural features of α- tetralone derivatives responsible for potential therapeutic applications are also described.

Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF’s active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), (23), (24), (26) and (32), reduced inflammatory macrophage activation. Two of the selected compounds (24) and (26), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound (24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF’s tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation.

The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase

Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure–activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with IC50 values of 0.036 and 0.0011 µM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC50 = 0.785 μM) and 1o (IC50 = 0.0075 μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors.Graphic abstractThe present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.Electronic supplementary materialThe online version of this article (10.1007/s11030-020-10143-w) contains supplementary material, which is available to authorised users.

Enantioseparation of Eight Pairs of Tetralone Derivative Enantiomers on Cellulose Based Chiral Stationary Phase by HPLC

Background: Tetralone derivatives, important resources for the development of new drugs which can act in the treatment of central nervous system disorders or participate in synthesis reaction for the synthesis of various pharmaceuticals, have great research value and a bright prospect in exploitation. Methods: A novel chiral HPLC method for efficient enantioseparation of eight tetralone derivative enantiomers was developed on cellulose based CHIRALPAK IC chiral stationary phase under normal mode by investigating the effects of type and content of organic modifier, column temperature and flow rate on retention and enantioselectivity. Besides, the specificity, linearity, stability, precision, accuracy and robustness of this method were also validated. Results: Satisfactory enantioseparation was obtained for all enantiomers in n-hexane/2-propanol mobile phase system at ambient temperature. The thermodynamic study indicated that the solute transfer from the mobile to stationary phase was enthalpically favorable, and the process of enantioseparation was mainly enthalpy controlled. This method met the requirements for quantitative determination of tetralone derivative enantiomers. Conclusion: This study can provide great and important application value for enantioseparation of eight pairs of newly synthesized tetralone derivative enantiomers under normal mode using CHIRALPAK IC chiral column.

Synthesis and Structure Activity Relationships of Chalcone based Benzocycloalkanone Derivatives as Adenosine A1 and/or A2A Receptor Antagonists.

Adenosine A1 and/or A2A receptor antagonists hold promise for the potential treatment of neurological conditions, such as Parkinson's disease. Herein, a total of seventeen benzocycloalkanone derivatives were synthesised and evaluated for affinity towards adenosine receptors (A1 and A2A AR). The obtained results allowed for the conclusion that affinity and/or selectivity of the 2-benzylidene-1-indanone and -tetralone derivatives toward A1 and/or A2A ARs may be modulated by the nature of the substituents (either -OH, -OCH3 or morpholine) attached at position C4 of the 1-indanone core and C5 of the 1-tetralone core as well as the meta (C3') and/or para (C4') position(s) on ring B. Several compounds (2A: -B: , 3B: -C: and 4A: -B: ) possessed affinity for the A1 and/or A2A AR below 10 µM. Additionally, compounds 2A: , 3B: and 4A: were A1 AR antagonists. These results, once again, confirmed the importance of C4 methoxy-group substitution on ring A in combination with meta (C3') and/or para (C4') hydroxyl-group substitution ring B of the 2-benzylidene-1-indanone scaffold leading to drug-like compounds 1H: and 1J: with affinity in the nanomolar-range.

Synthesis and Antiproliferative Evaluation of Novel Longifolene-Derived Tetralone Derivatives Bearing 1,2,4-Triazole Moiety.

Seventeen novel 2-(5-amino-1-(substituted sulfonyl)-1H-1,2,4-triazol-3-ylthio)-6- isopropyl-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one compounds were synthesized from the abundant and naturally renewable longifolene and their structures were confirmed by FT-IR, NMR, and ESI-MS. The in vitro cytotoxicity of the synthesized compounds was evaluated by standard MTT assay against five human cancer cell lines, i.e., T-24, MCF-7, HepG2, A549, and HT-29. As a result, compounds 6d, 6g, and 6h exhibited better and more broad-spectrum anticancer activity against almost all the tested cancer cell lines than that of the positive control, 5-FU. Some intriguing structure–activity relationships were found and are discussed herein by theoretical calculation.