Tetrahydrocarbazole Derivatives Research Articles

Anxiolytic-Like and Antidepressant Effects of a 13H-indolo[2,3-a]thiopyrano[2,3-g]quinolizine Derivative

Depressive and anxiety disorders constitute some of the most prevalent mental disorders around the world. For years, the development of new lead compounds for drug discovery in this field has been an area of great attention. Recently, a series of tetrahydrocarbazole derivatives have demonstrated important anxiolytic-like activity, associated with their structures and stereochemistry. Here, we present a study of the antidepressant effect and anxiolytic-like activity of a fused thiopyrano-piperidone-tetrahydrocarboline (compound 4). The antidepressant and anxiolytic-like effects of 4 (1–50 mg/kg p.o.) were assessed with the tail suspension test and the hole-board test, respectively. This study determined the possible mechanisms involved in the anxiolytic-like actions of 4 using inhibitors or neurotransmission and evaluated its interaction with 5HT2A receptors using a molecular docking study. As an analog to the tetrahydrocarbazole core, the tetrahydrocarboline derivative showed anxiolytic-like activity (ED50 = 13 mg/kg p.o.) in the hole-board test, with a comparable effect to the reference drug, 1.5 mg/kg clonazepam, with the possible participation of the serotonergic system.

Electrochemical Annulation of Indole-Tethered Alkynes Enabling Synthesis of Exocyclic Alkenyl Tetrahydrocarbazoles

An electrochemical sulfonylation-triggered cyclization reaction of indole-tethered terminal alkynes with sulfinates as sulfonyl sources has been developed, which affords exocyclic alkenyl tetrahydrocarbazoles in good chemical yields. This reaction features convenient operation and tolerates a wide scope of substrates with a variety of electronically and sterically diverse substituents. Furthermore, high E-stereoselectivity is observed for this reaction, which provides an efficient method for the preparation of functionalized tetrahydrocarbazole derivatives.

Iron‐Catalyzed Trifluoromethylation of Indole‐Tethered Alkene Enables Synthesis of CF3‐Containing Spiroindolenines and Tetrahydrocarbazoles

A novel iron-catalyzed trifluoromethylation of indole-tethered alkene with Togni’s reagent to construct CF3-containing spiro[indole-3,3’-pyrrolidine] and tetrahydrocarbazole derivatives under mild and convenient conditions has been disclosed. The mechanistic studies indicate that the reaction proceed through a CF3 radical addition to the alkene, followed by sequential dearomatizing spiocyclization of the indole and oxidation to afford the spiro[indole-3,3’-pyrrolidine] derivatives. Meanwhile, when the substituent at the C2 position of the indole is hydrogen, the CF3-containing tetrahydrocarbazole is obtained through trifluoromethylation of alkene and cyclization of indole.

Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT-774312.

Herein we report the structure-activity relationship (SAR) studies and optimization of new highly potent and selective CRTH2 receptor antagonists as potential follow-ups of our previous reported clinical candidate setipiprant (ACT-129968) for the treatment of respiratory diseases. Structural modification of the amide part of setipiprant (ACT-129968) led to the identification of the tetrahydrocarbazole derivative (S)-B-1 (ACT-453859) ((S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetic acid). This compound which displayed a substantial improvement in potency in the presence of plasma versus setipiprant (ACT-129968) has exhibited an excellent overall pharmacokinetic profile. Further lead optimization to overcome a safety issue as observed in non-clinical studies with (S)-B-1 (ACT-453859), led to the discovery of the 4-azaindole derivative (S)-72 (ACT-774312) ((S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid) which was selected as a potential follow-up of setipiprant (ACT-129968).

A simple and efficient method for constructing azocino[4,3-b]indole

A new synthetic procedure has been developed to prepare the biologically important azocino[4,3-b]indole via the tetrafluoro-1,4-benzoquinone (TFB)-mediated cyclization of a tetrahydrocarbazole derivative bearing an amide side chain at the C-2 position. For the first time, this strategy is based on a different method for the C-2 position of the tetrahydrocarbazole for the synthesis of methanoazocino[4,3-b]indole. The notable features of this protocol include its operational simplicity and high reaction yields. Furthermore, the structures of all the presently synthesized compounds were confirmed using spectroscopic methods (1H NMR, 13C NMR, FT-IR).

Synthesis and study of antimicrobial activity of some tetrahydrocarbazole derivatives substituted with NSAID

New tetrahydrocarbazole derivatives substituted at the heteroatom (N) by non-steroidal anti-inflammatory drug (NSAIDs) were synthesized by reaction of cyclohehexanon (C.H.N.) with phenyl hydrazine (P.H.Z.) to form tetrahydrocarbazole (THCZ), where the latter is reacted with NSAID (Ketoprofen) via amide bond to yield
 substituted THCZ, compounds chemical structures were verified by: 1H, 13C NMR and FTIR spectroscopy.
 Antifungal activity of the synthesized compounds was investigated by docking study and in vitro test to reveal good antifungal activity, but the in vitro test also showed that the compounds have weak to moderate antibacterial activity.

Assembly of tetracyclic tetrahydrocarbazoles via a visible-light promoted cascade process

A photocatalytic cascade reaction of alkene tethered indoles and bromodifluoroacetate esters has been developed, which provides a novel access to tetracyclic tetrahydrocarbazole derivatives.

Correction to: Highly efficient, recyclable cerium‑phosphate solid acid catalysts for the synthesis of tetrahydrocarbazole derivatives by Borsche–Drechsel cyclization

Correction to: Highly efficient, recyclable cerium‑phosphate solid acid catalysts for the synthesis of tetrahydrocarbazole derivatives by Borsche–Drechsel cyclization

Highly efficient, recyclable cerium-phosphate solid acid catalysts for the synthesis of tetrahydrocarbazole derivatives by Borsche–Drechsel cyclization

Highly efficient, recyclable cerium-phosphate solid acid catalysts for the synthesis of tetrahydrocarbazole derivatives by Borsche–Drechsel cyclization

Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.

ZG02 Improved Hepatic Glucose Metabolism and Insulin Sensitivity via Activation of AMPK/Sirt1 Signaling Pathways in a High-fat Diet/Streptozotocin-induced Type 2 Diabetes Model.

PurposeThe aim of the present study was to investigate the hypoglycemic activity and potential mechanism of tetrahydrocarbazole derivatives ZG02 in high-fat diet/streptozotocin-induced type 2 diabetes model.MethodsC57BL/6 mice (n=30) were randomly assigned to three groups: control group (n=10) was fed with normal diet, the diabetes group (n=10) was fed with high-fat diet for eight weeks followed by intraperitoneal injection of streptozotocin (25 mg/kg) and the ZG02 group (n=10) injected intraperitoneally with ZG02 (30 mg/kg/day) for two weeks after successful modeling. The changes of weight, fasting blood glucose, oral glucose tolerance and fasting blood insulin levels in each group were evaluated. In addition, we also assessed the expression level of total AMPK, phosphorylation AMPK, SIRT1, PGC-1 and the activity of G6PC in liver.ResultsThe results demonstrated that ZG02 could significantly antagonize the high-fat diet/streptozotocin-induced fasting hyperglycemia, restore fasting blood insulin levels and also improve activity of G6PC in liver. The results from Western blot indicated that ZG02 significantly restored the expression level of phosphorylation AMPK, Sirt1 and PGC-1.ConclusionZG02 improve hepatic glucose metabolism and insulin sensitivity via activation AMPK/Sirt1 signaling pathways in type 2 diabetes mice model.

Tetrahydrocarbazoles as Novel Class of DNA Biosynthesis Inhibitors in Bacteria

Background: High-throughput screening (HTS) of large-compound libraries is a convenient and cost-effective tool for novel drug discovery. However, in many cases, HTS platforms are not well adapted to perform cell-based screening assay with simultaneous identification of the mechanism of action for active compounds. Methods: Previously, we have described a unique double-reporter system that can be used to reveal compounds having antibacterial activity. This construction is based on two genes of Katushka2S and RFP that encode proteins with different imaging signature. The upregulated expression of the first gene attributes directly to translation inhibition in prokaryotes while the high expression of the second one is unambiguously associated with DNA biosynthesis restriction (SOS-response). Results: In the current work, we have applied this system for the identification of novel smallmolecule compounds with antibacterial activity in HTS scale. Compounds were selected from the ChemDiv in-house collection (of total 47K molecules) following the maximum diversity in structure. Based on the obtained results, we have revealed a small series of tetrahydrocarbazole derivatives with antibacterial activity. The hit compound inhibited bacterial growth with a MIC value of 21 μg/ml and blocked DNA biosynthesis. No activity towards translation has been observed. In spite of a relatively moderate potency, as compared to the control sample (erythromycin, MIC=3 μg/ml), this molecule provides good selectivity index (SI>333, HEK239). Conclusion: Tetrahydrocarbazole derivatives can be properly regarded as an attractive starting point for further development and optimization.

Carbene-Catalyzed Reaction of Indolyl Methylenemalononitriles and Enals for Access to Complex Tetrahydrocarbazoles.

A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers.

Discovery of potent ureido tetrahydrocarbazole derivatives for cancer treatments through targeting tumor-associated macrophages

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.

Catalysis Based on C−I⋅⋅⋅π Halogen Bonds: Electrophilic Activation of 2‐Alkenylindoles by Cationic Halogen‐Bond Donors for [4+2] Cycloadditions

AbstractHomo‐ and cross‐[4+2] cycloadditions of 2‐alkenylindoles, catalyzed by cationic halogen‐bond donors, were developed. Under mild reaction conditions, 3‐indolyl‐substituted tetrahydrocarbazole derivatives were obtained in good to excellent yields. Experimental and quantum calculation studies revealed that the electrophilic activation of 2‐alkenylindoles was achieved by C−I⋅⋅⋅π halogen bonds.

Catalysis Based on C-I⋅⋅⋅π Halogen Bonds: Electrophilic Activation of 2-Alkenylindoles by Cationic Halogen-Bond Donors for [4+2] Cycloadditions.

Homo- and cross-[4+2] cycloadditions of 2-alkenylindoles, catalyzed by cationic halogen-bond donors, were developed. Under mild reaction conditions, 3-indolyl-substituted tetrahydrocarbazole derivatives were obtained in good to excellent yields. Experimental and quantum calculation studies revealed that the electrophilic activation of 2-alkenylindoles was achieved by C-I⋅⋅⋅π halogen bonds.

Catalytic Enantioselective Diels-Alder Reactions of Benzoquinones and Vinylindoles with Chiral Magnesium Phosphate Complexes.

Tetrahydrocarbazole and its derivatives have received much attention due to the prevalence of this scaffold in natural products and their use in organic synthesis. We have developed a Diels-Alder reaction of benzoquinones and 3-vinylindoles catalyzed by chiral magnesium phosphate complexes to provide tetrahydrocarbazole derivatives in excellent yields and enantioselectivities (up to >99% yield, 99% ee). This transformation features a wide substrate scope, excellent enantioselectivities, and mild conditions.

Total Synthesis of Olivacine and Ellipticine via a Lactone Ring-Opening and Aromatization Cascade.

Effective preparation of olivacine and ellipticine via late-stage D-ring cyclization is described. Key features of the synthetic routes include trifluoroacetic acid-mediated formation of a lactone that is fused to a tetrahydrocarbazole derivative and its one-pot two-step ring opening and aromatization mediated by para-toluenesulfonic acid and palladium on carbon, respectively.

The Study of Cognitive-Stimulating Activity of Fluorinated Tetrahydrocarbazole Derivatives and Behavioral Responses in Transgenic Tg6799 Mice with Alzheimer’s Disease

The cognitive-stimulating, neuroprotective effects of promising fluorinated tetrahydrocarbazole derivatives (CA-7043x and CA-7050x) on the hippocampus-dependent memory of outbred mice (CD1) and transgenic Tg6799 mice, as well as their effect on anxiety, locomotor activity, and orienting-exploratory behavior of animals, were studied. It was found that both compounds have a pronounced cognitive-stimulating effect on CD1 mice, but do not show neuroprotective effects on memory support in Tg6799 mice. It is noted that, in the open-field test, the CA-7050x compound has a positive effect on the orientating behavior, and the CA-7043x compound has a positive effect on the exploratory response in the nontransgenic control.

Investigation of NMDA Receptor Channel Blockers in a Series of Methylene Blue Conjugates Using QSAR and Molecular Modeling

29 conjugates of methylene blue and four chemical structures, including derivatives of carbazole, tetrahydrocarbazole, substituted indoles and γ-carboline, combined with a 1-oxopropylene spacer have been studied as channel blockers of the NMDA receptor (binding site of MK-801) by using four QSAR methods (multiple linear regression, random forest, support vector machine, Gaussian process) and molecular docking. QSAR models have satisfactory characteristics. The analysis of regression models at the statistical level revealed an important role of the hydrogen bond in the complex formation. This was also confirmed by the study of modeled by docking complexes. It was found that the increase in the inhibitory activity of the part of compounds could be attributed to appearance of additional H bonds between the ligands and the receptor.