2, 9-deoxyflavonoids (= 3-aryl-1-indanones) from Aglaia odorata: Structure elucidation, biosynthetic pathway and lung protective activity.

Six previously undescribed 2, 9-deoxyflavonoids (1/2a, 1/2b, 6, and 7), along with six known compounds (3-5, and 8-10), were isolated from the twigs and leaves of Aglaia odorata. Their structures were determined by a combination of spectral analysis, ECD calculation and enzymatic hydrolysis assay. Surprisingly, (±) aglaindanone E (11a, 11b) were unexpectedly formed as the derivatives of compounds 3-6 when exposed to ambient natural light. Furthermore, the plausible biosynthetic pathway of 2, 9-deoxyflavonoids was proposed and chemically mimicked. In biological activity assay, compounds 1/2a, 1/2b, 4, and 6 showed potential protective effects in the 0.75%CSE-induced BEAS-2B cells injury model.

Asymmetric Mannich/Cyclization Reaction of 2-Benzothiazolimines and 2-Isothiocyano-1-indanones to Construct Chiral Spirocyclic Compounds.

An efficient and practical organocatalyzed asymmetric Mannich/cyclization tandem reaction strategy of 2-benzothiazolimines and 2-isothiocyanato-1-indanones was developed, and novel spirocyclic compounds containing benzothiazolimine and indanone scaffolds were obtained. This chiral thiourea-catalyzed Mannich/cyclization tandem reaction offers chiral spirocyclic compounds with continuous tertiary and quaternary stereocenters in good to high yields (up to 90%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 98% ee) at -18 °C. Additionally, the scaled-up synthesis was also performed with retained yield and stereoselectivity, and a reaction mechanism was also proposed.

Novel 1-Indanone derivatives containing oxime and oxime ether moieties as immune activator to resist plant virus.

BACKGROUND: Vegetable viruses are difficult to prevent and control in the field, causing massive economic losses of agricultural production in the world. A new natural product-based antiviral agent would be an effective means to control viral diseases. As a class of natural products, 1-indanones present various pharmacologically actives, while their application in agriculture remains to be found. RESULTS: A series of novel 1-indanone derivatives were designed and synthesized and the antiviral activities were systematically evaluated. Bioassays showed that most compounds exhibited good protective activities against cucumber mosaic virus (CMV), tomato spotted wilt virus (TSWV), and pepper mild mottle virus (PMMoV). Notably, compound 27 exhibited the best protective effects against PMMoV with EC50 values of 140.5 mg L-1 , superior to ninanmycin (245.6 mg L-1 ). Compound 27 induced immunity responses through multilayered regulation on mitogen-activated protein kinase, plant hormone signal transduction and phenylpropanoid biosynthesis pathways. CONCLUSION: These 1-indanone derivatives especially compound 27 can be considered as potential immune activators to resist plant virus. © 2023 Society of Chemical Industry.

Synthesis, in silico Studies and Pharmacological Evaluation of a New Series of Indanone Derivatives as Anti-Parkinsonian and Anti-Alzheimer's Agents.

OBJECTIVE: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders. METHODS: A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects. RESULTS: The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents. CONCLUSION: The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases.

1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Cyst development in ADPKD involves abnormal epithelial cell proliferation, which is affected by the primary cilia-mediated signal transduction in the epithelial cells. Thus, primary cilium has been considered as a therapeutic target for ADPKD. Since ADPKD exhibits many pathological features similar to solid tumors, we investigated whether targeting primary cilia using anti-tumor agents could alleviate the development of ADPKD. Twenty-four natural compounds with anti-tumor activity were screened in MDCK cyst model, and 1-Indanone displayed notable inhibition on renal cyst growth without cytotoxicity. This compound also inhibited cyst development in embryonic kidney cyst model. In neonatal kidney-specific Pkd1 knockout mice, 1-Indanone remarkably slowed down kidney enlargement and cyst expansion. Furthermore, we demonstrated that 1-Indanone inhibited the abnormal elongation of cystic epithelial cilia by promoting tubulin polymerization and significantly down-regulating expression of anterograde transport motor protein KIF3A and IFT88. Moreover, we found that 1-Indanone significantly down-regulated ciliary coordinated Wnt/ß-catenin, Hedgehog signaling pathways. These results demonstrate that 1-Indanone inhibits cystic cell proliferation by reducing abnormally prolonged cilia length in cystic epithelial cells, suggesting that 1-Indanone may hold therapeutic potential to retard cyst development in ADPKD.

Conformational analysis, molecular structure, spectroscopic, NBO, reactivity descriptors, wavefunction and molecular docking investigations of 5,6-dimethoxy-1-indanone: A potential anti Alzheimer's agent.

The objective of the present study is focused to elucidate the structure of potential anti-Alzheimer's compound 5,6-Dimethoxy-1-indanone (5,6-DMI) and study its binding interaction towards the active site by molecular docking studies. The structural and various spectroscopic tools are used to understand the various interaction behaviors of the title compound. The theoretical calculation of 5,6-DMI molecule is computed by Gaussian 09W software with Density functional B3LYP and CAM-B3LYP method utilizing 6-311G(d,p) as basis set. The Natural Bond Orbital (NBO) analysis has been performed to find all possible transition was correlate with electronic transition. The Non covalent interaction of 5,6-DMI molecule was examined by adopt Reduced Density Gradient (RDG) analysis and colour filled ELF diagram. Molecular docking results suggest that 5,6-DMI may exhibit inhibitory activity against apoE protein and may act as potential against Alzheimer's disease.

Influence of ligand geometry on cholinesterase enzyme - A comparison of 1-isoindolinone based structural analog with Donepezil.

Donepezil (DNPZ) is one of the few FDA-approved widely used medication in the clinical care of Alzheimer's disease (AD) patients. To investigate the effect of geometry and to find the significance of an enol form if any in DNPZ on acetylcholinesterase (AChE) inhibition, we changed the tetrahedral geometry of DNPZ to planar trigonal pyramidal geometry by replacing the α-carbon atom next to ketone functionality with a nitrogen atom. To mimic 1-indanone in DNPZ, we selected 1-isoindolinone framework to synthesize 25 new DNPZ derivatives and characterized using 1H NMR, 13C NMR and ESI-MS spectroscopy methods. Drug likeliness profile for each compound was predicted using Molinspiration online software following Lipinski's rule. Commercially available assay kits were used to measure AChE and butyrylcholinesterase (BuChE) inhibitory effects. NIH/3T3 mouse embryonic fibroblast cell line was used to measure cytotoxic and proliferation effects using LDH and MTT assay, respectively. Compound #20 was selected for comparative computational docking, modelling and physicochemical studies. Our results show that DNPZ with tetrahedral geometry has 3-fold higher AChE inhibition as compared to compound #20 with planar trigonal pyramidal geometry. Our approach may be useful as a novel indirect method to study the significance of the enol form in DNPZ (or similar compounds), since constant interconversion between the keto and enol forms does not permit a direct determination of the effect of the enol form of DNPZ in vivo. Overall, we conclude that the tetrahedral is a better fit and any change in geometry significantly drives down the cholinesterase inhibitory effect of DNPZ.

In vitro and in silico insights into tyrosinase inhibitors with (E)-benzylidene-1-indanone derivatives.

Tyrosinase is a key enzyme responsible for melanin biosynthesis and is effective in protecting skin damage caused by ultraviolet radiation. As part of ongoing efforts to discover potent tyrosinase inhibitors, we systematically designed and synthesized thirteen (E)-benzylidene-1-indanone derivatives (BID1-13) and determined their inhibitory activities against tyrosinase. Among the compounds evaluated, BID3 was the most potent inhibitor of mushroom tyrosinase (IC50 = 0.034 µM, monophenolase activity; IC50 = 1.39 µM, diphenolase activity). Kinetic studies revealed that BID3 demonstrated a mixed type of tyrosinase inhibition with K i value of 2.4 µM using l-DOPA as a substrate. In silico molecular docking simulations demonstrated that BID3 can bind to the catalytic and allosteric sites of tyrosinase to inhibit enzyme activity which confirmed in vitro experimental studies between BID3 and tyrosinase. Furthermore, melanin contents decreased and cellular tyrosinase activity was inhibited after BID3 treatment. These observations revealed that BID3 is a potent tyrosinase inhibitor and potentially could be used as a whitening agent for the treatment of pigmentation-related disorders.

Enantioselective separation of twelve pairs of enantiomers on polysaccharide-based chiral stationary phases and thermodynamic analysis of separation mechanism.

The enantioseparation of twelve pairs of structurally related 1-aryl-1-indanone derivatives was studied in the normal-phase mode using three different polysaccharide-type chiral stationary phases, namely Chiralpak IB, Chiralpak IC, and Chiralpak ID. n-Hexane/2-propanol and n-hexane/ethanol were employed as mobile phases. Among all the investigated chiral columns, Chiralpak IC exhibited the most universal and the best enantioseparation ability toward all the racemates, particularly with the mobile phase composed of n-hexane/2-propanol (90/10, v/v). Then the effects of column temperature on retention and enantioselectivity were examined in the range of 25-40°C. Satisfactory enantioseparation was obtained at ambient temperature. The natural logarithm of retention and separation factors (ln k and ln α) versus the reciprocal of absolute temperature (1/T) (Van't Hoff plots) were found to be linear for all racemates, indicating that the retention and separation mechanisms were independent of temperature in the range investigated. Then, the thermodynamic parameters (ΔΔH°, ΔΔS°, and ΔΔG°) were calculated from Van't Hoff plots. These values indicated that the solute transfer from the mobile to stationary phase was enthalpically favorable, and the process of enantioseparation was mainly enthalpy controlled. At last, the impact of small changes in molecular structures of the tested 1-indanone derivatives on enantioseparation was also discussed.

Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors.

A novel series of 2-benzyl-1-indanone analogs were investigated as IL-5 inhibitory activity. Among the synthesized compounds, 7-(cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7s, 100.0% inhibition at 30 µM, IC50 = 4.0 µM), and 7-(cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7t, 95.0% inhibition at 30 µM, IC50 = 6.0 µM) showed the best inhibitory activity against IL-5. The 2-benzyl-1-indanone analogs showed moderate to strong IL-5 inhibitory activity. Especially, hydroxyl (HBD/HBA) substituent at position 3 or 4 on phenyl ring B showed potent IL-5 inhibition. Additionally, the bulky hydrophobic cyclohexylmethoxy group at position 7 of the 1-indanone ring is favorable for the inhibitory activity.

Fine tuning the emission wavelengths of the 7-hydroxy-1-indanone based nano-structure dyes: Near-infrared (NIR) dual emission generation with large stokes shifts.

Near-infrared (NIR) fluorescent dyes have recently gained special attention due to their applications to use as molecular probes for imaging of biological targets and sensitive determination. In this study, photophysical properties of the 7-hydroxy-1-indanone based fluorophors A1, A2, A3, B1, B2 and 3R-B2 (R=CF3, NH2, NO2 and OMe) in the gas and three solution phases were probed using TD-DFT method at PBE0/6-311++G(d,p) and M06-2X/6-311++G(d,p) levels of theory. In addition to structural and photophysical properties as well as ESIPT mechanism of all mentioned molecules, the FC and relaxed potential energy surfaces of B2 and 3R-B2 (R=CF3 and NH2) molecules were explored in gas phase and acetonitrile, cyclohexane and water solvents. It is predicted that the A1, A3 and 3R-B2 chromophores afford normal (615-670nm) and NIR fluorescence emissions (770-940nm; biological window) with the large Stokes shifts of >160 and >300nm, respectively. A good aggrement was found between theoretical and experimental results. In sum, these new types of dyes may render the new approaches for the development of the most efficient NIR fluorescent probes for enhanced image contrast and optimal apparent brightness in biological applications.

Identification and preliminary structure-activity relationships of 1-Indanone derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer's disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein. The preliminary SAR was further explored and the binding mode with IDO1 protein was predicted by experiment along with molecular docking. Subsequent ADME properties of these active compounds were analyzed in silico, and the results showed good pharmacokinetic efficiencies. We believe this study contributes a lot to the structural diversity for the future development of highly potent IDO1 inhibitors.

Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene-1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages.

As a continuous effort to discover new potential anti-inflammatory agents, we systematically designed and synthesized sixty-one 2-benzylidene-1-indanone derivatives with structural modification of chalcone, and evaluated their inhibitory activity on LPS-stimulated ROS production in RAW 264.7 macrophages. Systematic structure-activity relationship study revealed that hydroxyl group in C-5, C-6, or C-7 position of indanone moiety, and ortho-, meta-, or para-fluorine, trifluoromethyl, trifluoromethoxy, and bromine functionalities in phenyl ring are important for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. Among all the tested compounds, 6-hydroxy-2-(2-(trifluoromethoxy) benzylidene)-2,3-dihydro-1H-inden-1-one (compound 44) showed the strongest inhibitory activity of ROS production. Further studies on the mode of action revealed that compound 44 potently suppressed LPS-stimulated ROS production via modulation of NADPH oxidase. The findings of this work could be useful to design 2-benzylidene-indanone based lead compounds as novel anti-inflammatory agents.

2-Benzylidene-1-indanone derivatives as inhibitors of monoamine oxidase.

In the present study, a series of twenty-two 2-benzylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 2-benzylidene-1-indanone derivatives are structurally related to a series of benzylideneindanone derivatives which has previously been found to be MAO-B inhibitors. This study finds that the 2-benzylidene-1-indanones are MAO-B specific inhibitors with IC50 values <2.74µM. Among the compounds evaluated, twelve compounds exhibited IC50<0.1µM and may be considered as high potency inhibitors. The 2-benzylidene-1-indanone derivatives also inhibited MAO-A with the most potent inhibition exhibited by 5g (IC50=0.131µM). An analysis of the structure-activity relationships for MAO-B inhibition show that substitution on the A-ring with a 5-hydroxy group and on the B-ring with halogens and the methyl group yield high potency inhibition. It may therefore be concluded that 2-benzylidene-1-indanone analogues are promising leads for design of therapies for disorders such as Parkinson's disease.

Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities.

Chalcones and Mannich bases are a group of compounds known for their cytotoxicities. In this study restricted chalcone analogue, compound 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one MT1, was used as a starting compound to synthesize new mono Mannich bases since Mannich bases may induce more cytotoxicity than chalcone analogue that they are derived from by producing additional alkylating center for cellular thiols. In this study, cyclic and acyclic amines were used to synthesize Mannich bases. All compounds were tested against Ca9-22 (gingival carcinoma), HSC-2, HSC-3 and HSC-4 (oral squamous cell carcinoma) as tumour cell lines and HGF (gingival fibroblasts), HPC (pulp cells) and HPLF (periodontal ligament fibroblasts) human normal oral cells as non tumour cell lines. Cytotoxicity, selectivity index (SI) values and potency selectivity expression (PSE) values expressed as a percentage were determined for the compounds. According to data obtained, the compound MT8 with the highest PSE value bearing N-methylpiperazine moiety seems to be a good candidate to develop new cytotoxic compounds and is suited for further investigation.

Novel 1-indanone Thiosemicarbazone Antiviral Candidates: Aqueous Solubilization and Physical Stabilization by Means of Cyclodextrins.

PURPOSE: To investigate cyclodextrin-mediated solubilization and physical stabilization of novel 1-indanone thiosemicarbazone (TSC) candidate drugs that display extremely high self-aggregation and precipitation tendency in water. METHODS: TSC/CD complexes were produced by co-solvent method, and TSC/CD phase-solubility diagrams were obtained by plotting TSC concentration as a function of increasing CD concentration. Size, size distribution, and zeta-potential of the different TSC/CD complexes and aggregates were fully characterized by dynamic light scattering. The morphology of the structures was visualized by atomic force microscopy. RESULTS: Results indicated the formation of Type A inclusion complexes; the solubility of different TSCs was enhanced up to 215 times. The study of physical stability revealed that, as opposed to free TSCs that self-aggregate, crystallize, and precipitate in water very rapidly, complexed TSCs remain in solution for at least 1 week. On the other hand, a gradual size growth was observed. This phenomenon stemmed from the self-aggregation of the TSC/CD complex. CONCLUSIONS: 1-indanone TSC/CD inclusion complexes improved aqueous solubility and physical stability of these new drug candidates and constitute a promising technological approach towards evaluation of their activity against the viruses hepatitis B and C.