Synthesis and biological evaluation of 3-carbamate smilagenin derivatives as potential neuroprotective agents

Studies indicated that smilagenin, isolated from Anemarrhena asphodeloides Bunge, could improve cognitive impairment and exhibit neuroprotective activity. On the basis of the structure of smilagenin, a series of derivatives were synthesized and evaluated for their neuroprotective effects of H₂O₂-induced, oxygen glucose deprivation-induced neurotoxicity in SH-SY5Y cells and LPS-induced NO production in RAW264.7 cells. Structure activity relationship of derivatives revealed that benzyl-substituted piperazine formate derivatives showed the potent neuroprotective activity such as A12. These findings may provide new insights for the development of neuroprotective agents against Alzheimer’s disease.     

Synthesis of a novel series of diphenolic chromone derivatives as inhibitors of NO production in LPS-activated RAW264.7 macrophages

A novel series of diphenolic chromone derivatives were synthesized and their inhibitory activity on nitric oxide (NO) production and cytotoxicity were evaluated using LPS-activated murine macrophages RAW264.7 assay and MTT method, respectively. Among these compounds, (5,7-dihydroxy-4-oxo-4H-chromen-3-yl) methyl esters (6b, 6c, 6f, 6g, and 6h) showed quite potent inhibitory activities with IC₅₀ values of 2.20, 3.48, 0.35, 0.80, and 0.61 μM, respectively. The MTT results showed that all of the active compounds exhibited no cytotoxicity at the effective concentrations. The preliminary mechanism of the most potent compounds (6b, 6c, 6f, 6g, and 6h) was further examined based on the RT-PCR results and the compounds 6f, 6g, and 6h inhibited NO production by suppressing the expression of iNOS mRNA in a dose dependent manner. Furthermore, a computational analysis of physicochemical parameters revealed that the most of the compounds possessed drug-like properties.     

Anti-inflammatory activity of benzophenone and xanthone derivatives isolated from Garcinia (Clusiaceae) species

Species of the genus Garcinia have been the source of many benzophenone and xanthone derivatives. Recent data regarding potent biological properties of natural compounds in Garcinia species led us to investigate the in vitro anti-inflammatory effect of three known xanthones, lichexanthone (1), 1,3,6,7-tetrahydroxyxanthone (2), 1,3,5,6-tetrahydroxyxanthone (3), two new xanthones 1-hydroxy-3,6,7-tri-O,O,O-triprenylxanthone (4), 1,6-dihydroxy-3,7-di-O,O-diprenylxanthone (5) and two benzophenones isoxanthochymol (6), guttiferone E (7), isolated from Garcinia nobilis and Garcinia punctata. The Griess assay was used for the measurement of nitric oxide (NO) production in RAW264.7 macrophages and the ferrous oxidation-xylenol orange assay was used to determine the 15-lipoxygenase (15-LOX) inhibitory activity. All the compounds had inhibitory effect on 15-LOX activity to different extents. Compound (7) had the highest anti-LOX activity with an IC₅₀ value of 43.05 μg/mL. At the highest studied concentration (25 μg/mL), compound (4) had the most potent inhibitory activity against NO release with a% of inhibition of 95.42% and less cytotoxic effect on RAW264.7 cells (% of cell viability of 81.40).The results presented here suggest that 1,3,5,6-tetrahydroxyxanthone (3) and guttiferone E (7) are promising inhibitors of NO production and 15-LOX activity. Further studies should be considered in order to elucidate the mechanism by which these compounds exert their inhibitory activities.     

Design,synthesis, and biological evaluation of novel 4-oxobenzo[d]1,2,3-triazin-benzylpyridinum derivatives as potent anti-Alzheimer agents

Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a–q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H₂O₂-induced PC12 oxidative stress, but low activity against β-secretase.     

Synthesis of tricyclic fused coumarin sulfonates and their inhibitory effects on LPS-induced nitric oxide and PGE2 productions in RAW 264.7 macrophages

The regulations of NO and PGE₂ productions are research topics of interest in the field of antiinflammatory drug development. In the present study, a series of tricyclic fused coumarin sulfonate derivatives was synthesized and evaluated for their abilities to inhibit NO and PGE₂ productions in LPS-induced RAW 264.7 macrophages. Among all the target compounds, compound 1g possessing p-(trifluoromethyl)phenyl and fused cycloheptane moieties showed the highest inhibitory effects on NO and PGE₂ productions. Compound 1g not only inhibited COX-2 activity but also reduced expressions of COX-2 and iNOS. Furthermore, ADME profiling showed that compounds 1g, 1j, 1m, and 1n are estimated to be orally bioavailable.     

Synthesis,anti-inflammatory,and antioxidant activities of 18β-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors

Twenty 18β-glycyrrhetic acid (18β-GA) derivatives 2–21 including 13 new 18β-GA derivatives were synthesized and evaluated as anti-inflammatory and antioxidant agents. Compounds 7 and 20 with a 3,4-seco-structure and compound 6 with a lactone moiety showed potent inhibitory effect on superoxide anion generation in rat neutrophils response to fMLP/CB and PMA, respectively. Compound 6 with a lactone moiety revealed stronger inhibitory effect on XO activity than those of compounds 13 and 14 with a 3,4-seco-struture. Compound 14, a 30-isoproylcarbamoyl seco-compound exhibited potent inhibitory effect on NO accumulation and iNOS protein expression while compounds 3, 10, 13, 15, 17, and 21 revealed potent inhibitory effect on tumor necrosis factor-α (TNF-α) formation in RAW 264.7 cells in response to lipopolysaccharide (LPS). The cleavage of ring A of 3 attenuated the inhibitory effect on TNF-α formation in RAW 264.7 cells in response to LPS except for 17. The present results suggested these compounds were potential to be served as anti-inflammatory and antioxidant agents.     

Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis techniques.     

Structure-Plant Phytotoxic Activity Relationship of 7,7′-epoxylignanes, (+)- and (−)-verrucosin: Simplification on the aromatic ring substituents

The synthesized 7-aryl derivatives of (7R,7′S,8S,8′S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1 mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (−95%) and the shoot (−60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7′R,8R,8′R)-(−)-verrucosin at 1 mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (−)-verrucosin against the root (−95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (−80%) than that of (−)-verrucosin (−60%). As the next step, (7S,7′R,8R,8′R)-7-(3-hydroxyphenyl)-7′-aryl-(−)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7′-(2-hydroxyphenyl) derivative 37 and 7′-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7′-aryl structures of 7,7′-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7′-aryl structures were simplified to show comparable activity to or higher activity than that of (−)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C_3b, was estimated as −80% inhibition at 1 mM against ryegrass roots.     

Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production

Butadiene-imide 1 (T-686) derivatives were synthesized and evaluated for their inhibitory activity against PAI-1 production and their ADMET (DMPK and toxicology) profiles. Among these derivatives, compound 15k (T-2639) showed good antithrombotic activity in two rat thrombosis models without affecting bleeding time, indicating reduction of haemorrhagic risk. We also describe in this report a practical synthesis of 15k suitable for scale-up using Z,E-selective Stobbe condensation.     

Synthesis of natural product-like polyprenylated phenols and quinones: Evaluation of their neuroprotective activities

Twenty-seven natural product-like polyprenylated phenols and quinones were synthesized and their neuroprotective activity was tested using human monoamine oxidase B (MAO-B) and SH-SY5Y cells. Eight compounds inhibited MAO-B (IC₅₀ values < 25 μM) and the inhibition mode and molecular docking of two (8c and 16c) were investigated. Compounds inhibiting MAO-B activity were additionally tested for their ability to protect SH-SY5Y cells from peroxide injury. Three derivatives (3c, 8c and 16c) exhibited both MAO-B inhibitory and neuroprotective activity. A structure activity-relationship study showed that a phenolic hydroxyl group and a longer side chain are important for both activities.     

Syntheses and bioactivities of songorine derivatives as novel G protein-coupled receptor antagonists

Songorine isolated from Aconitum brachypodum Diels possesses prominent activity of inhibiting G protein-coupled receptors (GPCRs) in the early screening process. In this paper, a series of Songorine derivatives were synthesized and their inhibitory activities on GPCRs were also evaluated by using the Double Antibody Sandwich ELISA (DAS-ELISA) in vitro. Among them, three derivatives (3a, 4, 7) exhibited significant inhibitory activity against GPCRs with IC₅₀ values of 0.08–0.29?nM. Moreover, the structure-activity relationships (SARs) of songorine derivatives were discussed in detail. They have great potentials as novel GPCRs antagonists in the future.     

Synthesis and biological evaluation of pyrano[4,3-b][1]benzopyranone derivatives as monoamine oxidase and cholinesterase inhibitors

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.     

Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: Design,synthesis and docking studies

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC₅₀ range of 6.4 – 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC₅₀ = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC₅₀ range of 1.77–4.91 nM comparing to meclofenamate sodium (IC₅₀ = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.     

Synthesis,structural characterization,docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates,novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors

In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, ¹H, ¹³C, ¹⁹F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer’s disease.     

Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone,an inhibitor of NF-κB

Synthesis of 9-methylstreptimidone analogs and their inhibitory activities against NF-κB (nuclear factor-κB) are reported. Among several active derivatives synthesized in this study, 8 with a relatively simple structure, exhibited inhibitory activity against LPS-induced NO production comparable to that of 9-methylstreptimidone.     

N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells

A series of N-acyl derivatives of tyramine, tryptamine, and serotonin were synthesized and tested on anti-melanogenic activity. The serotonin derivatives such as N-caffeoylserotonin (3) and N-protocatechuoylserotonin (9) were inhibitory to tyrosinase from mouse B16 and human HMV-II melanoma cells, while the corresponding derivatives of tryptamine and 5-methoxytryptamine were almost inactive or less active than the serotonin derivatives. The inhibitory activity of the serotonin derivatives increased with increasing number of phenolic hydroxyl groups in the acyl moiety. Melanin formation in the culture of B16 cells was suppressed by 3 and 9 with no cytotoxicity in the concentration range tested (IC₅₀ = 15, 3 and 111 μM for 3, 9, and kojic acid, respectively). Thus the N-acylserotonin derivatives having a dihydroxyphenyl group are potential anti-melanogenic agents. Their inhibition of tyrosinase is primarily performed through the 5-hydroxyindole moiety and further strengthened by the phenolic hydroxyl groups in the acyl moiety.     

Structures and biological evaluation of phenylpropanoid derivatives from Murraya koenigii

Four new phenylpropanoid derivatives (1–4), together with eleven known analogues (5–15) were isolated and identified by comparison with their references and extensive spectroscopic methods from Murraya koenigii for the first time. Compounds (1–15) were assayed for their inhibitory activities by measuring IL-6-induced STAT3 promoter activities in HepG2 cells, and found compounds 1, 2, 6, and 15 showed inhibitory effects with IC₅₀ values of 11.5, 18.7, 8.9, and 22.7 μM, respectively. The inhibitory activities of compounds (1–15) were screened against NO production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells, and found compounds 3, 4, 9, 11, and 14 exhibited inhibitions against LPS-induced NO production in RAW264.7 macrophages, with IC₅₀ values of 32.7, 7.9, 42.1, 58.9, and 62.4 μM, respectively.     

Synthesis and antibacterial activity of 5-methylphenanthridium derivatives as FtsZ inhibitors

5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4 µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity.     

Characterization of inhibitory constituents of NO production from Catalpa ovata using LC-MS coupled with a cell-based assay

An effective screening method for inhibitors of NO production in natural products using LC-QTOF MS/MS coupled with a cell-based assay was proposed. The ethyl acetate fraction of Catalpa ovata exhibited a strong inhibitory effect on NO production in lipopolysaccharide-induced BV2 microglia cells. We attempted to identify the active constituents of C. ovata by using LC-QTOF MS/MS coupled with a cell-based assay. Peaks at approximately 14–15 min on the MS chromatogram were estimated to be the bioactive constituents. A new iridoid compound, 6-O-trans-feruloyl-3β-hydroxy-7-deoxyrehamaglutin A (4), and nine known compounds (1–3, 5–10) were isolated from the ethyl acetate fraction of C. ovata by repeated column chromatography. Compounds 3, 4, 5, 7, and 8 significantly attenuated lipopolysaccharide-stimulated NO production in BV2 cells. Our results indicate that LC-QTOF MS/MS coupled with a cell-based NO production inhibitory assay successfully predicted active compounds without a time-consuming isolation process.     

Synthesis and evaluation of novel 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-diones for advanced glycation end product formation inhibitory activity

The synthesis of some biologically interesting pyrrolo-isoxazolidine derivatives was accomplished by the 1,3-dipolar cycloaddition reaction of substituted azomethine N-oxides 1 with substituted N-aryl maleimides 2 leading to the formation of new stereoisomeric 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione derivatives 3 in excellent yields. The synthesized compounds have been screened for their advanced glycation end (AGE) product formation inhibitory activity on the basis of their ability to inhibit the formation of AGEs in the bovine serum albumin (BSA)-glucose assay. All the synthesized compounds have been found to exhibit significant activity against AGE formation.