Averrhoa carambola L. is reported for its anti-obese and anti-diabetic activities. The present study aimed to investigate its aqueous methanol leaf extract (CLL) in vivo anti-obese activity along with the isolation and identification of bioactive compounds and their in vitro α-glucosidase inhibition assessment. CLL improved all obesity complications and exhibited significant activity in an obese rat model. Fourteen compounds, including four flavone glycosides (1–4) and ten dihydrochalcone glycosides (5–12), were isolated and identified using spectroscopic techniques. New compounds identified in planta included (1) apigenin 6-C--7-O-β-D-quinovopyranoside, (8) phloretin 3′-C-(2-O-(E)-cinnamoyl-3-O-β-D-fucopyranosyl-4-O-acetyl)-β-D-fucopyranosyl-6′-O-β-D fucopyranosyl-(1/2)-α-L arabinofuranoside, (11a) phloretin3′-C-(2-O-(E)-p-coumaroyl-3-O-β-D-fucosyl-4-O-acetyl)-β-D-fucosyl-6′-O-(2-O-β-D-fucosyl)-α-L-arabinofuranoside, (11b) phloretin3′-C-(2-O-(Z)-p-coumaroyl-3-O-β-D-fucosyl-4-O-acetyl)-β-D-fucosyl-6′-O-(2-O-β-D-fucosyl)-α-L-arabinofuranoside. Carambolaside M (5), carambolaside Ia (6), carambolaside J (7), carambolaside I (9), carambolaside P (10a), carambolaside O (10b), and carambolaside Q (12), which are reported for the first time from A. carambola L. leaves, whereas luteolin 6-C-α-L-rhamnopyranosyl-(1-2)-β-D-fucopyranoside (2), apigenin 6-C-β-D-galactopyranoside (3), and apigenin 6-C-α-L-rhamnopyranosyl-(1-2)-β-L-fucopyranoside (4) are isolated for the first time from Family. Oxalidaceae. In vitro α-glucosidase inhibitory activity revealed the potential efficacy of flavone glycosides, viz., 1, 2, 3, and 4 as antidiabetic agents. In contrast, dihydrochalcone glycosides (5–11) showed weak activity, except for compound 12, which showed relatively strong activity. The radical shift from malnutrition to overnutrition, as well as the increase in sedentary behaviour, has led to the increasing incidence of obesity, a complex chronic nutritional disorder characterized by an energy expenditure and intake imbalance. With estimates of 2.3 billion overweight individuals and 700 million obese adults, obesity with its comorbidities is considered the fifth-largest cause of death worldwide ,2. InsulMoreover, obesity and associated symptoms are predicted to cost the global economy USD 2 trillion per year nearly as much as smoking, armed conflict, and terrorism . The comLikewise, α-glucosidase inhibitors as typical anti-diabetic medicines reported to possess side effects despite their important function in lowering blood glucose levels . Only thAverrhoa carambola L., commonly known as starfruit, a member of the Oxalidaceae family, indigenous to the tropical southeast, is planted across the tropics for its edible fruit as well as its ornamental traits, and it was recently domesticated in other countries, including Ecuador and Egypt D25 −2.72 ; UV (MeOH) λmax nm (log ε) 225 (2.39), 271 (2.43) and 333 (2.49) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 3 (2.49) ; IR (FTI2.49) ; [α]D25 −2.2 ; UV (MeOH) λmax nm (log ε) 226 (2.23), 272 (2.25) and 329 (2.37) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 9 (2.37) ; Rt from3: Yellowish amorphous powder (MeOH); [α]D25 15.0289 ; UV (MeOH) λmax nm (log ε) 269 (1.33) and 335 (1.3) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 35 (1.3) ; Rt from4: Yellowish amorphous powder (MeOH); [α]D25 1.689 ; UV (MeOH) λmax nm (log ε) 269 (2.73) and 336 (2.75) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 6 (2.75) ; Rt from5: Yellowish amorphous powder (MeOH); [α]D25 +8.9 ; UV (MeOH) λmax nm (log ε) 232 (1.92) and 286 (1.94) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 6 (1.94) ; Rt from6: Yellowish amorphous powder (MeOH); [α]D25 −20.69 ; UV (MeOH) λmax nm (log ε) 228 (0.63) and 284 (0.54) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 4 (0.54) ; Rt from7: Yellowish amorphous powder (MeOH); [α]D25 −66.41 ; UV (MeOH) λmax nm (log ε) 231 (2.53) and 284 (2.58) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 4 (2.58) ; Rt from8: Yellowish amorphous powder (MeOH); [α]D25 −40.39 ; UV (MeOH) λmax nm (log ε) 230 (1.60) and 285 (1.65) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 5 (1.65) ; IR (FTI1.65) ; [α]D25 −31.379 ; UV (MeOH) λmax nm (log ε) 232 (1.99) and 290 (2.03) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 0 (2.03) ; Rt from10: Yellowish amorphous powder (MeOH); [α]D25 −102.778 ; UV (MeOH) λmax nm (log ε) 230 (1.94), 290 (1.99) and 310 (2.05) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 0 (2.05) ; Rt from11: Yellowish amorphous powder (MeOH); [α]D25 −95.42 ; UV (MeOH) λmax nm (log ε) 226 (1.27) and 286 (1.26) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 6 (1.26) ; IR (FTI1.26) ; [α]D25 −112.25 ; λmax nm (log ε) 226 (2.17), 290 (2.21) and 310 (2.19) ; 1H (600 MHz) and 13C (150 MHz) NMR data in CD3OD, see Compound 0 (2.19) ; Rt fromThe assay of α-glucosidase inhibitory activity of compounds was adopted from . Briefly50 values were calculated from plots of log concentration of inhibitor concentration against the percentage inhibition curves, using Microsoft Excel 2016. The data were expressed as mean ± standard deviation (SD) of at least three independent experiments (n = 3).The ICA. carambola leaf extract, in relation to its phenolic composition. To the best of our knowledge, this study presents the first comprehensive attempt to reveal the in vivo anti-obese activity of A. carambola leaf extract, leading to the isolation of new bioactive components. Oral administration of A. carambola leaf extract enhanced all obesity complications, viz., dyslipidemia, hyperglycemia, insulin resistance, and oxidative stress, and exhibited significant anti-obesity activity in obese rats  and 10 dihydrochalcone glycosides (5–12) with two non-separable mixtures, including four newly described compounds, i.e., 1, 8, 11a, and 11b were reported for the first time in the literature. Further, in vitro α-glucosidase inhibitory activity assessment of isolated compounds revealed the strong potency of isolated flavone glycosides, viz., compounds 1, 2, 3, and 4, as α-glucosidase inhibitors, compared to dihydrochalcone glycosides, except for compound 12. These results suggest for the role of flavone glycosides in alleviation of the major obesity comorbidity, i.e., diabetes via α-glucosidase inhibition, and has yet to be confirmed for other action mechanisms. An extended approach utilizing detailed studies on the molecular mechanisms of A. carambola leaf effect should now follow, together with subclinical and clinical trials on leaf crude extract, to be more conclusive, especially considering the known negative impact of its fruit on kidney functions. Moreover, assessment of the isolated phytoconstituents for their anti-obese activity using in vivo model or targeting other enzymes, i.e., lipases, etc., should now follow to correlate for the extract’s potential anti-obesity effect. This study poses A. carambola leaf as a new anti-obesity functional food and adds to its effects aside from its fruit’s more explored uses.Multiple chromatographic approaches of the leaf extract led to the isolation of 14 compounds, including 4 flavone glycosides (


Candida antarctica lipase B-catalyzed hydrolysis of carbocyclic 5–8-membered cis β-amino esters was carried out in green organic media, under solvent-free and ball-milling conditions. In accordance with the high enantioselectivity factor (E > 200) observed in organic media, the preparative-scale resolutions of β-amino esters were performed in tBuOMe at 65 °C. The unreacted β-amino ester enantiomers  and product β-amino acid enantiomers  were obtained with modest to excellent enantiomeric excess (ee) values (ees > 62% and eep > 96%) and in good chemical yields (>25%) in one or two steps. The enantiomers were easily separated by organic solvent/H2O extraction. Taking into consideration that CALB displays S-selective hydrolysis for the cis compounds and the analysis of GC chromatograms, the same enantio-preference for 16 was indicated.The absolute configurations of ethyl 12O), lit. [α]25D =O, lit. [2O) lit.  [α]25D =Candida antarctica), immobilized on acrylic resin such as CSI, cycloalkenes and most of the solvents of the highest analytical grade, and sodium sulfate, anhydrous (a.r.) used as drying agent, were purchased from Sigma Aldrich . 2-Methyl-2-butanol (98%) was from TCI , whereas ethyl acetate, chloroform, and acetone (a.r.) were from Novochem . Diethyl ether (a.r.) was from Molar Chemicals Kft . The ball-milling apparatus was Retsch 400. . Melting points were determined with Hinotek X-4 apparatus  and are uncorrected. The ee values for the unreacted β-amino carboxylic esters and the β-amino acid enantiomers produced were determined by GC equipped with a Chirasil-l-Val column after double derivatization [i) diazomethane [Caution! the derivatization with diazomethane should be performed under a well-ventilated hood] and (ii) acetic anhydride in the presence of 4-dimethylaminopyridine and pyridine . Retention times (min) for 7:  13.887 (antipode: 14.331); for 14:  12.963 (antipode: 12.674); for 8:  16.058 (antipode: 16.316); for 15:  14.563 (antipode: 14.292); . For 9:  40.975 (antipode: 41.865); for 16:  35.641 (antipode: 34.869); for 13:  57.405 (antipode: 59.240); for 17:  49.309 (antipode: 48.819). Optical rotations were measured with a Jasco P 2000 Polarimeter. 1H- and 13C-NMR spectra were recorded on a Bruker Avance  DRX 500 and 125 MHz spectrometer. The HRMS flow injection analysis was performed with Thermo Scientific Q Exactive Plus hybrid quadrupole-Orbitrap  mass spectrometer coupled to a Waters Acquity I-Class UPLCTM . . See .7–9 and 13 was carried out according to methods reported previously (the only exception is the synthesis of β-lactam 6), starting from 50 mmol cycloalkane . The next acylation step was carried out with Ac2O (15 μL) and a mixture of DMAP and pyridine (15 μL) in the same test tube, where the color immediately disappeared. Then the double-derivatized samples were analyzed by GC the lit. . 1H-NMR m/z [M + H]+ calcd for C8H15NO2: 158.11756; found: 158.11753.HRMS (ESI): c 0.20 EtOH)}, the 1H-NMR spectroscopic data were similar to those in the lit. the lit. . 1H-NMR m/z [M + H]+ calcd for C9H17NO2: 172,13321; found: 172.13313.HRMS (ESI): c 0.23 EtOH)}, the 1H-NMR : δ = 4.15 , 3.35–3.42 , 2.58–2.67 , 1.43–1.89 , 1.27 , 13C-NMR : δ = 14.21, 23.58, 24.58, 26.76, 28.41, 36.06, 50.56, 51.87, 60.06, 174.34.Yield: 30%, 0.16 mmol, light brown oil, {[α]m/z [M + H]+ calcd for C10H19NO2: 186.14886; found: 186.14882.HRMS (ESI): c 0.2 EtOH)}, the 1H-NMR spectroscopic data were similar to those in the lit. the lit. . 1H-NMR m/z [M + H]+ calcd for C11H21NO2: 200.16451; found: 200.16458.HRMS (ESI): c 0.20 H2O), lit. O), lit.  [α]25D =the lit. . 1H-NMR m/z [M + H]+ calcd for C6H11NO2: 130.08626; found: 130.08638.HRMS (ESI): c 0.25 H2O), lit. O), lit.  [α]25D =the lit. . 1H-NMR m/z [M + H]+ calcd for C7H13NO2: 144.10191; found: 144.10197.HRMS (ESI): c 0.25 H2O)}, the 1H-NMR : δ = 3.72–3.80 , 3.15–3.24 , 1.52–2.18 , 13C-NMR : δ = 23.2, 24.7, 26.2, 26.4, 30.1, 44.9, 52.8, 177.1.Yield: 32%, 0.20 mmol, light beige crystal, mp. 212–216 °C, {[α]m/z [M + H]+ calcd for C8H15NO2: 158.11757; found: 158.11756.HRMS (ESI): c 0.22 H2O) lit. 2O) lit.  [α]25D =m/z [M + H]+ calcd for C9H17NO2: 172.13321; found: 172.13324.HRMS (ESI): E, preparative-scale resolutions were performed in tBuOMe at 65 °C, resulting in the desired enantiomeric unreacted β-amino esters -7–9, 13, and product β-amino acids -14–17 with high eep values (>96%). Easy separation of the enantiomers could be achieved since the unreacted β-amino esters were soluble in organic solvent and the product β-amino acids in H2O. To the best of our knowledge, the lipase-catalyzed hydrolysis of 7- and 8-membered carbocyclic β-amino esters was described for the first time.Efficient enzymatic strategies have been developed for the enzymatic resolution of 5–8-membered carbocyclic β-amino esters through hydrolysis in green organic media, under solvent-free conditions and using ball milling. In view of the best


Spirulina platensis on barnyardgrass  Beauv.) and Chinese amaranth (Amaranthus tricolor L.). The crude ethyl acetate extract showed the highest inhibitory activity and was subsequently fractionated by column chromatography into 23 fractions based on thin-layer chromatography band pattern similarities. Four concentrations  of each fraction were tested for their allelopathic activity. Fractions E6 and E13 exhibited the most significant inhibitory effects against Chinese amaranth. The constituents of the highly active E6F3-E6F5 fractions determined by GC-MS, chromatography, and spectroscopy included the fatty acids, γ-linolenic acid 15, oleic acid 12, and predominantly palmitic acid 7; minor constituents included 2-ethyl-3-methylmaleimide 9 and C11 norisoprenoids (dihydroactinidiolide 10 and 4-oxo-β-ionone 13). Isolation of E13 fraction by column chromatography revealed four C13 norisoprenoids: 3-hydroxy-β-ionone 17, 3-hydroxy-5α,6α-epoxy-β-ionone 18, 3-hydroxy-5β,6β-epoxy-β-ionone 19, and loliolide 20. Their structures were elucidated by NMR spectroscopy. All six isolated norisoprenoids inhibited seed germination and seedling growth of Chinese amaranth at concentrations of 250–1000 ppm. Allelochemicals from S. platensis could be utilized in the development of novel bioactive herbicides.We determined the allelopathic effects of crude organic  extracts of the cyanobacterial  One major obstacle to improving the world’s agricultural efficiency is weed control. Weeds are simply those plants growing in an undesired location, and they complete with crops for resources, decrease crop yield, and contaminate cropland with their seeds, thereby perpetuating the problem into subsequent growing seasons ,2. PreveMost commonly defined as the direct or indirect effect of one plant on the germination, growth, or development of another plant through the production of chemicals released into the environment, allelopathy has been implicated in the patterning of vegetation and weed growth in agricultural systems and inhibition of crop development ,7. ChemiNostoc 31, exhibited allelopathic activity against cyanobacteria Anabaena 7120 [Gomphosphaeria aponina showed allelopathic potential against the red tide algae Gymnodinium breve but not vice versa [Allelopathic phenomena are routinely recognized in terrestrial plants, but very little is known about allelopathy in marine plants . Howeverena 7120 . Moreovece versa .Spirulina platensis, a photosynthetic cyanobacterium containing many nutrients and exhibiting numerous biological activities, has been the subject of much research, not only for its human nutritional characteristics but also for the development of potential pharmaceuticals [The blue-green algae euticals ,31,32. Weuticals ,34. In tS. platensis revealed that E6 and E13 fractions demonstrated the most significant inhibitory activity [The allelopathic screening bioassay of fractions E1–E23  was subjected to short column chromatography (CC) on silica gel, using a gradient solvent system of n-hexane, n-hexane-EtOAc, EtOAc-MeOH, and MeOH in increasing polar solvent proportion to produce 23 fractions (E1-E23). The fractions were tested for allelopathic activity on Chinese amaranth and barnyardgrass at concentrations of 250–2000 ppm. The most potent active fractions, E6 and E13, were further separated by CC and flash column chromatography (FCC). E6 (1.2 g) was fractionated by CC on silica gel by using a gradient solvent system of n-hexane-EtOAc (95:5) and EtOAc in increasing proportions of the polar solvent to yield seven subfractions (E6F1-E6F7) based on their TLC behavior. The subfractions were tested for allelopathic activity on the two test plant species at concentrations of 125–1000 ppm. E6F3 (255.2 mg) eluted with n-hexane-EtOAc 96:4), E6F4  and E6F5  showed the highest inhibitory activity. The active subfractions E6F3-E6F5 and E13F1-E13F4 were isolated and pure compounds were characterized by chromatographic and spectroscopic techniques. These major compounds were divided into two groups, fatty acids, and norisoprenoids. These results represent the first report of these norisoprenoids from 1–16, 7 (58.71%), palmitoleic acid 8 (12.82%), oleic acid 12 (11.76%), tetradecanoic acid 3 (3.97%), pentadecanoic acid 4 (2.16%), and the minor constituents, dodecanoic acid 1, 9-oxonanoic acid 5, azelaic acid 6, dihydroactinidiolide 10, stearic acid 11, 4-oxo-β-ionone 13, and linoleic acid 14. The most active subfraction, E6F4, consisted of linoleic acid 14 (72.19%), dihydroactinidiolide 10 (8.32%), palmitoleic acid 8 (4.55%), γ-linolenic acid 15 (3.02%), 2-ethyl-3-methylmaleimide 9 (2.90%), 5,8,11-eicosatrienoic acid 16 (2.53%), palmitic acid 7 (2.29%), 4-oxo-β-ionone 13 (2.15%), and the minor constituents, 9-oxonanoic acid 5, steric acid 11, and oleic acid 12. The active subfraction E6F5 consisted of palmitic acid 7 (31.41%), linoleic acid 14 (31.24%), γ-linolenic acid 15 (23.46%), 5,8,11-eicosatrienoic acid 16 (2.80%), oleic acid 12 (3.16%), palmitoleic acid 7 (2.71%), 4-oxo-β-ionone 13 (1.91%), and the minor constituents, neophytadiene, tetradecanoic acid 3, and stearic acid 11. E6F3, E6F4, and E6F5 were eluted using FCC to yield dihydroactinidiolide 10 (9.6 mg) and 4-oxo-β-ionone (13) (7.2 mg). Fifty milligrams each of subfractions E6F3, E6F4, and E6F5 were analyzed and the active compounds were identified by GC-MS as methyl ester derivatives (compounds n-hexane/EtOAc (95:5) and EtOAc to increase the proportions of the polar solvent. The six resulting subfractions were screened for allelopathic activity at concentrations of 125–1000 ppm. E13F2 , E13F3 , and E13F4  exhibited high inhibitory activity. Fifty milligrams of subfraction E13F2, E13F3, and E13F4 were combined and treated by FCC by using silica gel 60. The mixture was eluted by using an n-hexane/EtOAc gradient to obtain four known compounds shown in 17 (27.0 mg), 3-hydroxy-5α,6α-epoxy-β-ionone 18 (7.5 mg), 3-hydroxy-5β,6β-epoxy-β-ionone 19 (6.9 mg), and loliolide 20 (35.0 mg). By comparison of their spectral analyses with those reported in the literature, these compounds were identified as dihydroactinidiolide 10, 4-Oxo-β-ionone 13, 3-Hydroxy-β-ionone 17, 3-Hydroxy-5α, 6α-epoxy-β-ionone 18, 3-Hydroxy-5β, 6β-epoxy-β-ionone 19, and Loliolide 20. The isolated compounds were identified by 1H NMR and 13C NMR as shown below.Fraction E13 (650.0 mg) was re-eluted by CC on silica gel by using Dihydroactinidiolide10, colorless oil, 9.6 mg (0.027% from crude ethyl acetate extract); 1H NMR (CDCl3) 1.22 , 1.27 , 1.22–1.34 , 1.46 , 1.55 , 1.62–1.72 , 1.72–1.77 , 2.24 , 5.64 . 13C NMR (CDCl3), 19.65 (C-3), 24.18 and 29.83 (C-9 and C-10), 24.35 (C-11), 36.50 (C-1), 40.09 (C-4), 41.66 (C-2), 87.26 (C-5), 112.38 (C-7), 171.99 (C-6), 182.51 (C-8) [51 (C-8) . 4-Oxo-β-ionone13, waxy solid, 7.2 mg (0.018% from crude ethyl acetate extract); 1H NMR (CDCl3) 1.19 , 1.80 , 1.89 , 2.35 , 2.54 , 6.19 , 7.24 . 13C NMR (CDCl3), 13.43 (C-13), 27.35 , 27.94 (C-10), 34.21 (C-3), 35.60 (C-1), 37.41 (C-2), 131.14 (C-5), 133.57 (C-8), 140.31 (C-7), 157.16 (C-6), 198.00 (C-9), 198.50 (C-4) [50 (C-4) ,39.3-Hydroxy-β-ionone17, pale yellow oil, 27 mg (0.076% from crude ethyl acetate); 1H NMR (CDCl3) 1.11 , 1.12 , 1.50 , 1.65 , 1.78 , 1.78–1.82 , 2.09 , 2.30 , 2.44 , 3.96–4.06 , 6.12 , 7.21 . 13C NMR (CDCl3) 21.59 (C-13), 27.32 (C-10), 28.58 and 30.09 (C-11 and C-12), 36.92 (C-1), 42.78 (C-4), 48.44 (C-2), 64.54 (C-3), 132.26 (C-5), 132.39 (C-8), 135.66 (C-6), 142.33 (C-7), 198.52 (C-9) [52 (C-9) .3-Hydroxy-5α, 6α-epoxy-β-ionone18, colorless oil, 7.5 mg (0.021% from crude ethyl acetate); 1H NMR (CDCl3) 0.98 , 1.19 , 1.24 , 1.60–1.70 , 1.62–1.67 , 1.65–1.69 , 2.29 , 2.40 , 3.86–3.95 , 6.29 , 7.03 . 13C NMR (CDCl3) 19.87 (C-13), 25.00 (C-12), 28.29 (C-10), 29.35 (C-11), 35.12 (C-1), 40.60 (C-4), 46.68 (C-2), 64.02 (C-3), 67.24 (C-5), 69.49 (C-6), 132.63 (C-8), 142.35 (C-7), 197.38 (C-9) [38 (C-9) .3-Hydroxy-5β, 6β-epoxy-β-ionone19, colorless oil, 6.9 mg (0.020% from crude ethyl acetate); 1H NMR (CDCl3) 1.00 , 1.19 , 1.21 , 1.37 , 1.56–1.64 , 1.56–1.64 , 1.89 , 2.23 , 2.28 , 3.85–3.95 , 6.31 , 6.98 . 13C NMR (CDCl3) 20.98 (C-13), 25.78 (C-12), 26.84 (C-11), 28.49 (C-10), 34.86 (C-1), 38.92 (C-4), 43.51 (C-2), 63.73 (C-3), 66.00 (C-5), 71.00 (C-6), 133.13 (C-8), 141.02 (C-7), 197.21 (C-9) [21 (C-9) ,45.Loliolide20, needle solid  35 mg (0.099% from crude ethyl acetate); 1H NMR (CDCl3) 1.27 , 1.47 , 1.52 , 1.79 , 1.79 , 1.95 , 2.00 , 2.48 , 4.31–4.34 , 5.69 . 13C NMR (CDCl3) 26.50 (C-9), 27.03 (C-11), 30.67 (C-10), 35.98 (C-1), 45.66 (C-4), 47.33 (C-2), 66.67 (C-3), 86.92 (C-5), 112.79 (C-7), 172.08 (C-6), 182.79 (C-8) [79 (C-8) ,47,48.7, 11, 12, 14, and 15 were selected to represent primary natural fatty acids from S. platensis. Isolated norisoprenoids 10, 13, and 17–20 were tested for allelopathic activity at concentrations of 62.5–1000 ppm . These compounds were identified as essential fatty acids (linoleic acid 14 and α–linolenic acid) and phenolic compounds. The two fatty acids were the predominant components in the active fractions, comprising more than 80% of the total isolated material and these fractions inhibited the germination of lettuce seeds by 80–90% [Eichhornia crassipes root extract on the cyanobacterial, Chlorella sp., and Scendesmus obliquus, Jin and coworkers [9:0). This fraction reduced chlorophyll-a up to 95.3% in the target species. Rice husks were also observed to exert allelopathic effects, specifically on barnyardgrass, the most potent inhibitory effect was caused by a fraction composed of 9-octadecenoic acid, 7-octadecenoic acid, 5,8,11-heptadecatriecenoic acid, and androstan-17-one. This fraction completely inhibited seed germination of barnyardgrass at a concentration of 200 ppm and demonstrated a minimum inhibition concentration (MIC) of 50 ppm [Ulva fascica, and isolated three active compounds, the polyunsaturated fatty acids, hexadec-4,7,10,13-tetraenoic acid, octadeca-6,9,12,15-tetraenoic acid, and α-linolenic acid. These polyunsaturated fatty acids showed potent algicidal activity against red-tide phytoplankton Heterosigma akshiwo . Phytotoxic substances have also been identified from the early growth of barnyardgrass root exudates by Xuan and coworkers [10:0), myristic acid and stearic acid 11. At a concentration of 100 ppm, these three fatty acids showed approximately 4–20% allelopathic activity against barnyardgrass seed germination and seedling growth. In 1984, Spruell [18 fatty acids against several algae and zooplankton species. He found that the three acids, γ-linolenic acid 15, linoleic acid 14, and oleic acid 12, reduced the growth of Haematoccus lacustris, Synechococcus leopolienesis, and Botrydiopsis alpine by 50% at concentrations below 7 ppm. Fatty acids have long been explored for their allelopathic effects. In one of the earliest studies, in 1985 Browers and coworkers  isolatedoworkers  identifif 50 ppm . Alamsjaf 50 ppm  studied oworkers . They fo Spruell  studied S. platensis demonstrated a higher inhibitory effect on Chinese amaranth and barnyardgrass than saturated fatty acids. These results are consistent with previous research that reported the allelopathic activities of fatty acids depend on (i) the length of the carbon chain, (ii) the number of unsaturated linkages, and (iii) the positions of any double bonds. For examples, Kakisawa and coworkers [Heterosigma akashiwo. They found that arachidonic acid, and EPA exhibited similar activity to ODTA. The sodium salt of ODTA was as effective an allelopathic compound as free ODTA. More saturated fatty acids exhibited less activity. The ester of unsaturated fatty acids also exhibited more worthless activities than the corresponding free acids. Sodium lauryl benzenesulfonate and Tween 80 showed inhibitory activity to a lesser degree. Aliotta and coworkers [Typha latifolia L. that consisted of three steroids and three fatty acids . They found that the fatty acid most effective in inhibiting algae growth was α-linolenic acid. Murakami and coworkers [Phormidium tenue in its own culture. The active fraction (MIC 0.5 ppm) was a mixture of methyl myristate, methyl palmitate, methyl palmitoleate, methyl oleate, methyl cis-vaccenate, methyl linoleate, and methyl linolenate in a ratio of 5:4:5:4:1:47:36. They also examined the allelopathic effect of authentic fatty acids and found that unsaturated fatty acids such as palmitoleic acid 8, oleic acid 12, and cis-vaccenic acid were inhibitory at 2.5, 1.0, and 5.0 ppm, respectively. The more unsaturated fatty acids, linoleic acid 14 and γ-linolenic acid 15, demonstrated the highest inhibitory activity at 0.5 ppm, while saturated fatty acids were inactive even at 100 ppm. Suzuki and coworkers [Z, 8Z, 11Z, 14Z, 17Z)-eicosapentaenoic acid  and four commercially available unsaturated fatty acids, 5,8,11,14-eicosatetraenoic acid (arachidic acid), 8,11,14-eicosatrienoic acid (dihomo-γ-linolenic acid), 6,9,12,15-octadecatetraenoic acid and γ-linolenic acid 15 on Monostroma oxyspermum. The MICs of the polar acids were all 1 µg/mL, except 8,11,14-eicosatrienoic acid (10 µg/mL) and palmitic acid 8 inactive. Alamsjah and coworkers [14, isolated from Ulva fasciata and H. akashiwo. The lethal concentrations (LC50) of these two acids were 0.58 and 1.91 µg/mL. They then suggested that α-linolenic acid had higher toxicity than linoleic acid 14 due to a feature of α-linolenic acid’s chemical structure, such as the number of unsaturated double bonds.The authors found that unsaturated fatty acids extracted from oworkers  studied oworkers  isolatedoworkers  studied oworkers  studied oworkers  determinMyriophyllum spicatum on Microcystis aerugimosa. The active fractions contained the polyphenols, gallic acid, pyrogallic acid, ellagic acid, and (+)-catechin, and the fatty acids, nonanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid 11, 6-cis-octadecenoic acid, and 9-cis-octadecenoic acid. Pure nonanoic acid demonstrated the most potent inhibitory effect , 1.6 mg/L (9-cis-octadecenoic acid), 1 mg/L , 0.7 mg/L , 5.1 mg/L (ellagic acid) and 5.5 mg/L ((+)-catechin), all significantly demonstrating inhibition of M. aeruginosa growth. In contrast, tetradecanoic acid, hexadecanoic acid, and octadecanoic acid did not show any effect at 10 mg/L. Nonanoic acid’s total inhibitory effect on M. spicatum culture was unexpected because the apparent concentration of nonanoic acid in the M. spicatum culture solution was 50 µg/L, much lower than the EC50. They suggested that because polyphenols and fatty acids have different chemical properties, resulting in further growth inhibition modes, it is reasonable to expect that their cyanobacterial growth inhibition activities may be additive or synergistic. In addition, the inhibitory effect of 9-cis-octadecenoic acid was more potent than 6-cis-octadecenoic. Among the four saturated fatty acids identified, nonanoic acid, with the shortest carbon chain, was the only one that demonstrated significant growth inhibition of M. aeruginosa at 0.5 mg/L.Nakai and coworkers  studied R-(−)-3-hydroxy-β-ionone from Phaseolus vulgaris and found that this compound inhibited the hypocotyl growth of lettuce seedlings and hypocotyls segments of dwarf bean seedlings at concentrations greater than 0.3 µM. Macías and coworkers [Hordeum vulgare and Allium cepa). Moreover, Macías and coworkers [Melilotus messanensis on tomato (Lycopersicum esculentum) and barley (Hordeum vugare). They found that both loliolide 20 and isololiolide inhibited the germination of tomatoes and promoted the germination of barley. D’Abrosca and coworkers [13 norisoprenoids from the leaves of Cestrum parqui (Solanaceae). All compounds were tested for allelopathic activity on seed germination and Lactuca sativa L seedling growth. Except for the C13 norisoprenoid, the compounds did not affect germination. However, they moderately inhibited lettuce root and shoot growth. Xian and coworkers [Vallisneria spiralis Linn on M. aeruginosa Kütz. Analysis of the two active subfractions (extracted with chloroform), by high-resolution GC-MS, revealed that one subfraction consisted of 2-ethyl-3-methylmaleimide (77.10%), dihydroactinidiolide 10 (18.90%), and 4-oxo-β-ionone 13 (4.00%). The second subfraction consisted of 3-hydroxy-5,6-epoxy-β-ionone (38.30%), loliolide 20 (10.10%), 6-hydroxy-3-oxo-α-ionone (44.50%), and unknown . The allelopathic effects of norisoprenoids, particularly dihydroactinidiolide 10, were first reported by Stevens and Merrill ; this cooworkers  isolatedoworkers  examinedoworkers  isolatedoworkers  studied S. platensis against the tested plants in this study were consistent with that observation. Notably, barnyardgrass demonstrated a strong resistance against phytotoxins released by plants other than paddy weeds [10, and 4-oxo-β-ionone 13, dihydroactinidiolide 10 showed the highest activity. These compounds exhibited activity similar to subfraction E6F4, but the primary fatty acids such as linoleic acid 14, showed relatively lower activity. This may be due to the synergy of all compound mixtures of fatty acids, fatty acids and 2-ethyl-3-methylmalaimide 9 fatty acids and 4-oxo-β-ionone 13 or fatty acids and dihydroactinidiolide 10 because the synergy between aromatic compounds and dihydroactinidiolide 10 or aromatic compounds and fatty acids have already been reported [It has been reported that subfractions and isolated pure compounds exhibited significant inhibitory effects on the tested plant seeds and roots more than shoots because roots were in direct contact with inhibitors . At a hidy weeds . In the reported ,68,69.1H and 13C NMR spectra were provided by a Bruker AVANCE 300 NMR spectrometer , operating at 300 MHz and 75.5 MHz, respectively. FCC and quick column chromatography (QCC) were conducted by using Merck silica gel 60 (<0.063 mm) and Scharlau GE 0048 silica gel 60 (0.02–0.06 mm), respectively. For TLC, MERCK precoated silica gel 60 F254 plates were used. Spots on TLC were visualized under UV light and sprayed with an anisaldehyde-sulfuric acid reagent, then heated.All solvents used in this study were available from Italmar Co., Ltd. . All commercial fatty acids were purchased from Sigma-Aldrich (Singapore). The structure and purity of all identified compounds were confirmed by FT-NMR, and GC-MS analyses. S. platensis was obtained from the Department of Fisheries, School of Agricultural Technology, King Mongkut’s Institute of Technology Ladkrabang. Algal cultures were grown in Zarrouk medium [2 atmosphere at 25 °C and pH 10.5. The cultivated flasks were illuminated under 400 μmol m−2 s−1 light intensity. Cells were harvested at the late exponential phase by centrifugation and dried in an oven at 40 °C. The dried S. platensis (4.0 kg) were extracted successively by using n-hexane treatment for seven days at room temperature. The extract was then filtered through a Whatman No. 1 paper. The collected filtrate was evaporated to dryness under reduced pressure at 40 °C by using a rotary evaporator to yield crude n-hexane extract (25.9 g). The residue was then similarly extracted with ethyl acetate (EtOAc) or methanol (MeOH) to produce crude ethyl acetate (125.9 g) and methanol (795.6 g) extracts, respectively.Dried k medium  and main2SO4 in MeOH (20 mL), and the resulting solution was stirred at room temperature for 30 min. The mixture was heated until reflux at 80 °C for 2 h, and the reaction was completed by TLC. The mixture was cooled to room temperature, and excess methanol was removed under reduced pressure. The crude product was dissolved with ethyl acetate (20 mL) and washed with 0.5 M NaHCO3 (2 × 40 mL), then brine (10 mL). The product was dried (Na2SO4), filtered through Whatman No. 1 filter paper, and evaporated to dryness under reduced pressure to yield the fatty acid methyl ester products. These products were prepared to a concentration of 1500 ppm in ethyl acetate before GC-MS analysis. Subfractions, E6F3-E6F5, (30 mg) were methylated with 2% HThe GC-MS analyses were performed on an Agilent 6890 GC  equipped with a flame ionization detector. The automated split injection was executed by using an Agilent 7683 autosampler . The total run time of the active fractions was 30 min. The GC oven temperature program was as follows: 50 °C hold for 1 min, 25 °C/min increase to 230 °C, and 13 min hold. Fatty acid methyl esters (FAMEs) and other compounds were identified by comparing the retention time of the integrated peak of a specific FAME with those of authentic standard FAMEs and the databank of the Wiley 7N Edition (Agilent Part No. G1035B). The height of less than 1% is not qualified, and the mass range was scanned from 50 to 500 a.m.u.Amaranthus tricolor L.) seeds were purchased from the Thai Seed & Agriculture Co., Ltd.,  and barnyardgrass  Beauv.) seeds were randomly collected from rice fields in Phitsanulok province, Thailand in August 2019. The germination rate of the test seeds was >80%.Chinese amaranth  lined with germination paper and evaporated to dryness for 3 h at room temperature. After evaporation, 0.5 mL of distilled water was added to the germination paper to yield the final concentrations at 1000, 500, 250, and 125 ppm. Then ten seeds of tested plants were placed on the germination paper as per treatments. The control received only distilled water. The treatments were replicated four times in a completely randomized design. All vials were sealed with Parafilm® and maintained at 28–32 °C. After seven days, germination (%), shoot, and root growth were recorded for all treatments. Inhibition (%) relative to control was calculated as follows :InhibitiS. platensis showed the highest inhibitory activity in this study. Purification and identification of the crude extract revealed that the major active compound was linoleic acid 14. In addition to fatty acids, the extract also contained nonfatty acids which can play an allelochemical role, including 2-ethyl-3-methylmaleimide 9 and six norisoprenoids: dihydroactionidiolide 10, 4-oxo-β-ionone 13, 3-hydroxy-β-ionone 17, 3-hydroxy-5α,6α-epoxy-β-ionone 18, 3-hydroxy-5β,6β-epoxy-β-ionone 19, and loliolide 20 all potent at low concentrations. Isolation of these nonfatty acid compounds from S. platensis is reported here for the first time. Our data confirm that S. platensis has allelopathic potential against the dicotyledon, Chinese amaranth, more than the monocotyledon, barnyardgrass. The results indicated that the inhibitory activity depended on the specific extract fraction and applied concentrations. The most robust compound was dihydroactinidiolide 10. Allelochemicals from S. platensis could be developed into novel bioactive herbicides.The crude ethyl acetate extract from the cyanobacteria


All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition  was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a–e and 7a–e were evaluated. Compounds 4a–e and 7a–e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones  Over the past few decades, quinolones have transformed from a small and insignificant class of drugs primarily utilized for treating mild urinary tract infections to some of the most prescribed antibacterials globally ,2,3,4. A®), an EGFR-TK inhibitor . Co. CoVI’s Hybridization has emerged as a promising strategy in developing new drugs with the potential to overcome cross-resistance and improve affinity and efficacy compared with the parent drugs ,30. CombScaffold A (4a–e), which represents Syn-like-quinoline derivatives, and Scaffold B, which represents Anti-like-quinoline derivatives 7a–e, Motivated by the facts presented here, we present the synthesis of a small set of quinoline-1,2,3-triazole hybrids that will be evaluated for antiproliferative activity. The newly synthesized compounds consist of two scaffolds: 4a–e and 7a–e will be investigated using four cancer cell lines: A549 , MCF-7 (breast cancer cell line), Panc-1 (pancreas cancer cell line), and HT-29 (colon cancer cell line). The most effective antiproliferative agents will be examined further for their potential inhibitory activity against EGFR as a target for their mechanistic action. Furthermore, the most potent derivatives will be tested for their ability to trigger apoptosis against caspases 3, 8, and 9, cytochrome c, Bax, and the anti-apoptotic Bcl2.The antiproliferative activity of compounds 4a–e and 7a–e via the cycloaddition reaction of the obtained 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2)  -one)] .36H28N8O6 and molecular weight (m/z = 668). The 1H NMR spectrum for compound 4c showed six-singlet signals at δH = 12.20 (2H), 9.03 (2H), 6.94 (2H), 6.90 (2H), 5.51 (4H), and 3.67 (6H) ppm., which are assigned as quinolinone-NH, H-5, H-10, H-8, H-4a (-O-CH2), and H-11a (OCH3) groups, respectively. Further, the methoxy protons H-11a are distinctive at δH 3.67 ppm; HMBC and HSQC correlation with the carbon appears at δC 55.33 ppm, which is assigned as C-11a, and other HMBC correlations with the non-protonated carbon appear at δC 154.51 ppm, which is assigned as C-11. The protons H-4a and H-5 also give HMBC correlation with the nitrogen at δN 247.6, assigned as N-1. The other sp3 nitrogen, at δN 151.3, gives only HSQC correlation with H-6; this nitrogen is assigned as N-6. Additionally, the carbon at δC 126.03 ppm gives three HMBC correlations with the protons appearing at δH 7.85 , 7.45 , and 7.30 , ppm.; this carbon is assigned as C-4a’ and the signals were assigned as H-4′, H-3′ and H-2′, respectively. Furthermore, the carbon appeared at δC 125.47 ppm, giving one HSQC correlation with the proton at δH 7.45 and another HMBC correlation with the protons appearing at δH 7.85 and 7.30 ppm., and was assigned as C-3′.Elemental analysis and mass spectrometry agreed with its general formula C3a–e with highly symmetrical di-o-propargylated compound 6, obtained by propargylation of 1,5-dinaphthol (5), was promoted under an above similar condition, resulting in 76–84% yield of the corresponding symmetrical bis-quinolinone triazole-based anti-like targets 7a–e  were confirmed using different spectral data such as 1H NMR, 13C NMR, 2D-NMR spectrum, as well as mass spectrometry. For example, it exhibited a molecular formula of C16H12O2, which was compatible with its m/z = 236. Through the different data, we found that compound 6 fits perfectly with the previous compound 2 with a slight difference in the chemical shift’s values in its 1H NMR spectrum, and it also contains eight lines in this 13C NMR spectrum, while the previous compound 2 contains nine lines in this 13C NMR spectrum naphthalene (spectrum . In the H)-ones 7a–e was also confirmed on the bases of different spectral data. For example, we choose compound 7e which was assigned as  -one)] .7e which was assigned as . Elemental analysis and all spectral data were acceptable with this proposed structure with chemical formula C36H28N8O4 (m/z = 636). Through the interpretation of the various analyses that were conducted for compound 7e and all the previous compounds, it is undoubtedly clear that the proposed chemical composition is correct, and also, to prove the composition in another way, it was compared with spectral data for its analogous compound 4e (2) with 4-azido-1-methyl-1H-quinolin-2-one (3e). Additionally, the spectra are consistent with structure 7e but are very similar to those observed for sample 4e, for which 4e was assigned. The spectroscopic difference between these products is that, in 4e, C-4a’ and C-8a’ are nonequivalent, while in 7e, these two carbons are equivalent. However, in both compounds 4e and 2, C-8a’ was assigned as co-resonant with another carbon which could not be observed separately. Therefore, we suspect that the correct structure for both products is 4e; see To confirm our results, we choose compound pound 4e . This is4a–e and 7a–e can be rationalized as, upon mixing (1 mmol) of terminal alkynes 2 and/or 6 with Cu(1), the salt of compound 8 would form. On the addition of (2 mmol) of azides 3a–e dissolved in DMF, a nucleophilic addition takes place to give the adduct 9, which undergoes nucleophilic attack to the N-negative charged on triple bond to give the adduct 10, which then further accepts H+ and forms the intermediate 11, which then reacts with Cu(1) to give the final products 4a–e and 7a–e via further repeating the above steps as shown in The mechanism for the obtained products 4a–e and 7a–e on normal cell lines. In this investigation, a concentration of 50 µM of the studied compound is employed for four days, after which cell viability is assessed. The results showed that compounds 4a–e and 7a–e have no toxic effect and have more than 86% cell viability, as shown in A cell viability test was performed using MCF-10A  cell line ,42,43 to50 of each compound.The newly synthesized compounds were tested for antiproliferative activity against four different types of cancer cells ,45: A-544a–e and 7a–e displayed significant antiproliferative activity, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib with a GI50 of 33 nM against the four tested cancer cell lines. Three compounds with the highest antiproliferative activity were identified: 4a and 4b with a Syn quinoline backbone structure (Scaffold A), and 7d with an Anti-quinoline backbone structure (Scaffold B), with GI50 values ranging from 34 nM to 54 nM.Generally, the newly evaluated compounds 4a (R1 = R2 = R3 = H) was the most potent synthetic derivative, with a mean GI50 of 34 nM compared to the reference erlotinib’s GI50 of 33 nM. Compound 4a inhibited the MCF-7 (breast cancer) cell line more effectively than erlotinib, with an IC50 of 33 nM versus 40 nM. The antiproliferative effects of compounds 4e  and compound 7e , which have GI50 of 130 and 134 nM and are approximately 4-fold less potent than 4a, were greatly diminished when the free NH group in compound 4a was replaced with a methyl group. This finding highlights the significance of the free amino group at position-1 of the quinoline moiety for the antiproliferative action. Compound 4b  ranks second in efficacy against the cancer cell lines tested, with a GI50 of 45 nM, which is 1.4-fold less potent than erlotinib (GI50 = 33 nM). Compound 7b  shares the same substitution pattern as compound 4b, but was found to be 1.4 times less potent due to its anti-quinoline backbone structure. This finding emphasizes the impact of stereochemistry in the action of this class of organic compounds, with the syn derivatives being more active than the anti-derivatives. The same pattern becomes apparent when 4a (GI50 = 34 nM) and 7a (GI50 = 130 nM) are compared.Compound 50 of the 6-methyl quinoline derivative 4b  was found to be 1.8-fold more potent than that of the 6-methoxy derivative 4c , indicating that the methyl group was better tolerated than the methoxy group. Finally, 8-methyl quinoline derivative 4d  was found to be at least twofold less potent than that of the 6-methyl derivative 4b , demonstrating that the 6-position on the quinoline moiety was more tolerated than the 8-position.The nature and position of the substitution on the quinoline moiety were also studied. The GI4a, 4b, and 7d, the most potent derivatives as antiproliferative agents, were tested for their efficiency as EGFR inhibitors  cycloadditions, it was possible to link two quinolinone moieties to the naphthalene skeleton. Remarkably, this cycloaddition occurred, and all products obtained were hitherto unknown. Pharmacological screening of novel products showed interesting and promising results as EGFR inhibitors with potential apoptotic antiproliferative action.In conclusion, a straightforward way to tether different quinolinones derivatives to 1,5-dinaphthol and 1,8-dinaphthol via 1,2,3-triazole linkers was elaborated based on Cu-catalyzed [3 + 2] cycloaddition of General Details: See H)-ones 3a–e, naphthalene-1,8-diol (1) and naphthalene-1,5-diol (5) (Aldrich) were used as received. The 1,8-Bis(prop-2-yn-1-yloxy)naphthalene (2) and 1,5-bis(prop-2-yn-1-yloxy)naphthalene (6) were synthesized according to the literature.The materials 4-Azido-2-quinoline-(12) or 1,5-bis(prop-2-yn-1-yloxy)-naphthalene (6) (1.1 mmol) in 20 mL DMF, CuSO4.5H2O (0.4 mmol) and (0.4 mmol) of sodium ascorbate was stirred for 10 min at room temperature. To the above mixture, 4-azido compounds 3a–e (1.0 mmol) in 20 mL DMF were added dropwise. The reaction mixture was stirred at 50 °C for 24 h. After 14 hr, another portion of sodium ascorbate (0.4 mmol) was added to the reaction mixture to prevent the reversible process for Cu (+1). The reaction mixtures were monitored with TLC. After completion, the mixture was diluted with 100 gm ice, and the formed precipitate was filtered off and washed four times with cold water to give compounds 4a–e and 7a–e in excellent yields.A mixture of 1,8-bis(prop-2-yn-1-yloxy)naphthalene naphthalene (2) m.p 190–192 °C . H-1,2,3-triazole-4,1-diyl))-bis-(quinolin-2(1H)-one)] (4a) (4b). (4c) (4d) (4e). This compound was obtained as colorless powder (79%), m.p > 360 °C. NMR (DMSO-d6) . Anl. Calcd. for C36H28N8O4: C, 67.91; H, 4.43; N, 17.60; Found: C, 67.88; H, 4.55; N, 17.79.-d6) See  m/z = 631,5-Bis(prop-2-yn-1-yloxy)naphthalene (6). This compound was obtained as colorless powder (90%), m.p 150–152 °C. 1H NMR (DMSO-d6): δH = 7.75 , 7.44 , 7.10 , 5.01 , 3.34 , 13C NMR (DMSO-d6): δC = 152.55 (C-1), 125.97 (C-4a), 125.43 (C-3), 114.23 (C-4), 106.74 (C-2), 79.12 (C-1b), 78.38 (C-1c), 55.99 (-OCH2). M/z = 236 . Anl. Calcd. for C16H12O2: C, 81.34; H, 5.12; Found: C, 81.44; H, 4.97.H-1,2,3-triazole-4,1-diyl))-bis-(quinolin-2(1H)-one)] (7a) (7b). This compound was obtained as colorless powder (73%), m.p > 360 °C. 1H NMR (DMSO-d6): δH = 12.22 , 8.96 , 7.96 , 7.85 , 7.51–7.26 , 6.86 , 5.50 , 2.09 ppm . m/z = 636 . Anl. Calcd. for C36H28N8O4: C, 67.91; H, 4.43; N, 17.60; Found: C, 67.83; H, 4.38; N, 17.78. (7c). This compound was obtained as colorless powder (78%), m.p > 360 °C. 1H NMR (DMSO-d6): δH = 12.19 , 9.02 , 7.84 , 7.45 , 7.31 , 6.94 , 7.30 , 6.94 , 6.70 , 5.51 , 3.32 ppm , 13C NMR (DMSO-d6): δC = 160.52 (C-7), 154.51 (C-11), 153.32 (C-1′), 143.55 (C-4), 143.11 (C-9), 134.09 (C-13a), 126.35 (C-5), 126.03 (C-4a’), 125.47 (C-3′), 121.07 (C-12), 118.05 (C-8), 117.44 (C-13), 114.88 , 114.44 (C-8a’), 106.69 (C-2′), 105.49 (C-10), 61.62 (C-4a), 55.33 ppm (C-11a), 15N NMR (DMSO-d6): δN = 151.4 ppm (N-6). N-1, N-2 and N-3 n/o. m/z = 668 . Anl. Calcd. for C36H28N8O6: C, 64.66; H, 4.22; N, 16.76; Found: C, 64.79; H, 4.18; N, 16.59.H-1,2,3-triazole-4,1-diyl))-bis-(8-methylquinolin-2(1H)-one)] (7d). (7e). This compound was obtained as colorless powder (74%), m.p > 360 °C. 1H NMR (DMSO-d6) . Anl. Calcd. for C36H28N8O4: C, 67.91; H, 4.43; N, 17.60; Found: C, 67.78; H, 4.39; N, 17.74.-d6) See . m/z = 6® software within EGFR protein crystal structure with erlotinib as a co-crystallized ligand (PDB ID: 1M17). Docking protocol and other experimental details were used exactly as reported elsewhere [Molecular docking simulations were performed using MOElsewhere ,53,54. S


S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2--3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2--3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2--3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2--acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2--acrylonitrile, -2--3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, -2--3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2--3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2--acrylonitrile 32 μg/mL against Staphylococcus aureus.Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against  The recent report detailing bacterial isolates resistant to polymyxin removes the last effective class of antibiotics against multi-drug resistant (MDR) bacteria . With thCurrently most of the antibiotic development is focused on improvements to existing antibiotics. This lack of structural novelty progressing to the clinic positions generational compound development as a critical strategy for the near future, but it is not known if this approach is sustainable or can addresses the growing problem of antibiotic resistance. Governments are starting to react through initiatives such as the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) initiative, but a significant number of pharmaceutical companies are no longer pursuing antibiotic development ,11,12. DStaphylococcus aureus (MRSA), E. coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa; and the yeasts Candida albicans and Cryptococcus neoformans. We rationalized that the ease of synthetic access and further modification to amino alcohols, a class of compounds that spans the amphenicol and key macrolide antibiotics, positioned these compounds as logical development leads imidazole carboxaldehyde (3r); and nitro-benzaldehydes (3s–w) and amino-benzaldehydes    21]. Th. ThLibraLibrary B analogues at the initial screening concentration (32 μg/mL) with 2-bromopyrrole 1o showing 37% inhibition of C. albicans growth; 2,3-dibromopyrrole 1p 32% inhibition of S. aureus growth; 1H-benzo[d]imidazole (1r), 27% inhibition of P. aeruginosa growth. With the 2,6-dichlorophenylacrylonitrile (2b) based 3′-nitrophenyl (1u), 26% inhibition of C. neoformans growth; the 2,6-dichloro-3-nitrophenylacetonitrile (2c) based 2′-nitrophenyl (1s) 29% inhibition of C. neoformans growth. The corresponding diamino analogue to (1v), compound (1y), demonstrated the best activity of any in Library B, exhibiting 48% inhibition against A. baumannii growth. These data support retention of a nitrogen substituent, with the enhanced activity possibly due to electronic effects. The activity increases were limited, and with this in mind we revisited Library A where the most active analogues suggested a preference for a 4-substituted aromatic moiety. As amino alcohol containing macrolides are known to have antibiotic properties, we rationalized that introducing such a moiety might confer enhanced activity to our lead compounds described above . Su. Su4) waines see .Library C retained the 3,4-dichlorophenylacetonitrile (2a), with the introduction of simple anilines via epoxide ring opening of 6  saw introduction of simple cyclic aliphatic and small heterocyclic rings. This minor modification had a major effect on the degree and number of active compounds  55% inhibition of S. aureus; piperidine (8g) 67 and 50% inhibition of S. aureus and C. albicans growth, respectively.ompounds . Screeni8h), (8i) and racemic (8g) where prepared. Both (8h) and (8i) returned essentially identical inhibition of S. aureus at 92 and 90% inhibition, respectively, suggesting no stereochemical preference for the -OH moiety. However, racemic (8g) displayed 20% lower S. aureus at 67% inhibition.The introduction of the amino alcohol moiety also introduced a stereocenter with the added -OH moiety. To examine the effect of the two possible stereoisomers, optically pure  retained 90% inhibition of S. aureus growth. The piperazine acetamide (8k) and morpholino (8l), lost antibiotic activity but showed 53% and 35% growth inhibition of C. albicans, respectively. These latter compounds suggest that the presence of polar moieties on the heterocyclic ring are detrimental to antibiotic activity but may be favourable for fungal activity.With other Library E extended the substituents of these rings through the addition of a terminal aromatic moiety. The inclusion of the additional aromatic moiety saw modest activity, at the initial 32 μg/mL screening concentration, with acetophenone (8u) inhibiting P. aeruginosa growth (28%); 4-bromophenyl (8r) inhibited K. pneumoniae (28%); 4-(p-tolyl)piperazine (8p) inhibited C. neoformans (96%); and 4-methylpiperazinylphenol (8s) inhibited the C. albicans (65%) and C. neoformans (97%) fungal lines.Having established the preferential installation of small cyclic aliphatics and heterocyclic moieties, Having completed the initial screening of these focused libraries at 32 μg/mL, analogues showing >85% activity against at least one of the bacteria or fungi lines proceeded to full minimum inhibitory concentration (MIC) determination by broth micro-dilution dose response assay. These data are presented in 8e), (8h), (8i) and (8j) were all confirmed to be active with an MIC of 32 μg/mL against S. aureus, which is equipotent with the clinically used colistin, but less active than amoxicillin. These analogues did not show broad-spectrum antimicrobial activity with no activity at the highest tested concentration against the four Gram-negative strains, nor against the two yeasts tested. While this is modest, it does support the screening of biologically active scaffolds against alternative targets.As can be seen from the data presented in Library A, 4-NO2 (1e) was more active against P. aeruginosa than the corresponding 2-NO2 (1c) and 3-NO2 (1d). Modification of the 4-NO2 moiety to 4-NH2 with (1f) saw a loss of P. aeruginosa activity, but modest activity against A. baumannii. This was the sole aniline analogue to display activity. Incorporation of the N,N-dimethylamino moiety (1g) resulted in a slight potency reduction, whereas nitro-vanillin (1m) showed no antibiotic activity, but modest effects against C. albicans. Caution is required in ascribing definitive SAR outcomes in these series as they involve analysis of a single datapoint.Within the pool of 3,4-dichlorophenyl analogues, Library A analogues. Excepting 3′-amino (1y), with modest activity against A. baumannii. However, within this Library general trends were evident, with the di-Br (1p) the most active against S. aureus; mono-Br (1o) against C. albicans and benzimidazole (1r) against P. aeruginosa.Modification of either the parent phenylacrylonitrile via the 2,6-dichloro or 2,6-dichloro-3-nitro or 2,6-dichloro-3-amino phenylacrylonitrile or parent aldehyde with pyrrole, imidazole and nitrophenyl substituents all displayed lower levels of activity than Library C showed essentially no activity. The use of cyclic and heterocyclic amines in the oxiraine aminolysis step, gave analogues 8e–8l. This removal of the terminal aromatic moiety was rewarded with a significant increase in antibiotic activity, especially against S. aureus . Individual enantiomers (8h) and (8i) were equipotent (>90%), yet the racemate (8g) showed only partial inhibition of MRSA at 32 μg/mL (67%), supporting a negative cooperability of these isomers. This stereochemical preference will be examined and reported on in a future study. Alternatively, as the deuterated racemate (8j) showed the same activity as the pure isomers (8h) and (8i), incorporation of such moieties may negate the need to isolate single pure stereoisomers. This supported further development of this series with the introduction of an aromatic moiety appended to a saturated six-membered ring . Incorporation of polar moieties in the terminus of the heterocyclic, viz N-Ac (8k) and morpholino (18l), were detrimental to S. aureus activity, but these analogues showed modest activity against C. albicans.The development of analogues with the inclusion of the β-aminoalcohol moiety, while retaining the 3,4-dichlorophenyl moiety was readily accomplished in a series of simple flow chemistry mediated steps. However, the retention of the terminal aromatic moieties with Library E switching the ether linker position from 4- (8o) to 3- (8n) and 2- (8m) was detrimental to activity. These analogues were essentially devoid of antibacterial activity. The switch to antifungal activity was unexpected, but combined with the observed antibiotic activity strongly supports the on-going development of this class of compounds as novel antibacterial/antifungal agents. Of the analogues with antifungal activity, the piperidine  is more prevalent than piperazine (8p). This is fortuitous as phenylpiperazines are known to form highly reactive iminoquinone moieties  capable of reacting with glutathione ; HRMS: Exact mass calculated for C13H13Cl2N2O2 [M+H], 331.0339.The desired product (((Z)-3-(2-aminophenyl)-2-acrylonitrile (1f).Z)-2--3-(2-nitrophenyl)acrylonitrile  and iron powder  were combined with a mixture of glacial acetic acid (4 mL), ethanol (4 mL), and water (2 mL) and exposed to ultrasonic irradiation at 30 °C for 7 h. The reaction mixture was diluted with ethanol (30 mL) and filtered through a pad of Celite, before concentration under reduced pressure to afford the desired product as an off-white solid , m.p.: 157–159 °C. 1H NMR : δ 7.92 , 7.77 , 7.73 , 7.70 , 7.60 , 7.56 , 7.26 ; 13C NMR : δ 173.0, 156.5, 148.3, 139.4, 138.5, 133.2, 132.3, 132.0, 132.0, 130.7, 130.1, 128.7, 124.6, 123.7, 123.2; IR υmax/cm−1: 3073 (NH2), 2970 (NH2), 2219 (CN), 821 (C-Cl); LRMS (ESI−) m/z: 288 (C15H9Cl2N2) [M-H]; HRMS: Exact mass calculated for C15H11Cl2N2 [M+H], 289.0924.((Z)-2--3-(4-(oxiran-2-ylmethoxy)phenyl)-acrylonitrile (6) .The desired product -2--3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile (8h).3z, 1.071 g, 8.77 mmol), cesium carbonate  and [S]-(+)-glycidyl-3-nitrobenzene sulfonate  were combined with 30 mL DMF. Heated to 80 °C for 4 h. Reaction was diluted with water (50 mL) and EtOAc (30 mL), washed with water (5 × 30 mL) and brine (30 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). Organic extracts combined, dried over MgSO4 and concentrated under reduced pressure to afford the desired product as a pale brown oil. Yield not calculated and material carried directly through.4-Hydroxybenzaldehyde (S)-4-(oxiran-2-ylmethoxy)benzaldehyde  was combined with 15 mL water and heated to 50 °C for 10 min while stirring. 3,4-Dichlorophenylacetonitrile  was then added and the reaction stirred for a further 10 min. 10 mL Benzyltrimethylammonium hydroxide (40 wt % aq. solution) was added dropwise and the reaction left to stir at 50 °C for 6 h. Filtered under vacuum, washed with water (2 × 10 mL) and recrystallized from ethanol to afford the desired product as a yellow solid .(8h) was then prepared according to general procedure 3 from -2--3-(4-(oxiran-2-ylmethoxy)phenyl)acrylonitrile  and piperidine  to afford the desired compound as a yellow solid , m.p.: 100–102 °C. 1H NMR  δ 8.09 , 8.00 , 7.96 , 7.76 , 7.68 , 7.13 , 4.86 , 4.10–4.07 , 4.00–3.95 , 2.41–2.31 , 1.50–1.47 , 1.37 ; 13C NMR  δ 161.2, 144.3, 134.9, 132.0, 131.5 (2C), 131.2, 131.1, 127.0, 125.76, 125.74, 117.9, 115.1 (2C), 104.3, 71.5, 66.4, 61.7, 54.8 (2C), 25.7 (2C), 24.0; IR υmax/cm−1: 3300 cm−1 (OH), 2933 cm−1 (N-CH2), 2216 cm−1 (CN), 1182 cm−1 (C-O), 813 cm−1 (C-Cl); LRMS: (ESI+) m/z: 431 (C23H25Cl2N2O2) [M+H]; HRMS: Exact mass calculated for C23H25Cl2N2O2 [M+H], 431.1288.The desired product -2--3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile (8i).3z, 0.978 g, 8.00 mmol), cesium carbonate  and [R]-(−)-glycidyl-3-nitrobenzene sulfonate  were combined with 30 mL DMF. Heated to 80 °C for 4 h. Reaction was diluted with water (50 mL) and EtOAc (30 mL), washed with water (5 × 30 mL) and brine (30 mL). Aqueous back-extracted with EtOAc (3 × 30 mL). Organic extracts combined, dried over MgSO4 and concentrated under reduced pressure to afford the desired product as a pale brown oil .4-Hydroxybenzaldehyde (R)-4-(oxiran-2-ylmethoxy)benzaldehyde  was combined with 15 mL water and heated to 50 °C for 10 min while stirring. 3,4-Dichlorophenylacetonitrile  was then added, and the reaction stirred for a further 10 min. 10 mL benzyltrimethylammonium hydroxide (40 wt% aq. solution) was then added dropwise and the reaction left to stir at 50 °C for 6 h. Filtered under vacuum, washed with water (2 × 10 mL) and recrystallized from ethanol to afford the desired product as a yellow solid .(8i) was then prepared according to general procedure 3 from -2--3-(4-(oxiran-2-ylmethoxy)phenyl)acrylonitrile  and piperidine  to afford the desired compound as a yellow solid , m.p.: 101–103 °C. 1H NMR  δ 8.10 , 8.01 , 7.96 , 7.77 , 7.69 , 7.13 , 4.86 , 4.10–4.05 , 4.00–3.95 , 2.41–2.31 , 1.50–1.47 , 1.37 ; 13C NMR  δ 161.2, 144.3, 135.0, 132.0, 131.5 (2C), 131.2, 131.1, 127.0, 125.77, 125.75, 117.9, 115.1 (2C), 104.3, 71.5, 66.4, 61.7, 54.8 (2C), 25.7 (2C), 24.0; IR υmax/cm−1: 3366 cm−1 (OH), 2932 cm−1 (N-CH2), 2211 cm−1 (CN), 1182 cm−1 (C-O), 813 cm−1 (C-Cl); LRMS: (ESI+) m/z: 431 (C23H25Cl2N2O2) [M+H]; HRMS: Exact mass calculated for C23H25Cl2N2O2 [M+H], 431.1288.The desired product ((Z)-2--3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile (8p) ; HRMS: Exact mass calculated for C29H30Cl2N3O2 [M+H], 522.1710. Found 522.1713.Prepared according to general procedure 3 from ((Z)-3-(4-(3-(4-(4-Chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)-2--acrylonitrile (8q) ; HRMS: Exact mass calculated for (C28H27BrCl2N3O2) [M+H], 588.0638. Found 588.0617.Prepared according to general procedure 3 from ((Z)-2--3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile (8s).Z)-2--3-(4-(oxiran-2-ylmethoxy)phenyl)acrylonitrile  and 1-(4-hydroxyphenyl)piperazine . The resultant residue was recrystallised from methanol to afford the desired compound as a brown solid , m.p.: 162–164 °C. 1H NMR  δ 8.81 , 8.09 , 8.00 , 7.96 , 7.76 , 7.68 , 7.14 , 6.77–6.76 , 6.65–6.63 , 4.97 , 4.12–4.10 , 4.02–3.98 , 2.95 , 2.60 , 2.42 ; 13C NMR  δ 161.2, 150.8, 144.3, 144.2, 134.9, 132.0, 132.5 (2C), 131.2, 131.1, 127.0, 125.79, 125.77, 117.9, 117.7 (2C), 115.4 (2C), 115.1 (2C), 104.4, 71.4, 66.5, 60.9, 53.7 (2C), 50.1 (2C); IR υmax/cm−1: 3366 (OH), 2212 (CN), 1370 (OH), 1182 (C-O), 815 (C-Cl); LRMS (ESI+) m/z: 524 (C29H28Cl2N3O3) [M+H]; HRMS: Exact mass calculated for (C28H28Cl2N3O3) [M+H], 524.1403. Prepared according to general procedure 3 from ((Z)-2--3-(4-(2-hydroxy-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile (8t) ; HRMS: Exact mass calculated for (C29H27Cl2F3N3O2) [M+H], 576.4442. Found 576.4311.Prepared according to general proceure 3 from (Z)-2--3-(4-(oxiran-2-ylmethoxy)phenyl)acrylonitrile  and 1-(4-trifluoromethylphenyl)piperazine  to afford the desired compound as a pale yellow solid , m.p.: 159–161 °C. (Z)-2--3-(4-(3-(4-(4-acetamidophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)-acrylonitrile (8u) ; HRMS: Exact mass calculated for C30H30Cl2N3O3 [M+H], 550.1659. Found 550.1671.Prepared according to general procedure 3 from ((Z)-3-(4-(3-(4-(4-Nitrophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)-2-acrylonitrile (8v) ; HRMS: Exact mass calculated for (C28H27Cl2N4O4) [M+H], 553.1404. Found 553.1408.Prepared according to general procedure 3 from ((Z)-2--3-(4-(3-(4-(2-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)-acrylonitrile (8w); HRMS: Exact mass calculated for C28H27Cl2FN3O2 [M+H], 526.1459. Found 526.1465.Prepared according to general procedure 3 from ((Z)-3-(4-(3-(4-Cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2--acrylonitrile (8x) ; HRMS: Exact mass calculated for C29H29Cl2N2O2 [M+H], 507.1601. Found 507.1620.Prepared according to general procedure 3 from (


E)-4′-(1-(4-(2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)phenyl)-1H-phenanthroimidazol-2-yl)-N,N-diphenyl--4-amine (SMPI-TPA) and (E)-4-(4-(2-(4-(2-(4-(9H-carbazol-9-yl)phenyl)-1H-phenanthroimidazol-1-yl)styryl)-1H-phenanthroimidazol-1-yl)phenyl)morpholine (SMPI-Cz). These compounds show excellent thermal properties, dual charge transport properties and form thin films under thermal evaporation. Blue OLEDs  based on SMPI-TPA show efficient device performance  at low turn-on voltages. Both SMPI-TPA and SMPI-Cz were utilised as hosts for green OLEDs. The devices with SMPI-Cz (30 nm):5 wt% Ir(ppy)3 exhibit maximum luminance of 20 725 cd m−2, and ηc and ηp values of 61.4 cd A−1 and 63.8 lm W−1, respectively. In comparison, devices with SMPI-TPA (30 nm):5 wt% Ir(ppy)3 exhibit high ηc and ηp values of 65.2 cd A−1 and 67.1 lm W−1, respectively. Maximum ηex values of 19.6% and 23.4% were obtained from SMPI-TPA:Ir(ppy)3 and SMPI-Cz:Ir(ppy)3, respectively. These device performances indicate that the phenanthroimidazole unit is a tunable building unit for efficient carrier injection and it may also be employed as a host for green OLEDs.Comparative optical, electroluminescence and theoretical studies were performed for  The external quantum efficiency (ηex) can be deduced from the following equation: ηex = ηIQE × ηout = ηrec × ηPL × ηS × ηout, where ηIQE is the internal quantum efficiency, ηout (∼1/2n2) is the light out-coupling efficiency , ηrec is the electron–hole recombination efficiency (100%), ηPL is the photoluminescence efficiency and ηS is the utilization efficiency. The two key parameters ηPL and ηS required for high ηex can be tuned by altering the emitter molecular design.12Efficient green or red OLEDs with pure color CIE coordinates have been reportedET) may be employed as a host for green OLEDs.13–16 However, the high triplet energy enables green emitters to harvest the triplet energy of a blue emitter; also, efficient non-doped blue emitters are not suitable as hosts for phosphorescent OLEDs due to their low ET as well as poor carrier transport properties.17 Moreover, efficient hosts for green emitter exhibit low efficiency when they are used as emissive materials in blue OLEDs.18–20 Hence, efforts are still required to achieve efficient OLEDs based on blue emissive materials.A blue-emissive material with high triplet energy /acceptor (A) (electron/hole transport moieties) configuration has gained interest. To achieve deep blue emission, the donor–acceptor (D–A) molecule should have relatively weak charge transfer properties since a strong D–A geometry can induce red-shifted emission. In addition, the singlet–triplet splitting should be small to ensure that the triplet-excited state energy is high enough to excite the green phosphorescent dopant.Therefore, to develop dual-functional emissive materials, 21–23 herein we report the synthesis of (E)-4′-(1-(4-(2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)phenyl)-1H-phenanthroimidazol-2-yl)-N,N-diphenyl--4-amine (SMPI-TPA) and (E)-4-(4-(2-(4-(2-(4-(9H-carbazol-9-yl)phenyl)-1H-phenanthroimidazol-1-yl)styryl)-1H-phenanthroimidazol-1-yl)phenyl)morpholine (SMPI-Cz) derivatives and utilize them as blue emitters in non-doped devices and hosts for green OLEDs. These derivatives exhibit higher stability with balanced injection property, leading to excellent device performances.With our continuous interest to synthesize efficient n-type imidazole derivatives as OLED emitters,2.1H and 13C NMR spectroscopies and mass spectrometry, recorded using a Bruker spectrometer (400 MHz) and Agilent (LCMS VL SD), respectively. Redox potentials were measured using a potentiostat CHI 630A electrochemical analyzer. The Lambda 35 PerkinElmer instrument spectrophotometer with integrated sphere (RSA-PE-20) was used to measure absorbance in both solution and film states. Emissive properties (PL) were analyzed via PerkinElmer LS55 fluorescence spectrometer measurements. Thermal characteristics such as decomposition (Td) and glass transition (Tg) temperatures were analyzed using a PerkinElmer thermal analysis system and NETZSCH-DSC-204, respectively, with heating rate of 10 °C min−1 under N2 atmosphere. Lifetime measurements of SMPI-TPA and SMPI-Cz were recorded using a time-correlated single-photon counting spectrometer (TCSPC: Horiba Fluorocube-01-NL lifetime system). The Φ (PL quantum yield) was measured in dichloromethane using 0.5 M H2SO4:quinine (0.54) as reference.The structure of emissive materials was confirmed by 2.1.24 the electron density on frontier molecular orbitals of SMPI-TPA and SMPI-Cz was identified.Using the Gaussian 09 software package,2.2.−6 Torr on a precleaned ITO substrate with 20 Ω per square resistance (rate −0.1 nm s−1). LiF and Al were also evaporated thermally on the organic layer and the thickness was measured using a quartz crystal thickness monitor. A series of fabricated devices with multilayer configuration are denoted as follows: ITO/NPB -N-phenylamino]biphenyl) (50 nm)/TCTA (tris(4-carbazoyl-9-ylphenyl)amine) (5 nm)/SMPI-TPA (I) or SMPI-Cz (II) (30 nm)/TPBI -tris(1-phenyl-1-H-benzimidazole)) (15 nm)/LiF (1 nm)/Al (100 nm); ITO/NPB (50 nm)/SMPI-TPA (30 nm):5 wt% Ir(PPy)3 or (III) or SMPI-Cz (30 nm):5 wt% Ir(PPy)3 (IV)/BCP  (15 nm)/Alq3 (50 nm)/LiF (1 nm)/Al (100 nm). Further, single-carrier devices were also been fabricated. The hole-only device has the configuration of ITO/NPB (50 nm)/SMPI-TPA or SMPI-Cz (30 nm)/NPB (50 nm)/Al (200 nm), while the electron-only device has the configuration of ITO/TPBI (20 nm) SMPI-TPA or SMPI-Cz (30 nm)/TPBI (20 nm)/LiF (1 nm)/Al (200 nm). Electrical measurements were recorded using a Keithley 2400 sourcemeter.OLEDs with SMPI-TPA and SMPI-Cz emitters were fabricated by vacuum deposition at 5 × 102.2.1.2 stream). Then, 2-(4-nitrostyryl)-1-(4-morpholinophenyl)-1H-phenanthroimidazole was purified and used for further analyses : δ 2.97 , 3.58 , 6.54 , 7.13 , 7.18 , 7.32 , 7.52 , 7.71–7.83 , 8.02 , 8.13 , 8.51 .·13C NMR : δ 47.33, 62.42, 114.68, 119.43, 119.86, 120.31, 120.78, 121.12, 121.44, 122.85, 123.12, 123.85, 124.02, 124.70, 124.85, 126.17, 125.26, 125.39, 126.67, 126.19, 126.44, 126.53, 126.74, 129.72, 131.93, 133.45, 146.67. MS: m/z 526.58 [M+]; calcd 526.62.Phenanthrenequinone , 4-nitrocinnamaldehyde , 4-morpholinobenzenamine  and ammonium acetate , all in acetic acid (25 mL), were refluxed  and 10% Sn/HCl (250 mg) in 25 mL ethanol were refluxed under stirring. Then, 80% hydrazine hydrate (15 mL) was added, and stirring was continued for one day. The solution was treated with water : HCl mixture, and the obtained white product was used after purification. Anal. calcd C33H28N4O: C, 79.87; H, 5.62; N, 11.18. Found: C, 79.82; H, 5.60; N, 11.15. 1H NMR : δ 2.72 , 3.36 , 4.12 , 6.43 , 6.93 , 7.06 , 7.23 , 7.36 , 7.59–7.68 , 7.92 , 8.03 , 8.62 . 13C NMR : δ 42.28, 57.36, 112.61, 120.18, 120.76, 121.121, 121.43, 122.28, 122.67, 123.73, 124.08, 124.65, 125.12, 125.56, 125.92, 126.28, 126.32, 126.49, 127.52, 127.63, 127.82, 128.27, 128.56, 130.63, 132.53, 133.06, 145.27. MS: m/z 496.65 [M+]; calcd 496.60.Initially, 2-(4-nitrostyryl)-1-(4-morpholinophenyl)-12.2.3.E)-2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)benzenamine  and ammonium acetate , all in 25 mL acetic acid, were refluxed , and the obtained gray white solid was used for further analyses after purification. Anal. calcd C72H52N6O: C, 85.07; H, 5.17; N, 8.28. Found: C, 85.01; H, 5.11; N, 8.25. 1H NMR : δ 3.12 , 3.56 , 6.58 , 6.64–6.72 , 6.82 , 6.94 , 7.24–7.38 , 7.48 , 7.56 , 7.62 , 7.72–7.96 , 8.28 , 8.78 . 13C NMR : δ 52.81, 65.36, 112.82, 117.45, 122.42, 122.66, 122.92, 125.58, 125.82, 126.26, 126.59, 126.78, 126.92, 127.21, 127.83, 128.62, 128.89, 130.17, 130.43, 133.48, 137.48, 138.26, 140.62, 144.51, 149.68. MS: m/z 1016.45 [M+]; calcd 1016.40.Phenanthrenequinone , 4′-(diphenylamino)biphenyl-4-carbaldehyde , 4-((2.2.4.H-carbazol-9-yl)benzaldehyde , 4-((E)-2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)benzenamine  and ammonium acetate , all in 25 mL glacial acetic acid, were refluxed , and the obtained gray white solid was used for further analyses after purification. Anal. calcd C66H46N6O: C, 84.47; H, 4.92; N, 8.95. Found: C, 84.42; H, 4.89; N, 8.91. 1H NMR : δ 2.96 , 3.38 , 6.66 , 6.86 , 6.98 , 7.18 , 7.32–7.42 , 7.68 , 7.82 , 7.96–8.24 , 8.48 , 8.92 . 13C NMR : δ 49.42, 63.34, 109.48, 112.73, 114.23, 117.82, 121.38, 121.67, 122.48, 122.73, 122.98, 124.62, 125.34, 125.74, 126.18, 126.48, 126.67, 126.93, 127.74, 128.53, 128.77, 130.34, 133.52, 137.84, 138.43, 140.89, 144.68, 150.51. MS: m/z 938.42 [M+]; calcd 938.40.Phenanthrenequinone , 4-(93.E)-4′-(1-(4-(2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)phenyl)-1H-phenanthroimidazol-2-yl)-N,N-diphenyl--4-amine (SMPI-TPA) and (E)-4-(4-(2-(4-(2-(4-(9H-carbazol-9-yl)phenyl)-1H-phenanthro imidazol-1-yl)styryl)-1H-phenanthroimidazol-1-yl)phenyl)morpholine (SMPI-Cz) were prepared from phenanthrenequinone , 4′-(diphenylamino)biphenyl-4-carbaldehyde (SMPI-TPA)/4-(9H-carbazol-9-yl)benzaldehyde (SMPI-Cz), 4-((E)-2-(1-(4-morpholinophenyl)-1H-phenanthroimidazol-2-yl)vinyl)benzenamine and ammonium acetate in acetic acid . The formed SMPI-TPA and SMPI-Cz were analysed by various spectroscopic methods, from which their molecular structures were confirmed.As depicted in Scheme S1,3.1.Td5)/high glass transition (Tg) temperature: 526/163 °C-SMPI-TPA and 518/172 °C-SMPI-Cz] /N24–C25–C31–C26 (SMPI-TPA) was performed using DFT/B3LYP/6-31G . During calculation, all the geometrical parameters were simultaneously relaxed, while their respective torsional angles were varied in steps of 0°, 20°, 40°, 60°…360°. The potential energy surface diagrams  reveal tSMPI-Cz] ; Table 13.2.22 Moreover, SMPI-TPA and SMPI-Cz exhibit redox waves, supporting their carrier transport abilities. The HOMO energies of −5.41 eV (SMPI-TPA) and −5.39 eV (SMPI-Cz) are determined from their respective oxidation onset potentials of 0.61 V (SMPI-TPA) and 0.59 V (SMPI-Cz) [EHOMO = −(Eox + 4.8 eV)].23 The LUMO energies of −2.15 eV (SMPI-TPA) and −2.17 eV (SMPI-Cz) are calculated using the equation ELUMO = EHOMO − 1239/λonset. The charge-transporting properties of SMPI-TPA and SMPI-Cz were investigated by fabricating single-carrier devices. The hole-only device has the configuration of ITO/NPB (50 nm)/SMPI-TPA or SMPI-Cz (30 nm)/NPB (50 nm)/Al (200 nm) and the electron-only device has the configuration of ITO/TPBI (20 nm) SMPI-TPA or SMPI-Cz (30 nm)/TPBI(20 nm)/LiF (1 nm)/Al (200 nm). NPB on the cathode side of the hole-only device and TPBI benzene) on the anode side of the electron-only device were used to block electron injection from Al and hole injection from ITO, respectively. The HOMO of both SMPI-TPA and SMPI-Cz is localized on the fragment attached to phenanthrimidazole nitrogen, while the LUMO is distributed on the phenanthrimidazole with TPA (SMPI-TPA) and Cz (SMPI-Cz) fragments . The HOM3.3.λabs at around 248 nm originated from the aryl group attached to the nitrogen of phenanthrimidazole plane, while λabs at around 355 nm was attributed to π → π* electronic transition of the styryl phenanthrimidazole ring. The origin of absorption of SMPI-TPA and SMPI-Cz was studied by computational methods. The outcomes of computational and experimental methods are similar [HOMO–LUMO+1 transition; Table S1(a) & (b)EST) of SMPI-TPA and SMPI-Cz are 0.36 eV and 0.30 eV, respectively, which are unfavourable for TADF emission. A small ΔEST value is required for efficient energy transfer from host T* (triplet excited state) to green phosphorescent emitters. The observed intense blue emission and high Tg of SMPI-TPA and SMPI-Cz confirmed their suitability as blue emitters. The device performances of the blue emitters were analysed by fabricating non-doped OLEDs with a configuration of ITO/NPB (50 nm)/TCTA (5 nm)/SMPI-TPA (I)/SMPI-Cz (II) (30 nm)/TPBI (15 nm)/LiF (1 nm)/Al (100 nm). It is clear from ηex is calculated using the formula ηex = ηout × ηrc × ηγ × ΦPL,23 where ηout is the light out-coupling efficiency (20%), ηrc is the product of the charge recombination efficiency (100%), ηγ is the efficiency of radiative exciton formation (25%) and ΦPL is the photoluminescence quantum yield of emitters SMPI-TPA (0.56) and SMPI-Cz (0.71). Thus, the calculated ηex values of SMPI-TPA- and SMPI-Cz-based devices are 2.8 and 3.6%, respectively. However, the obtained external quantum efficiencies (ηex) of SMPI-TPA- and SMPI-Cz-based devices are 6.1 and 5.9%, respectively, and the current efficiencies (ηc) of SMPI-TPA- and SMPI-Cz-based devices are 5.3 and 5.1 cd A−1, respectively. The harvested ηex exceeds the theoretical limit since delayed fluorescence is not expected and the obtained high ηex is not in accordance with TADF.25–30 Time-resolved lifetime studies revealed monoexponential decay for SMPI-TPA and SMPI-Cz /TCTA (5 nm)/SMPI-TPA (I) or SMPI-Cz (II) (30 nm)/TPBI (15 nm)/LiF (1 nm)/Al (100 nm) shows that the TCTA layer plays a key role in achieving higher efficiency32 and the NPB layer was used as the hole-transporting layer (HTL) to be deposited in proximity to the SMPI-TPA and SMPI-Cz emissive layers. Due to the relatively small energy gap of NPB (Eg = −3.00 eV) in comparison to the energy gaps of the emissive layers SMPI-TPA (Eg = −3.26 eV) and SMPI-Cz (Eg = −3.22 eV), the excitons generated in the emissive layer are more likely to leak into HTL, leading to loss of excitons. However, herein, we used TCTA with Eg of −3.40 eV as a buffer layer to confine the excitons within the emissive layer, resulting in higher efficiency.33 Further, the EL spectra of the SMPI-TPA- and SMPI-Cz-based devices are identical to the corresponding PL emission of the thin film, implying balanced carrier transport and efficient confinement of excitons33  to understand whether these materials show aggregation-induced emission. When a small amount of water (fw = 10–90 vol%) was added to the THF solution of both SMPI-TPA and SMPI-Cz, the PL intensity remained unchanged, which shows that both SMPI-TPA and SMPI-Cz materials are AIE-inactive citons33 ; the hole Fig. S1.3-doped SMPI-TPA and Ir(ppy)3-doped SMPI-Cz was 0.61 and 0.79, respectively. In addition to high ηex and ηc, SMPI-TPA- and SMPI-Cz-based devices show high ηp (power efficiency) of 5.2 and 4.6 lm W−1, respectively. The blue emitters exhibit CIE coordinates of  and . The device based on SMPI-TPA shows maximum luminance of 12 680 cd m−2, and maximum current and power efficiencies of 5.3 cd A−1 and 5.2 lm W−1, respectively, at 3.1 V. These SMPI-TPA and SMPI-Cz compounds were also utilised as hosts for green dopants in the fabricated devices (3 or (III) or SMPI-Cz (30 nm):5 wt% Ir(PPy)3 (IV)/BCP  (15 nm)/Alq3 (50 nm)/LiF (1 nm)/Al (100 nm). The energy level diagram of the as-fabricated device and molecular structures of materials used in the devices are shown in 3 exhibit maximum luminance of 20 725 cd m−2, and ηc and ηp of 61.4 cd A−1 and 63.8 lm W−1, respectively, whereas SMPI-TPA:Ir(ppy)3-based devices exhibit high ηc and ηp values of 65.2 cd A−1 and 67.1 lm W−1, respectively. The maximum ηex values of 19.6% and 23.4% were exhibited by SMPI-TPA:Ir(ppy)3 and SMPI-Cz:Ir(ppy)3, respectively. The lower efficiency from SMPI-TPA:Ir(ppy)3-based devices could be attributed to the lower triplet energy (ET = 2.32 eV) of SMPI-TPA, which may cause back energy transfer from the guest triplet states to the host, resulting in loss of efficiency. The device performances reveal that SMPI-TPA and SMPI-Cz are universal hosts for green emitters. The EL spectra of devices III and IV were consistent with their corresponding PL spectra  high triplet energies of 2.32 eV (SMPI-TPA) and 2.40 eV (SMPI-Cz) efficiently suppress the energy return from the dopant to the host, resulting in higher efficiency and (ii) good thermal stability restrains the strong bimolecular interaction of the phosphorescent emitters to reduce the triplet–triplet annihilation.34 These results indicate that the introduction of a bipolar molecule is a practical strategy for achieving highly efficient OLEDs both as a blue emitter and as a host for green emission.The small singlet–triplet splitting and good carrier transport properties allow both SMPI-TPA and SMPI-Cz to be used as hosts to fabricate red, green and yellow phosphorescence-emitting layers for PhOLEDs. The calculated PLQY of Ir(ppy) devices  with a c spectra , and no  spectra , implyin4.−2 and maximum current (ηc) and power (ηp) efficiencies of 5.3 cd A−1 and 5.2 lm W−1, respectively, at 3.1 V. The device with configuration of SMPI-Cz (30 nm):5 wt% Ir(ppy)3 exhibits maximum luminance of 20 725 cd m−2, whereas the ηc and ηp exhibited by the SMPI-TPA:Ir(ppy)3 device are 65.2 cd A−1 and 67.1 lm W−1, respectively. The maximum ηex of 19.6% and 23.4% were exhibited by SMPI-TPA:Ir(ppy)3- and SMPI-Cz:Ir(ppy)3-based devices, respectively. The lower efficiency from SMPI-TPA:Ir(ppy)3-based devices could be attributed to the lower triplet energy (ET = 2.32 eV) of SMPI-TPA, which may cause back energy transfer from the guest triplet states to the host, resulting in loss of efficiency. The device performance indicates that introduction of a bipolar molecule is a practical strategy for achieving efficient OLEDs both as a blue emitter and as a host for green emission.In this study, we have reported the newly fabricated efficient deep blue-emissive materials with balanced transport and high thermal properties. Non-doped blue emitters with SMPI-TPA and SMPI-Cz exhibit higher electroluminescent efficiencies. Devices with SMPI-TPA show maximum luminance of 12 680 cd mThere are no conflicts to declare.RA-008-C8RA02840K-s001


Ganoderma luteomarginatum is one of the main species of Ganoderma fungi distributed in Hainan province of China, the fruiting bodies of which have been widely used in folk as a healthy food to prevent tumors. To explore the potential cytotoxic constituents from G. luteomarginatum, the phytochemical investigation on the ethyl acetate soluble fraction of 95% ethanolic extract from the fruiting bodies of this fungus led to the isolation of twenty-six lanostane triterpenoids (1–26), including three undescribed ones (1–3), together with eight ergostane steroids (27–34). The structures of three new lanostane triterpenoids were elucidated as lanosta-7,9(11)-dien-3β-acetyloxy-24,25-diol (1), lanosta-7,9(11)-dien-3-oxo-24,26-diol-25-methoxy (2), and lanosta-8,20(22)-dien-3,11,23-trioxo-7β,15β-diol-26-oic acid methyl ester (3) by the analysis of 1D, 2D NMR, and HRESIMS spectroscopic data. All isolates were assayed for their cytotoxic activities using three human cancer cell lines  and seven lanostane triterpenoids , and one ergostane steroid (34) showed definite cytotoxicity with IC50 values that ranged from 6.64 to 47.63 μg/mL. Among these cytotoxic lanostane triterpenoids, compounds 2 and 13 showed general cytotoxicity against three human cancer cell lines, while compounds 1 and 18 exhibited significant selective cytotoxicity against K562 cells with IC50 values of 8.59 and 8.82 μg/mL, respectively. Furthermore, the preliminary structure–cytotoxicity relationships was proposed.Macrofungus  Ganoderma, belonging to the family Ganodermataceae and known as “Lingzhi” in Chinese, has been widely used as traditional Chinese medicine and functional foods for health in China and Southeast Asia for thousands of years + 523.3754 , indicating seven degrees of unsaturation. The IR spectrum revealed the presence of hydroxyl groups (3475 cm−1), double bonds (1641 cm−1), and ester carbonyl (1696 cm−1). The 1H NMR spectral data , one proton related to oxygenated carbon , and two olefinic protons . The 13C NMR and DEPT (δC 171.2). The above-mentioned NMR data were closely similar to those of lanosta-7,9(11)-dien-3b-acetyloxy-24,25,26-trihydroxy and DEPT  spectra renate A  with a lspectrum , exhibitspectrum . The key4–26) and eight ergostane steroid (27–34), were identified as lanosta-8,24E-dien-7-oxo-3β- acetyloxy-26-ol (4) 27D −2.5° ; UV (MeOH) λmax (logε) 252 (3.62), 242 (5.24), 238 (4.50), 210 (1.21); IR (KBr) νmax cm−1 3475, 2938, 1696, 1641, 1302, 1028; 1H and 13C NMR data; see + 523.3754 .Lanosta-7,9(11)-dien-3β-acetyloxy-24,25-diol (2): White amorphous powder; [α]27D +4.0° ; UV (MeOH) λmax (log ε) 242 (5.60), 238 (5.03), 212 (2.32); IR (KBr) vmax cm−1 3424, 2952, 1724, 1644, 1386, 1020; 1H and 13C NMR data; see + 509.3597 .Lanosta-7,9(11)-dien-3-oxo-24,26-diol-25-methoxy (3): White amorphous powder; [α]27D −1.5° ; UV (MeOH) λmax (log ε) 250 (3.54), 210 (1.37); IR (KBr) vmax cm−1 3443, 2934, 1732, 1639, 1384, 1019; 1H and 13C NMR data; see + .Lanosta-8,20(22)-dien-3,11,23-trioxo-7β,15β-diol-26-oic acid methyl ester (50.All the compounds was assayed for their cytotoxic activity against three human tumor cell lines: K562 (leukemic cell line), BEL7402 (hepatoma cell line), and SGC7901 (gastric cancer cell line) using MTT methods reported previously [Ganoderma, which have extensive biological and pharmacological activities, especially possess cytotoxicity. The chemical investigation of the fruiting bodies of G. luteomarginatum led to the isolation of twenty-six lanostane triterpenoids (1–26), including three undescribed ones (1–3): lanosta-7,9(11)-dien-3β-acetyloxy-24,25-diol (1), lanosta-7,9(11)-dien-3-oxo-24,26-diol-25-methoxy (2), and lanosta-8,20(22)-dien-3,11,23-trioxo -7β,15β-diol-26-oic acid methyl ester (3), together with eight ergostane steroids (27–34). The cytotoxicity assay showed that seven lanostane triterpenoids  revealed definite cytotoxicity against K562, among which compounds 1, 13, and 18 showed the IC50 values of 8.59, 6.64, and 8.82 μg/mL, respectively, indicating the prospect of an antitumor. Some preliminary structure–cytotoxicity relationships of these lanostane triterpenoids showed that the conjugated double-bond ∆7,9(11) system in tetracyclic lanostane skeleton seemed to be more important than the (∆8)α,β-unsaturated ketone system for potential cytotoxic activity. The present study further enriched the understanding of the structural diversity of G. luteomarginatum, which also provides theoretical information for its subsequent anticancer drug development.Lanostane-type triterpenoids are the main characteristic natural products of the fungi of