New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

Phytochemicals from the Leaves of Cyclocarya paliurus and their 11β-HSD1 Enzyme Inhibitory Effects

Two new dammarane-type triterpenoid saponins, 3β-(α-l -arabinopyranosyloxy)-24,25-dihydroxydammar-20-en-12α-yl 6-deoxy-β-d -glucopyranoside ( 1 ) and (24R)-3β-[(4-O-acetyl-α-l -arabinopyranosyl)oxy]-25-hydroxy-20,24-epoxydammaran-12β-yl 6-deoxy-β-d -glucopyranoside ( 2 ), and fourteen known triterpenoids were isolated from the 70 % MeOH extract of the leaves of Cyclocarya paliurus. Their structures were established based on analyses of spectroscopic data. All compounds were tested for their inhibitory activities against the 11β-HSD1 enzyme. Hederagenin ( 13 ) exhibited moderate inhibitory effect for mouse 11β-HSD1 with an IC₅₀ value of 0.16±0.04 μM.     

New Dibenzocyclooctadiene Lignans and Phenolics from Kadsura heteroclite with Anti-Inflammatory Activity

A chemical investigation of K. heteroclite led to isolation of two new dibenzocyclooctadienes ( 1 and 2 ) together with 14 known compounds ( 3 – 16 ) by using multiple chromatographic techniques. New compounds ( 1 and 2 ) were obtained and identified by spectroscopic methods (HR-ESI-MS, 1D and 2D NMR, and ECD) as well as by comparison of their experimental data with those reported in the literatures. All the isolates were evaluated for their ability to modulate TNF-α production in lipopolysaccharide (LPS) stimulated RAW264.7 cells. Among them, compound 5 displayed the most inhibition against tumor necrosis factor (TNF)-α production with IC₅₀ value of 6.16±0.14 μM. Whereas, compounds ( 1 , 3 , and 6 ) showed the significant inhibition (IC₅₀ values ranging from 9.41 to 14.54 μM), and compounds ( 2 , 4 , 9 , 10 , 13 , 15 , and 16 ) exhibited moderate inhibition (IC₅₀ values ranging from 19.27 to 40.64 μM) toward TNF-α production, respectively.     

Diterpenes from Dysoxylum lukii Merr

Six new diterpenes and two known compounds were isolated from the stems of Dysoxylum lukii Merr and characterized on the basis of spectral data. Dysokusone F(1), 2-Oxoneoclerod-3, 13Z-dien-15-ol (2), 3α-(4-Hydroxy-3,5-dimethoxy-benzoyloxyl)-clerod-14-ene-4β,13-diol (3), 3α-(4-Hydroxybenzoyloxyl)-clerod-14-ene-4β,13-diol (4), and 3α-(4-Hydroxy-3-methoxybenzoyloxyl)-clerod-14-ene-4β,13-diol (5) exhibited inhibitory effects against PTP-1B with IC₅₀ values of 51.62±6.55, 56.74±7.96, 17.04±3.43, 28.96±4.59, and 19.70±2.57 μM, respectively.     

1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC₅₀ values below 200 μM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one ( 2 ) (IC₅₀=134.35±11.38 μM) exhibiting slightly better IC₅₀ value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one ( 15 ) (IC₅₀=147.51±14.87 μM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one ( 18 ) (IC₅₀=149.07±2.98 μM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one ( 22 ) (IC₅₀=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.     

α-Glucosidase Inhibition by Usnic Acid Derivatives

This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α-glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC₅₀>200 μM). Methyl (2E,3R)-7-acetyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethylidene)-3,5-dimethyl-2,3-dihydro-1-benzofuran-3-carboxylate ( 6b ) and 1,1′-(2,4,6-trihydroxy-5-methyl-1,3-phenylene)di(ethan-1-one) ( 6e ) were more potent than an acarbose positive control (IC₅₀ 93.6±0.49 μM), with IC₅₀ values of 42.6±1.30 and 90.8±0.32 μM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9bR)-2,6-Bis[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 1c ), (9bR)-3,7,9-trihydroxy-8,9b-dimethyl-2,6-bis[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 1g ), (9bR)-2-acetyl-6-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2d ), (9bR)-2-acetyl-6-[(2E)-3-(3-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2e ), (6bR)-8-acetyl-3-(4-chlorophenyl)-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3e ), (6bR)-8-acetyl-6,9-dihydroxy-5,6b-dimethyl-3-phenyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3h ), (6bR)-3-(2-chlorophenyl)-8-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 4b ), and (9bR)-6-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-2-[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 5c ) were the most potent α-glucosidase enzyme inhibitors, with IC₅₀ values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 μM, respectively.     

AMPA receptor agonists: Resolution,configurational assignment,and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA)

We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee ≥ 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [³H]AMPA binding (IC⁵⁰ = 0.19 ± 0.06 μM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC₅₀ = 4.5 ± 0.3 μM) comparable with AMPA (IC₅₀ = 0.040 ± 0.01 μM; EC₅₀ = 3.5 ± 0.2 μM), but much more potent than (+)-(S)-APPA (IC₅₀ = 5.5 ± 2.2 μM; EC₅₀ = 230 ± 12 μM). Like (-)-(R)-APPA (IC₅₀ > 100 μM), (-)-(R)-2-Py-AMPA (IC₅₀ > 100 μM) did not significantly affect [³H]AMPA binding, and both compounds were week AMPA receptor antagonists (K_i = 270 ± 50 and 290 ± 20 μM, respectively). Chirality 9:274–280, 1997. © 1997 Wiley-Liss, Inc.     

Antioxidant,anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives

During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-β-phenyl-α,β-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a–1n and one (Z)-2,3-DPA-derivative 1l′ using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ± 3.53%, IC₅₀ = 20.04 ± 1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ± 2.93%, IC₅₀ = 30.64 ± 1.27 μM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (−7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (−5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 μM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 μM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.     

Secolignans with antiangiogenic activities from Peperomia dindygulensis

Two new secolignans, peperomins G and H ( 1 and 2 , resp.), were isolated from the whole plant of Peperomia dindygulensis, together with five known secolignans, peperomin A ( 3 ), peperomin E ( 4 ), peperomin B ( 5 ), 2,3‐trans‐2‐methyl‐3‐{(3‐hydroxy‐4,5‐dimethoxyphenyl)[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 6 ), 2,3‐cis‐2‐(hydroxymethyl)‐3‐{bis[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 7 ). Their structures and configurations were elucidated by spectroscopic methods including 2D‐NMR techniques. Antiangiogenic effects of all compounds were evaluated using human umbilical vein endothelial cells (HUVEC) proliferation and tube‐formation tests, with compounds 4 and 5 being active in the bioassay. Compounds 4 and 5 induced obvious cell toxicity to HUVEC with IC₅₀ values of 1.64±0.19 and 8.44±0.4 μM , respectively. Compounds 4 and 5 also exhibited significant HUVEC tube formation‐inhibiting activity with IC₅₀ values of 3.13±0.09 and 6.24±0.12 μM , respectively.     

Phytochemical Profile and Anti-Inflammatory Activity of the Fraction from Artemisia lavandulaefolia

Artemisia lavandulaefolia, a traditional herbal medicine, has been utilized as anti-inflammatory and analgesia agent in clinic. Bioassay-guided fractionation resulted in a fraction (ALDF) with anti-inflammatory effect obtained from A. lavandulaefolia. Its main constituents were analyzed and identified by UPLC-ESI-Q-TOF-MS technology. ALDF showed the strong inhibitory activity on the nitrogen oxide (NO) production in LPS-induced RAW 264.7 macrophages with an IC₅₀ value of 1.64±0.41 μg/mL. Further results displayed that ALDF also significantly suppressed the secretion of key pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), prostaglandin E₂ (PGE₂) and interleukin-1β (IL-1β), and the increase of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression induced by LPS stimulation. Mechanism study indicated that ALDF was able to block NF-κB signaling pathway through inhibiting IκB and p65 phosphorylation, as well as NF-κB p65 nuclear translocation. Furthermore, in vivo results in mice revealed that treatments with ALDF evoked significant inhibition on ear edema induced by xylene and on the writhing responses induced by acetic acid. These results suggest that ALDF holds great potential in the prevention and treatment of inflammatory disorders.     

Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis,molecular modelling and in-silico ADME evaluation

A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC₅₀ values in lower micro-molar range (IC₅₀ = 0.33–7.14 μM for MAO-A, and 1.12–3.56 μM for MAO-B). The most active MAO-B inhibitor was N′-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC₅₀ value of 1.12 ± 0.02 μM, and N′-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC₅₀ value of 0.33 ± 0.01 μM. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.     

Five New Oleanane Triterpene Saponins from Camellia petelotii and Their Alpha-glucosidase Inhibitory Activity

Five new triterpenoid glycosides, named campetelosides A–E ( 1–5 ), together with three known compounds, chikusetsusaponin IVa ( 6 ), umbellatoside B ( 7 ), and silvioside E ( 8 ) were isolated from the leaves of Camellia petelotii (Merr.) Sealy. Their chemical structures were determined by interpretations of HR-ESI-MS and NMR spectra. In addition, compounds 1–8 were evaluated for their α-glucosidase inhibitory effects. Compounds 1–3 significantly showed α-glucosidase inhibitory activity with IC₅₀ values of 166.7±6.0, 45.9±2.6, and 395.3±10.5 μM, respectively, compared to that of the positive control, acarbose, with an IC₅₀ value of 200.4±10.5 μM.     

New Isopropyl Chromone and Flavanone Glucoside Compounds from the Leaves of Syzygium cerasiforme (Blume) Merr. & L.M.Perry and Their Inhibition of Nitric Oxide Production

A new isopropyl chromone ( 1 ) and a new flavanone glucoside ( 2 ) together with eleven known compounds ( 3–13 ) were isolated from the leaves of Syzygium cerasiforme (Blume) Merr. & L.M.Perry. Their structures were elucidated as 5,7-dihydroxy-2-isopropyl-6,8-dimethyl-4H-chromen-4-one ( 1 ), 5,7-dihydroxyflavanone 7-O-β-D-(6′′-O-galloylglucopyranoside) ( 2 ), strobopinin ( 3 ), demethoxymatteucinol ( 4 ), pinocembrin-7-O-β-D-glucopyranoside ( 5 ), (2S)-hydroxynaringenin-7-O-β-D-glucopyranoside ( 6 ), afzelin ( 7 ), quercetin ( 8 ), kaplanin ( 9 ), endoperoxide G3 ( 10 ), grasshopper ( 11 ), vomifoliol ( 12 ), litseagermacrane ( 13 ) by the analysis of HR-ESI-MS, NMR, and CD spectral data. Compounds 1 , 2 , 5 , 6 and 10 inhibited NO production on LPS-activated RAW264.7 cells with IC₅₀ values of 12.28±1.15, 8.52±1.62, 7.68±0.87, 9.67±0.57, and 6.69±0.34 μM, respectively, while the IC₅₀ values of the other compounds ranging from 33.38±0.78 to 86.51±2.98 μM, compared to that of the positive control, N^G-monomethyl-L-arginine acetate (L-NMMA) with an IC₅₀ value of 32.50±1.00 μM.     

Synthesis,characterization, and anticancer evaluation of novel 4-hydrazinothiazole analogs

Single-step synthesis of novel 4-hydrazinothiazole derivatives 6a–e was achieved under mild conditions using the sequential four-components method involving isothiocyanate, aminoguanidine, carbonyl adduct, and α-haloketone derivatives. Deprotection of these hydrazinothiazoles was influenced by acylation, providing a novel group of diacylated molecular structures with a broader scope for the design of thiazolyl-containing drugs 7a and 7b . FTIR, ¹H/¹³C NMR, LC–MS spectroscopy, and CHN elemental analyses were used to study the compound chemical structures. Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human periodontal ligament fibroblast (HPDLF) cells, the 4-hydrazinothiazole derivatives were screened for cytotoxicity in an in vitro cytotoxicity investigation. The 4-hydrazinothiazole compound 6b bearing an isopropylidene-hydrazino group demonstrated strongly potent cytotoxicity against CAKI1 (IC₅₀ = 1.65 ± 0.24 μM) and A498 (IC₅₀ of 0.85 ± 0.24 μM). Furthermore, the chloroacetyl-containing thiazole compound 7a displayed efficient inhibition of growth against the test cell lines CAKI1 and A498 at low micromolar concentrations, IC₅₀ 0.78 and 0.74 μM, respectively.     

Formation of 5α-dihydrotestosterone from 5α-androstane-3α,17β-diol in prostate cancer LAPC-4 cells – Identifying inhibitors of non-classical pathways producing the most potent androgen

5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen, following non-classical pathways. We reported the chemical synthesis of non-commercially available [4-¹⁴C]-3α-diol from [4-¹⁴C]-T, and the development of a biological assay to identify inhibitors of the 5α-DHT formation from radiolabeled 3α-diol in LAPC-4 cell PC model. We measured the inhibitory potency of 5α-androstane derivatives against the formation of 5α-DHT, and inhibition curves were obtained for the most potent compounds (IC₅₀ = 1.2–14.1 μM). The most potent inhibitor 25 (IC₅₀ = 1.2 μM) possesses a 4-(4-CF₃-3-CH₃O-benzyl)piperazinyl methyl side chain at C3β and 17β-OH/17α-CCH functionalities at C17 of a 5α-androstane core.     

Phytoconstituents of Selaginella effusa Alston and Their α-Glucosidase as well as Urease Inhibitory Activities

Three new compounds ( 1 – 2 , 14 ), as well as 22 known compounds ( 3 – 13 , 15 – 25 ), were extracted for the first time from the Selaginella effusa Alston (S. effusa). For the unknown compounds, the planar configurations were determined via NMR and by high-resolution mass spectrometry, while their absolute configurations were determined by calculated electronic circular dichroism (ECD), and the configuration of the stereogenic center of biflavones 4 – 5 were established for the first time. The pure compounds ( 1 – 25 ) were tested in vitro to determine the inhibitory activity of the enzyme-catalyzed reactions. Compounds 1 – 9 inhibited α-glucosidase with IC₅₀ values ranging from 0.30±0.02 to 4.65±0.04 μM and kinetic analysis of enzyme inhibition indicated that biflavones 1 – 3 were mixed-type α-glucosidase inhibitors. Compounds 12 – 13 showed excellent inhibitory activity against urease, with compound 12 (IC₅₀=4.38±0.31 μM) showing better inhibitory activity than the positive control drug AHA (IC₅₀13.52±0.61 μM). In addition, molecular docking techniques were used to simulate inhibitor-enzyme binding and to estimate the binding posture of the α-glucosidase and urease catalytic sites.     

2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis,in vitro and in silico studies

Twenty-five thiadiazole derivatives 1–25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC₅₀ = 26.05 ± 0.60 μM), 2 (IC₅₀ = 42.53 ± 0.80 μM), 4 (IC₅₀ = 38.74 ± 0.70 μM), 5 (IC₅₀ = 9.30 ± 0.29 μM), 6 (IC₅₀ = 6.74 ± 0.26 μM), 7 (IC₅₀ = 18.40 ± 0.66 μM), and 15 (IC₅₀ = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d-saccharic acid-1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.     

Bioactive secondary metabolites from the marine-associated fungus Aspergillus terreus

Three new compounds, including a prenylated tryptophan derivative, luteoride E (1), a butenolide derivative, versicolactone G (2), and a linear aliphatic alcohol, (3E,7E)-4,8-dimethyl-undecane-3,7-diene-1,11-diol (3), together with nine known compounds (4–12), were isolated and identified from a coral-associated fungus Aspergillus terreus. Their structures were elucidated by HRESIMS, one- and two-dimensional NMR analysis, and the absolute configuration of 2 was determined by comparison of its electronic circular dichroism (ECD) spectrum with the literature. Structurally, compound 1 featured an unusual (E)-oxime group, which occurred rarely in natural products. Compounds 1–3 were evaluated for the α-glucosidase inhibitory activity, and compound 2 showed potent inhibitory potency with IC₅₀ value of 104.8 ± 9.5 μM, which was lower than the positive control acarbose (IC₅₀ = 154.7 ± 8.1 µM). Additionally, all the isolated compounds were evaluated for the anti-inflammatory activity against NO production, and compounds 1–3, 5–7, and 10 showed significant inhibitory potency with IC₅₀ values ranging from 5.48 to 29.34 μM.     

Undescribed Phenolic Glycosides from Syzygium attopeuense and Their Inhibition of Nitric Oxide Production

Four undescribed phenolic glycosides including three stilbene derivatives ( 1 and 3 ) and sodium salt of 3 ( 2 ), and a chalcone glycoside ( 4 ), together with thirteen known compounds ( 5 – 17 ) were isolated from the leaves of Syzygium attopeuense (Gagnep.) Merr. & L.M.Perry. Their chemical structures were elucidated to be (Z)-gaylussacin ( 1 ), 6′′-O-galloylgaylussacin sodium salt ( 2 ), 6′′-O-galloylgaylussacin ( 3 ), 4′-O-[β-D-glucopyranosyl-(1→6)-glucopyranosyl]oxy-2′-hydroxy-6′-methoxydihydrochalcone ( 4 ), gaylussacin ( 5 ), pinosilvin 3-O-β-D-glucopyranoside ( 6 ), myricetin-3-O-(2′′-O-galloyl)-α-L-rhamnopyranoside ( 7 ), myricetin-3-O-(3′′-O-galloyl)-α-L-rhamnopyranoside ( 8 ), myricetin-3-O-α-L-rhamnopyranoside ( 9 ), quercitrin ( 10 ), myricetin-3-O-β-D-glucopyranoside ( 11 ), myricetin-3-O-β-D-galactopyranoside ( 12 ), quercetin 3-O-α-L-arabinopyranoside ( 13 ), myricetin-3-O-2′′-O-galloyl)-α-L-arabinopyranoside ( 14 ), (+)-gallocatechin ( 15 ), (−)-epigallocatechin ( 16 ), and 3,3’,4’-trimethoxyellagic acid 4-O-β-D-glucopyranoside ( 17 ) by the analysis of HR-ESI-MS, 1D and 2D NMR spectra in comparison with the previously reported data. Compounds 1–3 , 5 , and 6 significant inhibition of NO production in LPS-activated RAW264.7 cells, with IC₅₀ values ranging from 18.37±1.38 to 35.12±2.53 μM, compared to a positive control (dexamethasone) with an IC₅₀ value of 15.37±1.42 μM.     

1-[(4′-Chlorophenyl) carbonyl-4-(aryl) thiosemicarbazide derivatives as potent urease inhibitors: Synthesis,in vitro and in silico studies

A series of 1-[(4′-chlorophenyl)carbonyl-4-(aryl)thiosemicarbazide derivatives 1–25 was synthesized and characterized by spectroscopic techniques such as EI-MS and ¹H NMR. All compounds were screened for urease inhibitory activity in vitro and demonstrated excellent inhibitory activity in the range of IC₅₀ = 0.32 ± 0.01–25.13 ± 0.13 μM as compared to the standard thiourea (IC₅₀ = 21.25 ± 0.13 μM). Amongst the potent analogs, compounds 3 (IC₅₀ = 2.31 ± 0.01 μM), 6 (IC₅₀ = 2.14 ± 0.04 μM), 10 (IC₅₀ = 1.14 ± 0.06 μM), 20 (IC₅₀ = 2.15 ± 0.05 μM), and 25 (IC₅₀ = 0.32 ± 0.01 μM) are many folds more active than the standard. Structure-activity relationship (SAR) was rationalized by looking at the effect of diversely substituted aryl ring on inhibitory potential which predicted that regardless of the nature of substituents, their positions on aryl ring is worth important for the potent activity. Furthermore, to verify these interpretations, in silico study was performed on all compounds and a good correlation was perceived between the biological evaluation and docking study of compounds.