Hits-to-Lead Optimization of the Natural Compound 2,4,6-Trihydroxy-3-geranyl-acetophenone (tHGA) as a Potent LOX Inhibitor: Synthesis, Structure-Activity Relationship (SAR) Study, and Computational Assignment

A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a–g (half maximal inhibitory concentration (IC50) values ranging from 35 μ M to 95 μ M) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μ M) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μ M, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a–g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

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Thioester-Containing Benzoate Derivatives with α-Glucosidase Inhibitory Activity from the Deep-Sea-Derived Fungus Talaromyces indigoticus FS688

Marine Drugs ◽

10.3390/md20010033 ◽

2021 ◽

Vol 20 (1) ◽

pp. 33

Author(s):

Mingqiong Li ◽

Saini Li ◽

Jinhua Hu ◽

Xiaoxia Gao ◽

Yanlin Wang ◽

...

Keyword(s):

Inhibitory Activity ◽

Deep Sea ◽

Spectroscopic Analysis ◽

X Ray Diffraction ◽

Docking Analysis ◽

X Ray ◽

Structure Activity ◽

Ic50 Value ◽

Ic50 Values ◽

Benzoate Derivatives

Eurothiocins C–H (1–6), six unusual thioester-containing benzoate derivatives, were isolated from the deep-sea-derived fungus Talaromyces indigoticus FS688 together with a known analogue eurothiocin A (7). Their structures were elucidated through spectroscopic analysis and the absolute configurations were determined by X-ray diffraction and ECD calculations. In addition, compound 1 exhibited significant inhibitory activity against α-glucosidase with an IC50 value of 5.4 μM, while compounds 4 and 5 showed moderate effects with IC50 values of 33.6 and 72.1 μM, respectively. A preliminary structure–activity relationship is discussed and a docking analysis was performed.

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Characterization of Maltase and Sucrase Inhibitory Constituents from Rhodiola crenulata

Foods ◽

10.3390/foods8110540 ◽

2019 ◽

Vol 8 (11) ◽

pp. 540 ◽

Cited By ~ 2

Author(s):

Wen-Tai Li ◽

Yu-Hsuan Chuang ◽

Jung-Feng Hsieh

Keyword(s):

Inhibitory Activity ◽

Inhibitory Concentration ◽

Epicatechin Gallate ◽

Competitive Inhibitors ◽

Inhibition Kinetic ◽

Ic50 Values ◽

Rhodiola Crenulata ◽

Inhibition Constants

The inhibitory properties of epicatechin-(4β,8)-epicatechingallate (B2-3’-O-gallate), epicatechin gallate (ECG), and epicatechin (EC) isolated from Rhodiola crenulata toward maltase and sucrase were investigated. The half-maximal inhibitory concentration (IC50) values for maltase were as follows: B2-3’-O-gallate (1.73 ± 1.37 μM), ECG (3.64 ± 2.99 μM), and EC (6.25 ± 1.84 μM). Inhibition kinetic assays revealed the inhibition constants (Ki) of the mixed-competitive inhibitors of maltase, as follows: B2-3’-O-gallate (1.99 ± 0.02 μM), ECG (3.14 ± 0.04 μM), and EC (7.02 ± 0.26 μM). These compounds also showed a strong inhibitory activity toward sucrase, and the IC50 values of B2-3’-O-gallate, ECG, and EC were 6.91 ± 3.41, 18.27 ± 3.99, and 18.91 ± 3.66 μM, respectively. Inhibition kinetic assays revealed the inhibition constants (Ki) of the mixed-competitive inhibitors of sucrase as follows: B2-3’-O-gallate (6.05 ± 0.04 μM), ECG (8.58 ± 0.08 μM), and EC (13.72 ± 0.15 μM). Overall, these results suggest that B2-3’-O-gallate, ECG, and EC are potent maltase and sucrase inhibitors.

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Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

Phytothérapie ◽

10.3166/phyto-2018-0074 ◽

2018 ◽

Vol 17 (3) ◽

pp. 134-139

Author(s):

R.M. Perez-Gutierrez

Keyword(s):

Protein Tyrosine Phosphatase ◽

Inhibitory Activity ◽

Spectroscopic Data ◽

Methanol Extract ◽

Tyrosine Phosphatase ◽

Positive Control ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Ic50 Value ◽

Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

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Novel photochromic inhibitor for mitotic kinesin Eg5 which forms multiple isomerization states

The Journal of Biochemistry ◽

10.1093/jb/mvab035 ◽

2021 ◽

Author(s):

Islam Md Alrazi ◽

Kei Sadakane ◽

Shinsaku Maruta

Keyword(s):

Inhibitory Activity ◽

Molecular Motor ◽

The Novel ◽

Precise Control ◽

Atpase Assay ◽

Ic50 Value ◽

Motor Activities ◽

Ic50 Values ◽

Kinesin Eg5 ◽

Mitotic Kinesin Eg5

Abstract The mitotic kinesin Eg5 is a plus-end directed homotetrameric molecular motor essential for the formation of bipolar spindles during cell division. Kinesin Eg5 is overexpressed in cancer cells and hence considered as a target for cancer therapy; the inhibitors specific for Eg5 have been developed as anticancer drugs. In this study, we synthesized a novel functional photoresponsive inhibitor composed of spiropyran and azobenzene derivatives to control Eg5 function with multistage inhibitory activity accompanied by the formation of different isomerization states. The photochromic inhibitor spiropyran-sulfo-azobenzene (SPSAB) exhibited three isomerization states: spiro (SP)-trans, merocyanine (MC)-cis and MC-trans, upon exposure to visible light, ultraviolet and in the dark, respectively. SPSAB-induced reversible changes in the inhibitory activity of ATPase and motor activities correlating with photoisomerization among the three states. Among the three isomerization states of SPSAB, the SP-trans isomer showed potent inhibitory activity at an IC50 value of 30 µM in the basal ATPase assay. MC-trans and MC-cis exhibited less inhibitory activity at IC50 values of 38 and 86 µM, respectively. The results demonstrated that the novel photochromic inhibitor enabled precise control of Eg5 function at three different levels using light irradiation.

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Inhibitory Activity of Extracts from Mycelia Materials of Several Mushrooms on the Angiotensin I-Converting Enzyme

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.610-613.3541 ◽

2012 ◽

Vol 610-613 ◽

pp. 3541-3544

Author(s):

Pei Sheng Yan ◽

Xiu Jun Gao

Keyword(s):

Liquid Medium ◽

Inhibitory Activity ◽

Water Extract ◽

Angiotensin I ◽

Water Extracts ◽

Angiotensin I Converting Enzyme ◽

Ic50 Value ◽

Ic50 Values ◽

The Difference ◽

Ace Inhibitory

ACE inhibitory activities of water extracts from mycelia of 6 kinds of mushrooms in liquid fermentation were investigated. All strains cultivated in shaking flask containing liquid medium, and yield of mycelia ranged from 0.051 to 1.392 g mycelia/day/L liquid medium in average. Resulting mycelia were extracted with distilled water at 50°Cfor 200 min, and the yield of water extracts from mycelia ranged from 287.475 to 490.088 mg/g dried mycelia. These water extracts were used to assay their ACE inhibitory activity. Results showed that their IC50 values ranged from 1.277 to 5.250 mg/ml. The difference among IC50 values of these water extracts were significant (p<0.05 or p<0.001). Lactarius camphorates (IC50: 1.646±0.061mg/mL) was the specie which had relatively lower IC50 value than others, as well as relatively higher water extract yield. The results highlighted the potential for making antihypertensive functional foods or drugs from liquid cultured mycelia of Lactarius camphorates.

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Isolation of Endophytic Fungi QPS 05 from Quercus phillyraeoides A. Gray and Its Potential for α-Glucosidase Inhibitory Activity

Jurnal Kimia Terapan Indonesia ◽

10.14203/jkti.v20i1.372 ◽

2018 ◽

Vol 20 (1) ◽

pp. 1-7

Author(s):

Anastasia Wheni Indrianingsih ◽

Amalia Indah Prihantini ◽

Sanro Tachibana

Keyword(s):

Fatty Acids ◽

Endophytic Fungi ◽

Inhibitory Activity ◽

Endophytic Fungus ◽

Inhibitory Concentration ◽

Life Cycles ◽

Ic50 Values ◽

Quercus Phillyraeoides ◽

Alternaria Sp ◽

Harmful Effects

AbstractEndophytic fungi are the microorganisms that spend all or part of their life cycles within plant tissue without causing harmful effects on the plant. In this study, 14 endophytic fungus from Quercus phillyraeoides A. Gray were isolated. Alternaria sp. QPS 05, an endophytic fungi which was isolated from the stem of Q. phillyraeoides A. Gray showed the highest α-glucosidase inhibitory activity. Further separation of ethyl acetate extract from the fungus led to the isolation of active substance from hexane-soluble fraction which give fatty acids mixture consist of palmitic acid, oleic acid, linoleic acid and linolenic acid (1) strong inhibitory activity against α-glucosidase. Isolated fatty acids (1) had inhibitory concentration (IC50) values against Saccharomyces cerevisiae was 12.10 μg/mL. The results of the present study showed that endophytic fungus from Alternaria sp. QPS 05 potentially contained a rich source of natural antidiabetic medicine.

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Study on α-glucosidase inhibitory activity of 40 kinds of vegetables, tubers, and fruits in An Giang

Vietnam Journal of Science Technology and Engineering ◽

10.31276/vjste.63(4).42-46 ◽

2021 ◽

Vol 63 (4) ◽

pp. 42-46

Author(s):

Thi-My-Linh Lam ◽

◽

Minh-Tuan Le ◽

Manh-Ha Bui ◽

◽

...

Keyword(s):

Glycine Max ◽

Inhibitory Activity ◽

Positive Control ◽

Syzygium Cumini ◽

Inhibition Rate ◽

Ic50 Value ◽

Areca Catechu ◽

Ic50 Values

A study on the α-glucosidase inhibitory activity of 40 kinds of vegetables, tubers, and fruits found in the An Giang province was conducted. The results indicated that all 40 extracted samples displayed α-glucosidase inhibitory activity at a concentration of 250 μg ml-1, 36 extracted samples showed an inhibition rate greater than 50% at 250 μg ml-1, 25 extracted samples had over 50% at 100 μg ml-1, 17 extracted samples possessed more than 50% at 50 μg ml-1, 7 extracted samples sampled showed over 50% at 25 μg ml-1, 5 extracted samples were greater than 50% at 10 μg ml-1, and 1 extracted sample was greater than 50% at 1 μg ml-1. Among the 40 samples, those taken from the seeds of Areca catechu, the fruits of Cassia grandis, the fruits of Syzygium cumini, the seeds of Glycine max,andthe stems of Enydra fluctuansexhibited the strongest α-glucosidase inhibitory activity in methanol, with IC50 values of 0.15, 2.54, 4.05, 5.17 and 8.68 μg ml-1, respectively, which were stronger than the positive control acarbose with an IC50 value of 214.5 μg ml-1

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Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

Molecules ◽

10.3390/molecules26216640 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6640

Author(s):

Derya Osmaniye ◽

Berkant Kurban ◽

Begüm Nurpelin Sağlık ◽

Serkan Levent ◽

Yusuf Özkay ◽

...

Keyword(s):

Inhibitory Activity ◽

Active Sites ◽

Docking Study ◽

Fluorometric Method ◽

Mao B ◽

Micromolar Concentration ◽

Ic50 Value ◽

Competitive Inhibitors ◽

New Compounds

MAO-B inhibitors are frequently used in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Due to the limited number of compounds available in this field, there is a need to develop new compounds. In the recent works, it was shown that various thiosemicarbazone derivatives show hMAO inhibitory activity in the range of micromolar concentration. It is thought that benzofuran and benzothiophene structures may mimic structures such as indane and indanone, which are frequently found in the structures of such inhibitors. Based on this view, new benzofuran/benzothiophene and thiosemicarbazone hybrid compounds were synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The compounds including methoxyethyl substituent (2b and 2h) were found to be the most effective agents in the series against MAO-B enzyme with the IC50 value of 0.042 ± 0.002 µM and 0.056 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition of compounds 2b and 2h was investigated by Lineweaver–Burk graphics. Compounds 2b and 2h were reversible and non-competitive inhibitors with similar inhibition features as the substrates. The Ki values of compounds 2b and 2h were calculated as 0.035 µM and 0.046 µM, respectively, with the help of secondary plots. The docking study of compound 2b and 2h revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound.

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α-Glucosidase Inhibitory Activity of Cycloartane-Type Triterpenes Isolated from Indonesian Stingless Bee Propolis and Their Structure–Activity Relationship

Pharmaceuticals ◽

10.3390/ph12030102 ◽

2019 ◽

Vol 12 (3) ◽

pp. 102 ◽

Cited By ~ 7

Author(s):

Niken Pujirahayu ◽

Debu Kumar Bhattacharjya ◽

Toshisada Suzuki ◽

Takeshi Katayama

Keyword(s):

Inhibitory Activity ◽

Antioxidant Activities ◽

Stingless Bee ◽

Structure Activity Relationships ◽

Glucosidase Inhibitor ◽

Structure Activity ◽

Glucosidase Inhibitors ◽

Ic50 Values ◽

New Type ◽

Treatment Of Diabetes

This study reports on the antioxidant activity and α-glucosidase inhibitory activity of five cycloartane-type triterpenes isolated from Indonesian stingless bee (Tetragonula sapiens Cockerell) propolis and their structure–activity relationships. The structure of the triterpenes was determined to include mangiferolic acid (1), Cycloartenol (2), ambonic acid (3), mangiferonic acid (4), and ambolic acid (5). The inhibitory test results of all isolated triterpenes against α-glucosidase showed a high potential for inhibitory activity with an IC50 range between 2.46 and 10.72 µM. Among the compounds tested, mangiferonic acid (4) was the strongest α-glucosidase inhibitor with IC50 2.46 µM compared to the standard (–)-epicatechin (1991.1 µM), and also had antioxidant activities with IC50 values of 37.74 ± 6.55 µM. The study on the structure–activity relationships among the compounds showed that the ketone group at C-3 and the double bonds at C-24 and C-25 are needed to increase the α-glucosidase inhibitory activity. The carboxylic group at C-26 is also more important for increasing the inhibitory activity compared with the methyl group. This study provides an approach to help consider the structural requirements of cycloartane-type triterpenes from propolis as α-glucosidase inhibitors. An understanding of these requirements is deemed necessary to find a new type of α-glucosidase inhibitor from the cycloartane-type triterpenes or to improve those inhibitors that are known to help in the treatment of diabetes.

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Synthesis and Evaluation of Glycyrrhetic Acid-aromatic Hybrids as Anti-inflammatory Agents

Medicinal Chemistry ◽

10.2174/1573406415666190603095502 ◽

2020 ◽

Vol 16 (6) ◽

pp. 715-723

Author(s):

Zhi Chen ◽

Shi-Chao Chen ◽

Bo Li ◽

Yong-An Yang ◽

Jing Zhang

Keyword(s):

Biological Response ◽

Glycyrrhetic Acid ◽

X Ray Diffraction ◽

X Ray ◽

New Class ◽

Structure Activity ◽

Body Tissues ◽

Ic50 Values ◽

Anti Inflammatory ◽

Sar Study

Background: : Inflammation is a biological response of body tissues to harmful stimuli, so it is desirable to search for novel anti-inflammatory agents with improved pharmaceutical profiles and reduced adverse effects. Objective: : This study was to explore natural anti-inflammatory agents and improve therapeutic application of glycyrrhetic acid (GA) through molecular hybridization with active aromatics. Methods: : Fourteen novel GA-aromatic hybrids were synthesized and evaluated for their antiinflammatory activities by inhibiting LPS-induced nitric oxide (NO) release in RAW264.7 cells. The synthesized compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR and HRMS. Result: : The structure-activity relationship (SAR) study indicated that compounds with styryl displayed better NO inhibitory activity. Among them, compounds 2a and 3c exhibited the most promising activity with IC50 values of 9.93 μM and 12.25 μM, respectively. In addition, X-ray singlecrystal diffraction data for compounds 2e and 3c showed that the absolute configuration of GA skeleton was consistent with that of natural 18 β-glycyrrhetic acid. Conclusion: : The results showed that GA-aromatic hybrids were a new class of anti-inflammatory agents and this study provided useful information on further optimization.

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