scholarly journals Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4630
Author(s):  
Liang Xia ◽  
Yan Zhang ◽  
Jingbo Zhang ◽  
Songwen Lin ◽  
Kehui Zhang ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Heterocyclic Compounds ◽  
Kinase Inhibitors ◽  
High Resolution Mass Spectrometry ◽  
Inhibitory Potency ◽  
Docking Analysis ◽  
Ic50 Value ◽  
Phosphoinositide 3 Kinase ◽  
Sar Study ◽  
Potent Inhibitory Activity

A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.

scholarly journals 1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2805
Author(s):  
Yanlin Jian ◽  
Fabian Hulpia ◽  
Martijn D. P. Risseeuw ◽  
He Eun Forbes ◽  
Guy Caljon ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Cell Activity ◽  
Fold Increase ◽  
Antimycobacterial Activity ◽  
Inhibitory Potency ◽  
Substitution Pattern ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Ic50 Value ◽  
Strain H37rv

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

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

Marine Drugs ◽  
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.

In SilicoDesign and Synthesis of Targeted Curcumin Derivatives as Xanthine Oxidase Inhibitors

2019 ◽  
Vol 20 (5) ◽  
pp. 593-603
Author(s):  
Neelam Malik ◽  
Priyanka Dhiman ◽  
Anurag Khatkar
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Pyrimidine Ring ◽  
Inhibitory Potency ◽  
Curcumin Derivatives ◽  
Xanthine Oxidase Inhibitors ◽  
Excess Production ◽  
Ic50 Values ◽  
Inhibitory Potential ◽  
Potent Inhibitory Activity

Background: Curcumin is a well-known pharmacophore and some of its derivatives are shown to target xanthine oxidase (XO) to alleviate disorders caused by the excess production of uric acid. </p><p> Objective: Curcumin based derivatives were designed, synthesized and evaluated for their antioxidant and xanthine oxidase inhibitory potential. </p><p> Method: In this report, we designed and synthesized two series of curcumin derivatives modified by inserting pyrazole and pyrimidine ring to central keto group. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. </p><p> Results: Results showed that pyrazole analogues of curcumin produced excellent XO inhibitory potency with the IC50 values varying from 06.255 &#181;M to 10.503 &#181;M. Among pyrimidine derivatives compound CU3a1 having ortho nitro substitution exhibited more potent xanthine oxidase inhibitory activity than any other curcumin derivative of this series. </p><p> Conclusion: Curcumin derivatives CU5b1, CU5b2, CU5b3, and CU3a1 showed a potent inhibitory activity against xanthine oxidase along with good antioxidant potential.

scholarly journals Inhibition of Soybean 15-Lipoxygenase by Naturally Occurring Acetophenones and Derricidin

2015 ◽  
Vol 10 (4) ◽  
pp. 1934578X1501000
Author(s):  
Vito Alessandro Taddeo ◽  
Francesco Epifano ◽  
Salvatore Genovese ◽  
Serena Fiorito
Keyword(s):  
Secondary Metabolites ◽  
Inhibitory Activity ◽  
Inhibitory Potency ◽  
Naturally Occurring ◽  
Potent Inhibitory Activity

Three selected naturally occurring oxyprenylated secondary metabolites, namely 2-hydroxy4-isopentenyloxyacetophenone (1), 4-geranyloxy-2-hydroxyacetophenone (2), 4-farnesyloxyacetophenone (3), and derricidin (4) were synthesized and their inhibitory potency against soybean 15-lipoxygenase evaluated. Compounds 1 and 4 showed the most potent inhibitory activity with IC50 values of 2.5 μM and 0.6 μM.

scholarly journals Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4461 ◽  
Author(s):  
Haiyan Sun ◽  
Linsheng Zhuo ◽  
Huan Dong ◽  
Wei Huang ◽  
Nengfang She
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Biological Screening ◽  
Binding Interactions ◽  
Lead Structure ◽  
Lead Compounds ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Insight Into

The 2,7-naphthyridone scaffold has been proposed as a novel lead structure of MET inhibitors by our group. To broaden the application of this new scaffold, a series of 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one derivatives were designed and synthesized. Preliminary biological screening resulted in the discovery of a new lead of c-Kit and VEGFR-2 kinase inhibitors. Compound 9k exhibited excellent c-Kit inhibitory activity, with an IC50 value of 8.5 nM, i.e., it is 38.8-fold more potent than compound 3 (IC50 of 329.6 nM). Moreover, the compounds 10l and 10r exhibited good VEGFR-2 inhibitory activity, with IC50 values of 56.5 and 31.7 nM, respectively, i.e., they are 5.0–8.8-fold more potent than compound 3 (IC50 of 279.9 nM). Molecular docking experiments provided further insight into the binding interactions of the new lead compounds with c-Kit and VEGFR-2 kinase. In this study, an 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one scaffold was identified as the new lead structure of c-Kit and VEGFR-2 kinase inhibitors.

scholarly journals 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

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2509 ◽  
Author(s):  
Chean Ng ◽  
Kamal Rullah ◽  
Faridah Abas ◽  
Kok Lam ◽  
Intan Ismail ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Inhibitory Concentration ◽  
Alkyl Chain ◽  
Kinetics Study ◽  
Toxicity Prediction ◽  
Structure Activity ◽  
Ic50 Value ◽  
Competitive Inhibitors ◽  
Ic50 Values ◽  
Sar Study

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.

scholarly journals Phloroglucinol Derivatives from Dryopteris crassirhizoma as Potent Xanthine Oxidase Inhibitors

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 122
Author(s):  
Heung Joo Yuk ◽  
Ji-Yul Kim ◽  
Yoon-Young Sung ◽  
Dong-Seon Kim
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Etoac Extract ◽  
Xanthine Oxidase Inhibitors ◽  
Ic50 Value ◽  
Phloroglucinol Derivatives ◽  
Acetyl Group ◽  
Potent Inhibitory Activity ◽  
Better Than ◽  
Comparative Activity

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3′ is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1–4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.

EVALUATION OF MANGROVE PLANTS AS PUTATIVE HIV-PROTEASE INHIBITORS

INDIAN DRUGS ◽  
2013 ◽  
Vol 50 (07) ◽  
pp. 41-44
Author(s):  
A. A. Rege ◽  
◽  
A. S Chowdhary
Keyword(s):  
Inhibitory Activity ◽  
In Vitro Study ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Reverse Transcriptase ◽  
Mangrove Plants ◽  
Ic50 Value ◽  
Anti Hiv ◽  
Potent Inhibitory Activity

Ethanol (Direct) extracts of mangrove plants, namely, Avicennia officinalis Linn. and Rhizophora mucronata Lam. were included for the present in vitro study. Pepsin was used as a substitute for HIV-protease to evaluate inhibitory activity of these extracts, as pepsin has close resemblance with HIV-protease in proteolytic activity. R. mucronata revealed potent inhibitory activity than A. officinalis with IC50 value of 14.63 µg/mL. In our earlier study, R. mucronata exerted anti-HIV activity via multiple mechanisms of action; viz., interference with the gp120 / CD4 interaction and inhibition of HIV-reverse transcriptase. In the present study, it also showed potent inhibitory activity against pepsin enzyme (indirectly against HIV-protease) which may be due its high flavonoids content.

scholarly journals Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Stéphane L. Raeppel ◽  
Frédéric Gaudette ◽  
Hannah Nguyen ◽  
Normand Beaulieu ◽  
James Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Residual Activity ◽  
Significant Activity ◽  
Trka Receptor ◽  
Sar Study ◽  
Nanomolar Range ◽  
Receptor Tyrosine Kinase Inhibitors

A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.

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