Yeast@MOF bioreactor as a tumor metabolic symbiosis disruptor for the potent inhibition of metabolically heterogeneous tumors

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

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Synthesis of Novel 8-Hydroxyquinoline Derivatives through Mannich Reaction and their Biological Evaluation as Potential Immunomodulatory Agents

Medicinal Chemistry ◽

10.2174/1573406415666190626121650 ◽

2020 ◽

Vol 16 (4) ◽

pp. 531-543

Author(s):

Shaheen Faizi ◽

Tahira Sarfaraz ◽

Saima Sumbul ◽

Almas Jabeen ◽

Sobia A. Halim ◽

...

Keyword(s):

Mannich Reaction ◽

Aromatic Aldehydes ◽

Mannich Bases ◽

Biological Evaluation ◽

Mechanism Of Inhibition ◽

Potent Inhibition ◽

Tnf Α ◽

Elisa Technique ◽

Factor Α ◽

New Compounds

Background: In continuation of our work on Mannich reaction on 8-hydroxyquinoline, fifteen different combinations of aromatic aldehydes and aniline were subjected to Mannich reaction from which twelve products (eight Mannich bases, two imines and two intramolecularly cyclized products with benzofuranone skeleton) were obtained. Among them six compounds (1, 2, 6, 8, 9 and 12) are the new compounds. The structures of the compounds were characterized by UV, IR, MS and 1H NMR. Method: The compounds were tested for the inhibition of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) at a concentration of 25 µg/mL. The cytokines were produced by THP-1 cells differentiated with PMA for 24hrs and stimulated with LPS for 4 hrs and supernatant were analyzed through ELISA technique. Results and Discussion: Compounds 1-5, 8 and 9 inhibited the production of TNF-α and IL-1β. Compounds 1, 3, and 8 exerted potent inhibitions of TNF-α with 71%, 71%, and 83% inhibition, respectively. Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Conclusion: Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Notably compound 8 showed the most potent inhibition of these cytokines. Additionally, the effect of compounds on viability of THP-1 cells was also evaluated. Moreover, molecular docking was carried out to study the mechanism of inhibition of TNF-α production.

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Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

Pharmaceuticals ◽

10.3390/ph14010038 ◽

2021 ◽

Vol 14 (1) ◽

pp. 38

Author(s):

Hyo Jeong Lee ◽

Pyeonghwa Jeong ◽

Yeongyu Moon ◽

Jungil Choi ◽

Jeong Doo Heo ◽

...

Keyword(s):

Thyroid Cancer ◽

Thyroid Carcinoma ◽

Kinase Inhibitor ◽

Point Mutations ◽

Carcinoma Cells ◽

Medullary Thyroid ◽

Potent Inhibition ◽

Kinase Inhibitory Activity

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

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Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

Antibiotics ◽

10.3390/antibiotics10020162 ◽

2021 ◽

Vol 10 (2) ◽

pp. 162

Author(s):

Ahmed Ragab ◽

Sawsan A. Fouad ◽

Ola A. Abu Ali ◽

Entsar M. Ahmed ◽

Abeer M. Ali ◽

...

Keyword(s):

Antimicrobial Activity ◽

Fungal Growth ◽

Dna Gyrase ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Design Synthesis ◽

Potent Inhibition ◽

Ic50 Values ◽

Dhfr Inhibitors ◽

Positive Controls

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.

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Structural and Functional Basis of Potent Inhibition of Leishmanial Leucine Aminopeptidase by Peptidomimetics

ACS Omega ◽

10.1021/acsomega.1c02386 ◽

2021 ◽

Author(s):

Saleem Yousuf Bhat ◽

Insaf Ahmed Qureshi

Keyword(s):

Leucine Aminopeptidase ◽

Functional Basis ◽

Potent Inhibition

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Assessment of the Aromatase Inhibitory Activity of Ma-Huang-Tang (MHT) and Its Active Compounds

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/4809846 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Dong Ho Jung ◽

Joo Tae Hwang ◽

Bo-Jeong Pyun ◽

Song Yi Yu ◽

Byoung Seob Ko

Keyword(s):

Herbal Medicines ◽

Inhibitory Effect ◽

Aromatase Activity ◽

Cytochrome P450 Enzyme ◽

Active Components ◽

Glycyrrhizae Radix ◽

Potent Inhibition ◽

P450 Enzyme ◽

Medicine Prescription ◽

Ma Huang

Aromatase, a cytochrome P450 enzyme that converts androgens into estrogens, is an important drug target for hormone-dependent diseases. The purpose of this study was to elucidate the aromatase inhibitory effects of Ma-Huang-Tang (MHT), a traditional Korean herbal medicine prescription, and to identify its active ingredients. In this study, the inhibitory effect of MHT on aromatase activity was observed using dibenzylfluorescein (DBF) and KGN cells, and the dose-dependent effect of MHT was verified (IC50 values of 251 μg/mL and 246 μg/mL as determined by the two methods, respectively). Furthermore, among the six herbal medicines that constitute MHT, Ephedrae Herba, Cinnamomi Ramulus, and Glycyrrhizae Radix et Rhizoma showed the most potent inhibition of aromatase activity. Furthermore, upon identification of the active MHT compounds, three markers from Glycyrrhizae Radix et Rhizoma, liquiritin (5), liquiritin apioside (6), and liquiritigenin (7), were verified (IC50 values of 530 μM, 508 μM, and 1.611 mM and 499 μM, 522 μM, and 1.41 mM as determined by the two methods, respectively). In addition, their contents were confirmed to be 15.58, 19.80, and 2.22 mg/g, respectively, by HPLC/DAD analysis. These results indicate that the aromatase inhibitory effect of MHT results from the synergistic action of its active components and that MHT has potential as a preventive agent against aromatase activity.

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Potent Inhibition of Hendra Virus Infection via RNA Interference and Poly I:C Immune Activation

PLoS ONE ◽

10.1371/journal.pone.0064360 ◽

2013 ◽

Vol 8 (5) ◽

pp. e64360 ◽

Cited By ~ 5

Author(s):

Jana L. McCaskill ◽

Glenn A. Marsh ◽

Paul Monaghan ◽

Lin-Fa Wang ◽

Timothy Doran ◽

...

Keyword(s):

Rna Interference ◽

Virus Infection ◽

Immune Activation ◽

Hendra Virus ◽

Poly I:C ◽

Potent Inhibition

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Design and synthesis of a novel 5-(aminomethylene)thiazolidine-2,4-dione derivatives as potent hepatitis-B virus polymerase inhibitors

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i2.21876 ◽

2015 ◽

Vol 10 (2) ◽

pp. 271

Author(s):

Wei-Guo Li ◽

He-Qun Wang

Keyword(s):

Hbv Dna ◽

Biologically Active ◽

Secondary Amines ◽

Design And Synthesis ◽

H Nmr ◽

Viral Antigens ◽

Polymerase Inhibitors ◽

Potent Inhibition ◽

B Virus ◽

C Nmr

A series of novel thiazolidinedione analogues (TZD) were designed and synthesized potent inhibitors of HBV capsid assembly. The synthesis of thiazolidine-2,4-dione derivatives (4a–4o), starting from the condensation of 5-(ethoxymethylene)thiazolidine-2,4-dione (1) with various secondary amines (3) derived from biologically active compounds. The newly synthesized TZD analogues 4a-4o were characterized by 1H NMR, 13C NMR, and MS and evaluated for their anti-HBV activity. Most of the compounds inhibited the expression of viral antigens at low concentration. Six compounds, 4g, 4h, 4l, 4m, 4n, and 4o, demonstrated potent inhibition of HBV DNA replication at submicromolar range. Of these five initial hits, compound 4o was the most active when compared with lamivudine.

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