11 results on '"Mohamed K. El-Ashrey"'
Search Results
2. 1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights
- Author
-
Tarfah Al-Warhi, Hadia Almahli, Raed M. Maklad, Zainab M. Elsayed, Mahmoud A. El Hassab, Ohoud J. Alotaibi, Nada Aljaeed, Rezk R. Ayyad, Hazem A. Ghabour, Wagdy M. Eldehna, Mohamed K. El-Ashrey, Maklad, Raed M [0000-0002-5219-4842], El Hassab, Mahmoud A [0000-0002-6795-4816], Ghabour, Hazem A [0000-0002-1011-0276], Eldehna, Wagdy M [0000-0001-6996-4017], El-Ashrey, Mohamed K [0000-0002-3548-3888], Apollo - University of Cambridge Repository, Maklad, Raed M. [0000-0002-5219-4842], El Hassab, Mahmoud A. [0000-0002-6795-4816], Ghabour, Hazem A. [0000-0002-1011-0276], Eldehna, Wagdy M. [0000-0001-6996-4017], and El-Ashrey, Mohamed K. [0000-0002-3548-3888]
- Subjects
anti-proliferative ,thiazole ,isatin ,MCF-7 cells ,A-549 cells ,VEGFR-2 inhibitor ,molecular dynamics ,Molecular Structure ,Organic Chemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Vascular Endothelial Growth Factor Receptor-2 ,Article ,Analytical Chemistry ,Molecular Docking Simulation ,Structure-Activity Relationship ,Chemistry (miscellaneous) ,Drug Discovery ,MCF-7 Cells ,Molecular Medicine ,Humans ,Physical and Theoretical Chemistry ,Drug Screening Assays, Antitumor ,Protein Kinase Inhibitors ,Cell Proliferation - Abstract
Human health is experiencing several obstacles in the modern medical era, particularly cancer. As a result, the cancer therapeutic arsenal should be continually expanded with innovative small molecules that preferentially target tumour cells. In this study, we describe the development of two small molecule series (7a–d and 12a–e) based on the 1-benzyl-5-bromoindolin-2-one scaffold that connected through a hydrazone linker to a 4-arylthiazole (7a–d) or 4-methyl-5-(aryldiazenyl)thiazole (12a–e) moiety. The anticancer activity of all the reported indolin-2-one derivatives was assessed against breast (MCF-7) and lung (A-549) cancer cell lines. The 4-arylthiazole-bearing derivatives 7c and 7d revealed the best anticancer activity toward MCF-7 cells (IC50 = 7.17 ± 0.94 and 2.93 ± 0.47, respectively). Furthermore, the VEGFR-2 inhibitory activity for 7c and 7d was evaluated. Both molecules disclosed good inhibitory activity, and their IC50 values were equal to 0.728 µM and 0.503 µM, respectively. Additionally, the impacts of 7d on the cell cycle phases as well as on the levels of different apoptotic markers (caspase-3, caspase-9, Bax, and Bcl-2) were assessed. Molecular docking and dynamic simulations are carried out to explore the binding mode of 7d within the VEGFR-2 active site.
- Published
- 2023
3. Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as Anti-colorectal Agents
- Author
-
Nahed N. E. El-Sayed, Norah M. Almaneai, Abir Ben Bacha, Mohamed K. El-Ashrey, Maha I. Al-Zaben, and Zainab M. Almarhoon
- Subjects
General Chemical Engineering ,General Chemistry - Abstract
Colorectal carcinogenesis is a complex process, which is linked to dysregulation of human secretory phospholipases A
- Published
- 2022
4. Pharmacophore based virtual screening for natural product database revealed possible inhibitors for SARS-COV-2 main protease
- Author
-
Mohamed K. El-Ashrey, Riham O. Bakr, Marwa A.A. Fayed, Rana H. Refaey, and Yassin M. Nissan
- Subjects
Molecular Docking Simulation ,Biological Products ,SARS-CoV-2 ,Virology ,Humans ,Protease Inhibitors ,Antiviral Agents ,Pandemics ,Coronavirus 3C Proteases ,Peptide Hydrolases ,COVID-19 Drug Treatment - Abstract
The challenge continues globally triggered by the absence of an approved antiviral drug against COVID-19 virus infection necessitating global concerted efforts of scientists. Nature still provides a renewable source for drugs used to solve many health problems. The aim of this work is to provide new candidates from natural origin to overcome COVID-19 pandemic. A virtual screening of the natural compounds database (47,645 compounds) using structure-based pharmacophore model and molecular docking simulations reported eight hits from natural origin against SARS-CoV-2 main proteinase (Mpro) enzyme. The successful candidates were of terpenoidal nature including taxusabietane, Isoadenolin AC, Xerophilusin B, Excisanin H, Macrocalin B and ponicidin, phytoconstituents isolated from family Lamiaceae and sharing a common ent-kaurane nucleus, were found to be the most successful candidates. This study suggested that the diterpene nucleus has a clear positive contribution which can represent a new opportunity in the development of SARS-CoV-2 main protease inhibitors.
- Published
- 2022
5. Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer
- Author
-
Mohamed K. El-Ashrey, Seham Alterary, Shimaa Kamal, Hamed A. Derbala, Mona Alonazi, Nahed N. E. El-Sayed, and Abir Ben Bacha
- Subjects
chemistry.chemical_classification ,Antioxidant ,Chemistry ,General Chemical Engineering ,medicine.medical_treatment ,General Chemistry ,Sodium Dichloroacetate ,Metabolism ,Enzyme ,Biochemistry ,Cell culture ,medicine ,Cytotoxic T cell ,Cytotoxicity ,QD1-999 ,ADME - Abstract
Initiation of colorectal carcinogenesis may be induced by chromosomal instability caused by oxidative stress or indirectly by bacterial infections. Moreover, proliferating tumor cells are characterized by reprogrammed glucose metabolism, which is associated with upregulation of PDK1 and LDHA enzymes. In the present study, some 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in addition to Fe3O4 and Fe3O4/SiO2 nanoparticles (NPs) supported with a new Schiff base were synthesized for biological evaluation as PDK1 and LDHA inhibitors as well as antibacterial, antioxidant, and cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer (CRC). The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC50 values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. NPs12a,b and compound 1b exhibited the strongest antioxidant properties with IC50 values (μg/mL) of 80.0, 95.0, and 110.0 μg/mL, respectively, compared to 54.0 μg/mL, which was produced by butylated hydroxy toluene. Moreover, NPs12a and carbamate derivative 3b exhibited significant cytotoxic activities with IC50 values (μg/mL) of 57.15 and 81.50 (LoVo cells) and 60.35 and 71.00 (HCT-116 cells). Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.
- Published
- 2021
6. Novel Pyridothienopyrimidine Derivatives: Design, Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents
- Author
-
Eman M. Mohi El-Deen, Manal M. Anwar, Amina A. Abd El-Gwaad, Eman A. Karam, Mohamed K. El-Ashrey, and Rafika R. Kassab
- Subjects
antimicrobial activity ,thieno[2,3-b]pyridine ,Pharmaceutical Science ,Organic chemistry ,Antineoplastic Agents ,Analytical Chemistry ,Molecular Docking Simulation ,cyclization reactions ,QD241-441 ,Pyrimidines ,Anti-Infective Agents ,Chemistry (miscellaneous) ,Cell Line, Tumor ,Drug Design ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Humans ,HepG-2 cells ,MCF-7 cells ,Physical and Theoretical Chemistry ,pyridothienopyrimidines ,EGFR-PK inhibition ,molecular docking - Abstract
The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC50 ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC50 ranges of 7.27–17.29 nM, higher than that of erlotinib, IC50 = 27.01 nM.
- Published
- 2021
7. Some 2-(4-bromophenoxymethyl)-6-iodo-3-substituted quinazolin-4(3H)ones: Synthesis, cytotoxic activity, EGFR inhibition and molecular docking
- Author
-
Safinaz E-S. Abbas, Nagwa M. Abdel-Gawad, Riham F. George, Mohamed G. Abu Elyazid, Marwa A. Zaater, and Mohamed K. El-Ashrey
- Subjects
Inorganic Chemistry ,Organic Chemistry ,Spectroscopy ,Analytical Chemistry - Published
- 2022
8. Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile
- Author
-
Mohamed K. El-Ashrey, Bahia Abbas Moussa, Asmaa A. El-Zaher, and Marwa A. Fouad
- Subjects
Cyclopropanes ,Male ,Metabolite ,Cmax ,Aminopyridines ,Pharmaceutical Science ,01 natural sciences ,High-performance liquid chromatography ,Analytical Chemistry ,Rats, Sprague-Dawley ,Hydroxylation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Tandem Mass Spectrometry ,In vivo ,medicine ,Animals ,Humans ,Environmental Chemistry ,030216 legal & forensic medicine ,Chromatography, High Pressure Liquid ,Spectroscopy ,Roflumilast ,Chromatography ,Chemistry ,010401 analytical chemistry ,Blood Proteins ,Rats ,0104 chemical sciences ,Liver ,S9 fraction ,Benzamides ,Phosphodiesterase 4 Inhibitors ,Protein Binding ,medicine.drug - Abstract
With the aim of studying their in vitro and in vivo pharmacokinetics, new chromatographic methods were developed for the determination of three new roflumilast synthetic analogs (I-III) as PDE-4B inhibitors in rat liver S9 fraction, phosphate buffered saline, pH 7.4, and human and rat plasma. The developed high performance liquid chromatography-ultra violet (HPLC-UV) methods were performed on a Zorbax Eclipse C8 column and UV detection was carried out at 215 nm. The three compounds were tested for their metabolic stability and were found to be metabolically more stable than roflumilast especially the 2-mercaptobenzothiazol-6-yl analog (III) which displayed an in vitro half-life time (247.55 minutes) higher than that of roflumilast (12.29 minutes) and a low in vitro clearance of 5.67 mL/min./kg. Possible phase I metabolites were investigated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showing hydroxylation of the unsubstituted benzothiazol-2-yl (I) and benzothiazole-6-yl (II) analogs and a cleaved benzothiazole metabolite of the 2-mercaptobenzothiazol-6-yl analog (III). Plasma protein binding affinity was tested using equilibrium membrane dialysis method showing a very high percentage (more than 95%) of plasma protein binding of compounds I and II where compound III exhibited lower percentage (53.71%) demonstrating its accessibility for tissue distribution. Also, a UPLC-MS/MS method was developed using an Acquity UPLC BEH shield RP C18 column to be applied to an in vivo pharmacokinetic study in rats following a subcutaneous dose (1 mg/kg). Compounds I-III showed improved in vivo pharmacokinetic parameters especially compound III which displayed a half-life 3-fold greater than roflumilast (21 hours) and a Cmax value of 113.958 ng/mL. Accordingly, this new chemical entity should be subjected to further investigation as it can be a good drug candidate for treating chronic obstructive pulmonary disease.
- Published
- 2019
9. Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme
- Author
-
Eman M. Mohi El-Deen, Manal M. Anwar, Amina A. Abd El-Gwaad, Eman A. Karam, Mohamed K. El-Ashrey, and Rafika R. Kassab
- Subjects
Chemistry ,EGFR inhibitors ,Pyridothienopyrimidines ,General Chemical Engineering ,General Chemistry ,Antimicrobial activity ,QD1-999 ,Anticancer activity - Abstract
A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFRWT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFRL858R and EGFRT790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFRWT and its mutant forms EGFRL858R and EGFRT790M than that obtained by erlotinib (IC50 = 0.021, 0.053, 0.081 µM, respectively, IC50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFRWT.
- Published
- 2022
10. Repurposing of renin inhibitors as SARS-COV-2 main protease inhibitors: A computational study
- Author
-
Mohamed K El-Ashrey, Yassin M. Nissan, and Rana H. Refaey
- Subjects
Models, Molecular ,Antagonists & inhibitors ,medicine.drug_class ,medicine.medical_treatment ,Pharmacology ,Renin inhibitor ,Article ,03 medical and health sciences ,Catalytic Domain ,Virology ,Renin ,medicine ,Protease Inhibitors ,Coronavirus 3C Proteases ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Virtual screening ,Protease ,biology ,SARS-CoV-2 ,030302 biochemistry & molecular biology ,Drug Repositioning ,Imidazoles ,COVID-19 ,Active site ,COVID-19 Drug Treatment ,Drug repositioning ,Enzyme ,chemistry ,biology.protein ,Remikiren ,Pharmacophore ,Computational study ,Repurposing ,Protein Binding - Abstract
The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42–5892) of Hoffmann–La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme., Graphical abstract Image 1, Highlights • For rapid management of COVID-19, drug repurposing was widely carried out. • Renin inhibitors downregulate ACE2, decreasing the risk of SARS-COV-2 infection. • SARS-COV-2 main protease is a potential target for renin inhibitors. • Pharmacophore model was generated and virtually screened on renin inhibitors. • Remikiren was a hit, furtherly studied through molecular docking and dynamics.
- Published
- 2021
- Full Text
- View/download PDF
11. Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile
- Author
-
Marwa A. Fouad, Bahia Abbas Moussa, Mohamed K. El-Ashrey, and Asmaa A. El-Zaher
- Subjects
0301 basic medicine ,Cyclopropanes ,Stereochemistry ,Cmax ,Aminopyridines ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Pulmonary Disease, Chronic Obstructive ,Pharmacokinetics ,Catalytic Domain ,Drug Discovery ,medicine ,Cyclic AMP ,Potency ,Benzamide ,Roflumilast ,Pharmacology ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Chemistry ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Active site ,Hydrogen Bonding ,General Medicine ,0104 chemical sciences ,Amino acid ,Molecular Docking Simulation ,030104 developmental biology ,Benzamides ,biology.protein ,Phosphodiesterase 4 Inhibitors ,Selectivity ,medicine.drug - Abstract
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a Cmax value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.