Reem K. Arafa

Zewail City of Science and Technology

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i-10 index

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Co-Authors

Mohamed A. Ismail

Cairo University

W. David Wilson

Georgia State University

Reto Brun

Swiss Tropical and Public Health Institute

Mostafa M. Ghorab

Egyptian Atomic Energy Authority

Ibrahim M. El‐Sherbiny

Zewail City of Science and Technology

Nehal H. Elghazawy

Zewail City of Science and Technology

Tanja Wenzler

University of Basel

David W. Boykin

Georgia State University

Nada K. Sedky

Zewail City of Science and Technology

Manoj Munde

Jawaharlal Nehru University

Cooperative Institutions

Cairo University

Zewail City of Science and Technology

Al-Azhar University

National Research Centre

Georgia State University

Centre National de la Recherche Scientifique

Inserm

Mansoura University

Al-Azhar University

Bu-Ali Sina University

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Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides

Journal of Enzyme Inhibition and Medicinal Chemistry (2014)

Mostafa M. Ghorab Maureen Higgins Mansour S. Alsaid Reem K. Arafa Abdelaaty A. Shahat

In biological systems, the Keap1/Nrf2/antioxidant response element pathway determines the ability of mammalian cells to adapt and survive conditions of oxidative, electrophilic and inflammatory stress by regulating the production of cytoprotective enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) being one of them. Novel biologically active benzenesulfonamides 2, 3, 5–7, penta-2,4-dienamide 4 and chromene-2-carboxamide 8 structurally augmented with an electron-deficient Michael acceptor enone or cyanoenone functionalities were prepared. A new biological activity was conferred to these molecules, that of induction of NQO1. The potency of induction was increased by incorporation of a nitrile group adjacent to the enone and the dinitrophenyl derivative 3 was the most promising inducer. Also, molecular docking of the new compounds in the Nrf2-binding site of Keap1 was performed to assess their ability to inhibit Keap1 which biologically leads to a consequent Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed considerable interactions between the new molecules and essential binding site amino acids.

Enone

Docking (animal)

KEAP1

10.3109/14756366.2013.858146

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Citations (7)

Design, synthesis and structure–activity relationship of novel semi-synthetic flavonoids as antiproliferative agents

European Journal of Medicinal Chemistry (2014)

Fatma A. Ragab Tawfeek Ahmed Ali Yahya Mona M. El-Naa Reem K. Arafa

Flavones

Structure–activity relationship

10.1016/j.ejmech.2014.06.007

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Citations (34)

New oxadiazoles with selective-COX-2 and EGFR dual inhibitory activity: Design, synthesis, cytotoxicity evaluation and in silico studies

European Journal of Medicinal Chemistry (2019)

Nehad A. El-Sayed Mai S. Nour M. Alaraby Salem Reem K. Arafa

ADME

MTT assay

10.1016/j.ejmech.2019.111693

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Citations (57)

Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents

ACS Chemical Neuroscience (2022)

Nehal H. Elghazawy Dalia Zaafar Reham R. Hassan Mohamed Y. Mahmoud Loay Bedda

Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC50 = 50.87 nM) and BuChE (IC50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDA-approved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark β-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.

Butyrylcholinesterase

IC50

Docking (animal)

10.1021/acschemneuro.1c00766

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Citations (19)

Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

Biomolecules (2021)

Amr El‐Demerdash Ahmed M. Metwaly Afnan Hassan Tarek Mohamed Abd El‐Aziz Eslam B. Elkaeed

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

Phosphoprotein

Guanidine

Binding affinities

10.3390/biom11030460

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Citations (71)

Antibacterial and anticancer profiling of new benzocaine derivatives: Design, synthesis, and molecular mechanism of action

Archiv der Pharmazie (2022)

Heba S. A. Elzahabi Eman S. Nossier Safya M. Mousa Heba A. Hassan Al Shimaa Gamal Shalaby

The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents.

ADME

Mechanism of Action

Benzocaine

10.1002/ardp.202100451

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Citations (7)

Synthesis and in vitro investigation of novel cytotoxic pyrimidine and pyrazolopyrimidne derivatives showing apoptotic effect

Bioorganic Chemistry (2020)

Fatma A. Ragab Yassin M. Nissan Emad M. Seif Ahmed Maher Reem K. Arafa

IC50

10.1016/j.bioorg.2020.103621

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Citations (18)

Computer-assisted drug discovery of potential natural inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase through a multi-phase in silico approach

Antiviral Therapy (2023)

Eslam B. Elkaeed Bshra A. Alsfouk Tuqa H. Ibrahim Reem K. Arafa Hazem Elkady

The COVID-19 pandemic has led to significant loss of life and economic disruption worldwide. Currently, there are limited effective treatments available for this disease. SARS-CoV-2 RNA-dependent RNA polymerase (SARS-CoV-2 RdRp) has been identified as a potential target for drug development against COVID-19. Natural products have been shown to possess antiviral properties, making them a promising source for developing drugs against SARS-CoV-2.The objective of this study is to identify the most effective natural inhibitors of SARS-CoV-2 RdRp among a set of 4924 African natural products using a multi-phase in silico approach.The study utilized remdesivir (RTP), the co-crystallized ligand of RdRp, as a starting point to select compounds that have the most similar chemical structures among the examined set of compounds. Molecular fingerprints and structure similarity studies were carried out in the first part of the study. The second part of the study included molecular docking against SARS-CoV-2 RdRp (PDB ID: 7BV2) and Molecular Dynamics (MD) simulations including the calculation of RMSD, RMSF, Rg, SASA, hydrogen bonding, and PLIP. Moreover, the calculations of Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) Lennard-Jones and Columbic electrostatic interaction energies have been conducted. Additionally, in silico ADMET and toxicity studies were performed to examine the drug likeness degrees of the selected compounds.Eight compounds were identified as the most effective natural inhibitors of SARS-CoV-2 RdRp. These compounds are kaempferol 3-galactoside, kaempferol 3-O-β-D-glucopyranoside, mangiferin methyl ether, luteolin 7-O-β-D-glucopyranoside, quercetin-O-β-D-3-glucopyranoside, 1-methoxy-3-indolylmethyl glucosinolate, naringenin, and asphodelin A 4'-O-β-D-glucopyranoside.The results of this study provide valuable information for the development of natural product-based drugs against COVID-19. However, the elected compounds should be further studied in vitro and in vivo to confirm their efficacy in treating COVID-19.

Docking (animal)

DrugBank

ADME

10.1177/13596535231199838

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Citations (11)

In vitro activity and preliminary toxicity of various diamidine compounds against Trypanosoma evansi

Veterinary Parasitology (2010)

Kirsten Gillingwater Arvind Kumar Mohamed A. Ismail Reem K. Arafa Chad E. Stephens

Trypanosoma evansi

Trypanosoma brucei rhodesiense

Diminazene

10.1016/j.vetpar.2010.01.019

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Citations (15)

Development and validation of an LC‒MS/MS method for the determination of cyclocreatine phosphate and its related endogenous biomolecules in rat heart tissues

BMC Chemistry (2024)

Ibrahim F. Abo-Elmagd Amr M. Mahmoud Medhat A. Al‐Ghobashy Marianne Nebsen Mostafa A. Rabie

The cardioprotective drug cyclocreatine phosphate has been awarded Food and Drug Administration-orphan drug designation for the prevention of ischemic injury to enhance cardiac graft recovery and survival in heart transplantation. Cyclocreatine phosphate is the water-soluble derivative of cyclocreatine. Estimating the levels of Cyclocreatine phosphate, Adenosine triphosphate, Creatine Phosphate, Creatine and Cyclocreatine helps us in understanding the energy state as well as evaluating the heart cells' function. The quantification of endogenous compounds imposes a challenging task for analysts because of the absence of a true blank matrix, whose use is required according to international guidelines. Recently, the International Council for Harmonization issued a new guideline that contains guidance on the validation of methods used to quantify endogenous components, such as the background subtraction approach that was employed in our current study. Specifically, we developed and validated a sensitive, reliable and accurate liquid chromatography-tandem mass spectrometry assay to determine simultaneously the levels of mentioned endogenous compounds in rat heart tissue. Tissue samples were prepared by protein precipitation extraction using water: methanol (1:1). Using Ultra Performance Liquid Chromatography, Chromatographic separation was achieved with ZORBAX Eclipse Plus C18 4.6 × 100 mm,3.5 μm column and conditions as following: ammonium acetate (pH 8.5): acetonitrile, 70:30 mobile phase, 0.7 mL/min flow rate and 25 °C temperature. Electrospray ionization mass detector with Multiple reaction monitoring mode was then employed, using both positive and negative modes, Analysis was carried out using 5.00–2000.00 ng/mL linear concentration range within 2 min for each analyte. According to Food and Drug Administration guidelines for bioanalytical methods, validation was carried out. We investigated the matrix effect, recovery efficiency and process efficiency for the analyte in neat solvent, postextraction matrix and tissue. The results stated mean percentage recoveries higher than 99%, accuracy 93.32–111.99%, and Relative Standard Deviation (RSD) below 15% within the concentration range of our study which indicated that target analytes' stability in their real matrix is sufficient under the employed experimental conditions. Development of a validated LC‒MS/MS method to quantify levels of CCrP, ATP, CrP, Crt, and CCr, simultaneously. LC‒MS/MS method is sensitive, simple and suitable for preclinical trials for CCrP quantitation in different biological fluids. Validated method with good selectivity, linearity, and stability for CCrP in the rat heart. Efficient CCrP quantitation to improve outcomes for heart transplant patients.

Biomolecule

10.1186/s13065-024-01304-1

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Citations (0)