First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-<i>N</i>-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent

Farag, Ahmed Karam,Hassan, Ahmed H.E.,Jeong, Hyeanjeong,Kwon, Youngji,Choi, Jin Gyu,Oh, Myung Sook,Park, Ki Duk,Kim, Yun Kyung,Roh, Eun Joo Elsevier 2019 European journal of medicinal chemistry Vol.162 No.-

<P><B>Abstract</B></P> <P>Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound <B>3l</B>, the most potent DAPK1 inhibitor in the <I>in vitro</I> kinase assay (IC<SUB>50</SUB> = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC<SUB>50</SUB> = 5.0 μM). Also, compound <B>3l</B> elicited potent inhibition of CSF1R in the <I>in vitro</I> kinase assay (IC<SUB>50</SUB> = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound <B>3l</B> as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the <I>in silico</I> calculations illustrated binding of compound <B>3l</B> to the substrate-binding site of DAPK1. Hence, compound <B>3l</B> might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Multifunctional DAPK1 and CSF1R inhibitors for targeting tauopathies. </LI> <LI> <B>3l</B> shows good potency and excellent affinity and within-family selectivity for both kinases. </LI> <LI> Mechanistic study showed <B>3l</B> as non-ATP-competitive DAPK1 inhibitor and ATP-competitive CSF1R inhibitor. </LI> <LI> <B>3l</B> has tau aggregation inhibition and anti-neuroinflammatory activity in cellular assays. </LI> <LI> hERG binding and PAMPA assays revealed <B>3l</B> as a cardiosafe and has a high membrane penetration. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Review of the chemistry of first-generation Tau PET tracers

Ahmed Karam Farag,임창근,강충모,이용진 대한방사성의약품학회 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.1

Alzheimer’s disease (AD) is one of the challenging conditions that have no cure, yet early diagnosis can help to control the disease. PET imaging of tau has several advantages, such as being a noninvasive, safe diagnostic technique that correlates directly with the disease progression. Many tau tracers have been reported to date; however, the chemical scaffolds of them fall in a narrow chemical window, and none was approved yet as none is entirely selective and sensitive to tau. These problems are being solved as new tracers emerge constantly. In this report, the first-generation tau tracers such as [11C]PBB3, 2-arylquinoline (THK) series, [18F]T808, and [18F]AV-1451 ([18F]T807) are reviewed from an organic and radiochemistry perspective; thus the most effective chemical approach to synthesize these tracers is discussed. This would help to design novel tracers which can meet the challenges faced by the current tracers.

Review of the chemistry of first-generation Tau PET tracers

Farag, Ahmed Karam,Im, Changkeun,Kang, Choong Mo,Lee, Yong Jin Korean Society of Radiopharmaceuticals and Molecul 2020 Journal of radiopharmaceuticals and molecular prob Vol.6 No.1

Alzheimer's disease (AD) is one of the challenging conditions that have no cure, yet early diagnosis can help to control the disease. PET imaging of tau has several advantages, such as being a noninvasive, safe diagnostic technique that correlates directly with the disease progression. Many tau tracers have been reported to date; however, the chemical scaffolds of them fall in a narrow chemical window, and none was approved yet as none is entirely selective and sensitive to tau. These problems are being solved as new tracers emerge constantly. In this report, the first-generation tau tracers such as [¹¹C]PBB3, 2-arylquinoline (THK) series, [¹⁸F]T808, and [¹⁸F]AV-1451 ([¹⁸F]T807) are reviewed from an organic and radiochemistry perspective; thus the most effective chemical approach to synthesize these tracers is discussed. This would help to design novel tracers which can meet the challenges faced by the current tracers.

Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

Farag, Ahmed Karam,Elkamhawy, Ahmed,Londhe, Ashwini M.,Lee, Kyung-Tae,Pae, Ae Nim,Roh, Eun Joo Elsevier 2017 European Journal of Medicinal Chemistry Vol.141 No.-

<P><B>Abstract</B></P> <P>Tyrosine kinases including LCK and FMS are involved in inflammatory disorders as well as many types of cancer. Our team has designed and synthesized thirty novel pyrimidine based inhibitors targeting LCK, classified into four different series (amides, ureas, imines (Schiff base) and benzylamines). Twelve of them showed nanomolar IC<SUB>50</SUB> values. Compound <B>7g</B> showed excellent selectivity profile and was selectively potent over FMS kinase (IC<SUB>50</SUB> value of 4.6 nM). Molecular docking study was performed to help us rationalize the obtained results and predict the possible binding mode for our compounds in both LCK and FMS. Based on the obtained biological assay data and modelling results, a detailed SAR study was discussed. As a further testing regarding the anti-inflammatory effect of the new compounds, <I>in vitro</I> cellular assay over RAW 264.7 macrophages was performed. Compound <B>7g</B> exhibited excellent anti-inflammatory effect. Therefore, we report the design of novel phenoxypyrimidine derivatives as potent and selective LCK inhibitors and the discovery of <B>7g</B> as potent and selective FMS/LCK dual inhibitor for the potential application in inflammatory disorders including rheumatoid arthritis (RA).</P> <P><B>Highlights</B></P> <P> <UL> <LI> Potent LCK/FMS inhibitors have been designed and synthesized. </LI> <LI> Nanomolar IC<SUB>50</SUB> values over both kinases were obtained. </LI> <LI> Excellent selectivity for LCK/FMS over closely related kinases was found. </LI> <LI> <B>7g</B> showed excellent anti-inflammatory activity on RAW 264.7 macrophages cell line. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

The enhancing of 2-pyrazinecarboxamide inhibition effect on the acid corrosion of carbon steel in presence of iodide ions

Ahmed A. Farag,Tamer Awad Ali 한국공업화학회 2015 Journal of Industrial and Engineering Chemistry Vol.21 No.1

The inhibition effect of 2-pyrazinecarboxamide (PCA), KI and their synergistic effect on the corrosion ofcarbon steel in 0.5 M H2SO4 solution was studied by electrochemical techniques. Scanning electronmicroscopy (SEM) was used to characterize the steel surface. The inhibition efficiency increases with theconcentration of PCA and KI and increase further in the presence of PCA/KI mixture. The open circuitpotential and polarization measurements suggested that PCA and its mixture with KI act as mixed-typeinhibitor; while, KI only acts as mixed-type inhibitor with a predominant anodic inhibitor. Theadsorption of PCA and KI on the metal surface in 0.5 M H2SO4 solution obeys the Langmuir adsorptionisotherm. The thermodynamic parameters Kads and DG8ads are calculated and discussed. The probableinhibitory mechanism is proposed from the viewpoint of adsorption theory. The synergism parametersuggests that there is a cooperative mechanism between the iodide anion and PCA cations.

Performance Evaluation of Blackhole Attack on VANET's Routing Protocols

Eman Farag Ahmed,Reham Abdellatif Abouhogail,Ahmed Yahya 보안공학연구지원센터 2014 International Journal of Software Engineering and Vol.8 No.9

Therapeutic Potential of Artichoke in the Treatment of Fatty Liver: A Systematic Review and Meta-Analysis

Ahmed Mohamed Kamel,Mohamed Ali Farag 한국식품영양과학회 2022 Journal of medicinal food Vol.25 No.10

Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and death. Artichoke leaf extract (ALE) is well known in folk medicine for its hepatoprotective effect. Till recent times, no sufficient data from randomized clinical trials (RCTs) exist to support such use. This meta-analysis summarizes evidence from recent RCTs that evaluated ALE in NAFLD patients. Electronic databases were searched for RCTs that used ALE in NAFLD patients. The random-effects model was used to pool effect sizes (standardized change score). Data synthesis from five RCTs (333 patients) showed that ALE resulted in a significant reduction in alanine aminotransferase (standardized mean difference [SMD]: 1.1; 95% confidence interval [CI], 0.79–1.73; P < .001) and aspartate aminotransferase levels (SMD: 1.01; 95% CI, 0.52–1.51; P < .001) compared with the control group. ALE also resulted in a significant reduction in total cholesterol (SMD: 0.98; 95% CI, 0.53–1.43; P = .004), low-density lipoprotein (SMD: 0.96; 95% CI, 0.3–1.62; P < .001) and triglycerides (SMD: 0.95; 95% CI, 0.58–1.32; P < .001). The current review provides evidence from RCTs to support the use of ALE as a hepatoprotective agent in NAFLD patients. The study was registered on the PROSPERO database with the Registration No. CRD42020182502 (https://www.crd.york.ac.uk/prospero).

A Comprehensive Large-Wind-Turbine Emulator for Accurate Wind-Energy Harvest Evaluation

Farag Wael A.,Hemeida Ahmed M.,Mahgoub Osama A. 대한전기학회 2024 Journal of Electrical Engineering & Technology Vol.19 No.3

Robust modeling and emulation are required to support the design of ultra-wind turbines and analyze the efects of various factors, parameters, and environmental disturbances. The models that are constructed based on pure computational methods, in which the entire emulator is created in computational software are cost-efective, and their speed depends on the employed computation platform. However, these methods' practical signifcance and accuracy are considerably lower than that of the combined physical and computational platform methods. Therefore, A comprehensive 5 MW wind turbine emulator’s design and implementation are investigated thoroughly in this paper. A separately excited DC motor set under the control of a current-controlled drive forms the basis of the suggested emulation. The emulation algorithms that simulate the features of the 5 MW wind turbine are executed on a digital signal processor. These algorithms regulate the DC motor's current, which in turn regulates the torque. The results obtained demonstrate that the system was successful in accurately simulating the transient and steady-state characteristics of the 5 MW wind turbine. The emulator system was initially tested and validated with simulation results using MATLAB/Simulink code attached to both the FAST and TurbSim models. Furthermore, step and stochastic wind profles were used to experimentally verify and test it. Nearly all of the power that is available in the wind turbine system is successfully acquired using the maximum power point tracking technique, which is used to fnd the optimum operating point. The developed wind turbine emulator can be used to precisely assess energy harvesting by examining various mechanical and electrical input/output values of the Permanent Magnet Synchronous Generator vastly used in ultra-large wind turbine nacelles.

Performance improvement of hybrid renewable energy sources connected to the grid using artificial neural network and sliding mode control

Elnozahy, Ahmed,Yousef, Ali M.,Abo‑Elyousr, Farag K.,Mohamed, Moayed,Abdelwahab, Saad A. Mohamed The Korean Institute of Power Electronics 2021 JOURNAL OF POWER ELECTRONICS Vol.21 No.8

The main purpose of this paper to compare and analyze three types of controllers in the three phases DC-AC inverters in hybrid renewable energy source (HRES) systems. To achieve this, two modern controllers are developed and compared based on sliding mode control (SMC) and artificial neural network techniques. The HRESs comprise photovoltaic (PV), wind turbines, battery storage systems, and transmission lines connected to infinite bus bars via a step-up transformer. The developed controllers at the inverter side utilize both voltage control and current regulation. A DC-DC boost converter is employed to set up a voltage demand at the point of common coupling (PCC). Then, the formulation of an HRES with the developed controllers is presented. The developed controllers are considered to operate under various solar radiations, temperatures, and wind speed loading conditions. The HRESs with the developed controllers are simulated via MATLAB/Simulink to verify the effectiveness of the developed controllers. The obtained results demonstrate that adaptive SMC and artificial ANN control techniques give better results in terms of input power, output power, current, and voltage when compared to classic PI control.

Optimal Economic and Environmental Indices for Hybrid PV/ Wind-Based Battery Storage System

Elnozahy Ahmed,Yousef Ali M.,Ghoneim Sherif S. M.,Abdelwahab Saad A. Mohamed,Mohamed Moayed,Abo-Elyousr Farag K. 대한전기학회 2021 Journal of Electrical Engineering & Technology Vol.16 No.6

This paper shows an application of hybrid PV/wind energy and battery storage in the islanded area. This work’s main target allows the distributed energy resources to contribute effi ciently in the economic feasibility and enhance the environmental impact of the hybrid renewable energy source. Several factors such as levelized cost of energy (COE), greenhouse gas (GHG) emissions, and loss of power supply probability are studied. A combined solution is to compromise the economic and environmental aspects via the Utopia point approach is investigated. The optimal confi guration of the hybrid PV/wind along with battery-storage and diesel engine as secondary source is obtained via meta-heuristic optimizers: Genetic Algorithm (GA) and Particle-Swarm Optimization (PSO) and impartial comparison of the results with HOMER software. The results of Utopia point solution show that the PV (about 46%) and wind turbine (about 13%) are shared signifi cantly as primary renewable sources and battery storage (about 39%) as storage options. Meanwhile, the diesel engine (about 3%) has insignifi cant sharing in feeding the demand load. The optimal COE and GHG, which are achieved via GA and PSO optimization techniques are 0.182$/kWh and 12076 kg/year, agansit 0.343$/kWh and 17618 kg/year that are obtained via HOMER software, respectively. This corssponing to 47% and 31% reduction in COE and GHG, respectively. Sensitivity studies demonstrate that the variation of the wind energy sharing from 50 to 150% shows that the wind energy has a slight eff ect considering the GHG emissions. Contrarily, lower PV sharing ratios undesirably raises the levelized COE, however, reduces the GHG emissions.