PHR-Theses-MSc
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Item Restricted Protocol analytical study of some hormonal drugs in bulk powder and pharmaceutical preparations /Abdelsalam, Mohamed Ismail,; Supervisor : Samy El Sayed Emara, Ghada Mekawy Haddad Tawfeik, Omneya Mohamed Kamel. Includes Ararbic Summary.Item Restricted Simple and reliable analytical techniques for drug analysis in pharmaceutical and bio-fluids forms /Maghraby, Abdelrahman Nabil,; Suoervisor : Rasha Mahmoud Ahmed, Randa Abdel-Salam, Noha Ibrahim Shaaban. Includes Ararbic Summary.In the field of pharmaceutical analysis, a recent challenge involves quantifying and resolving drugs within a variety of matrices. These matrices contain different endogenous compounds that can interfere with drug analysis. The compounds investigated throughout this work were determined in pharmaceutical dosage form, human plasma, and urine. These compounds include amlodipine, olmesartan, and molnupiravir. The thesis consists of five parts. Part I: General Introduction and Literature Review This part provides an overview of common analytical and extraction techniques used for separating mixtures, and a brief on the experimental design. Also it discusses pharmacological effect of selected compounds, their structures and solubility in different solvents and literature review about techniques for detection of drugs in pharmaceutical dosage and bio-fluids forms. Part II: Chromatographic determination of Amlodipine and Olmesartan in pharmaceutical dosage form and human plasma using HPLC. This part is subdivided into four sections: Section A: Chromatographic determination of Amlodipine and Olmesartan in pharmaceutical dosage form using HPLC coupled with UV-detector. In this section, High-Performance Liquid Chromatography (HPLC) technique using UV detector has been developed for the determination of amlodipine and olmesartan in pharmaceutical dosage forms. The method focused on obtaining the optimal conditions for separating these drugs effectively. Separation was achieved by using a mobile phase consisting of acetonitrile and 0.01M potassium dihydrogen phosphate ratio (40:60, v/v) at pH 2.5. Elution was performed isocratically at a wavelength of 254.0 nm, with a flow rate of 1.0 mL/min. This proposed method was successfully applied to pharmaceutical dosage forms available in the local market. Section B: Chromatographic determination of Amlodipine and Olmesartan in human plasma using HPLC coupled with UV-detector. In this section, HPLC technique using UV detector has been developed for the determination of amlodipine and olmesartan in human plasma. The method focused on using the optimal conditions for separating these drugs effectively without interference from the plasma endogenous compounds. Separation was achieved by using a mobile phase consisting of acetonitrile and 0.01M potassium dihydrogen phosphate (32:68, v/v) at pH 2.5. Elution was performed isocratically at a wavelength of 254.0 nm, with a flow rate of 1.0 mL/min. Section C: Chromatographic determination of Amlodipine in pharmaceutical dosage form using HPLC coupled with Fluorescence-detector. In this study, an HPLC method with Fluorescence detection includes the determination of amlodipine in its drug formulation. The separation was carried out at using mobile phase composed of acetonitrile and potassium dihydrogen phosphate buffer (pH 2) in ratio (40:60, v/v%), The isocratic elution performed at emission adjusted at 439 nm and the excitation at 254 nm and the flow rate was 1.0 mL/min. Section D: Chromatographic determination of Amlodipine in human plasma using HPLC coupled with Fluorescence-detector. In this section, an HPLC method using fluorescence detector, enables the determination of amlodipine with good accuracy and precision to allow its detection in human plasma. The developed method was based on obtaining optimum conditions to separate the drug and avoid the interference of the plasma endogenous compounds. The separation was carried out with mobile phase of acetonitrile and 0.01M dihydrogen phosphate (pH 2.5) in ratio (32:68, v/v%). The flow rate was adjusted to 1.0 mL/min at emission wavelength of 439.0 nm and excitation wavelength at 254.0 nm. Part III: Spectroscopic methods for the determination of Amlodipine and Olmesartan with the aid of chemometrics This part is subdivided into three sections: Section A: Introduction to chemometrics This section includes an introduction about most common multivariate data analysis techniques used to identify drugs in binary mixtures. Also it demonstrates the process of multivariate calibration, data preprocessing, and model validation. Section B: Spectrophotometric method for the determination of Amlodipine and Olmesartan with the aid Of Chemometrics In this section, a spectrophotometric method for analysis of binary mixtures containing amlodipine and olmesartan was demonstrated. At first principal component regression (PCR) was used for obtaining the outer layers and scores. Partial least squares (PLS) was applied as multivariant method a calibration sets were prepared of different ratios of the binary mixtures. A leave one out cross-validation procedure was employed to find out the optimum numbers of latent variables at wavelength of 200.0-400.0 nm. This proposed method was successfully applied to pharmaceutical dosage form. Section C: Spectrofluorimetric method for the determination of Amlodipine and Olmesartan with the aid of Chemometrics In this study, a spectrofluorimetric method was applied for the determination of the binary mixture amlodipine and olmesartan. To obtain maximum intensity for both drugs the calibration sets were prepared in different ratios of the mixture in 50:50 methanol and distilled water with the addition of 1.0% sodium lauryl sulfate (SLS) surfactant and measured at excitation wavelength of 254.0 and emission wavelength of 439.0 nm. Principle component regression (PCR) was used for detecting the outer layers while Partial least squares (PLS), was applied as multivariant method. This proposed method was successfully applied to pharmaceutical formulations. Part IV: A Green Voltammetric Determination of Molnupiravir Using a Disposable Screen-Printed Reduced Graphene Oxide Electrode: Application for Pharmaceutical Dosage and Biological Fluid Forms In this part the proposed analytical platform involves the use of a disposable laboratory made screen-printed reduced graphene oxide 2.5.0% modified electrode (rGO-SPCE 2.5%) for the first time to measure MOV with high specificity. The surface morphology of the sensor was investigated by using a scanning electron microscope armed with an energy-dispersive X ray probe. The fabricated sensor attained reached high sensitivity when sodium dodecyl sulfate (SDS) surfactant (3 µM) was added to the supporting electrolyte solution of 0.04 M Britton– Robinson buffer at pH 2.0. The electrochemical activity of rGO-SPCE was examined in comparison with two different working electrodes in order to demonstrate that it was the most competitive sensor for MOV monitoring. This proposed method was successfully applied to pharmaceutical formulations.Item Restricted Advanced analytical techniques for analysis of Some therapeutic agents used in the treatment of cardiovascular diseases in dosage forms and biological fluids /Zaki, Mariam Wasim Beniamin,; Supervisor : Ahmed Emad El-Gendy, Maha Abd Elmonem Hegazy, Lubna Ahmed Kormod. Includes Arabic Summary.This thesis consists of three parts. • Part I: General introduction and literature review This part includes a general introduction to the pharmacological and biological effects of cardiovascular drugs of interest. This part presents the drugs of the first combination in this study, felodipine and metoprolol, and the second co administered combination, bisoprolol, rosuvastatin, and clopidogrel, this section includes all the structure-related details and physical characteristics of the compounds of interest, along with their pharmacological action. A complete and updated literature review of the different methods of analysis was summarized for the studied compounds. • Part II: Determination of Cardiovascular Drugs in Bulk and Pharmaceutical Dosage Form by Different Spectrophotometric Methods. This part is divided into four sections. Section A: Ratio Spectra Derivative for Determination of Felodipine and Metoprolol in their Pure and Pharmaceutical Dosage Form. In this section, the determination of felodipine and metoprolol was achieved by calculating first derivative ratio spectra using the numerical differentiation method despite their spectral overlap in zero-order measurements. The proposed method was adopted for the simultaneous estimation of both drugs in the range of 0.30- 15.00 µg/mL for FDP and 0.40- 22.00 µg/mL for MTP in their pure forms, laboratory prepared mixtures, and in their pharmaceutical dosage form. The statistical comparison of the results obtained with those of a reported HPLC method was made. Section B: Mean Centering of Ratio Spectra Method for Determination of Felodipine and Metoprolol in their Pure and Pharmaceutical Dosage form. In this section, the determination of felodipine and metoprolol was achieved by calculating the mean centering of ratio spectra method despite their spectral overlap in zero-order measurements. The proposed method was adopted for the simultaneous estimation of both drugs in the range of 0.30- 15.00 µg/mL for FDP and 0.40- 22.00 µg/mL for MTP in their pure forms, laboratory prepared mixtures, and in their pharmaceutical dosage form. The statistical comparison of the results obtained with those of a reported HPLC method was made. Section C: Ratio Difference Spectrophotometric Method for Determination of Felodipine and Metoprolol in their Pure and Pharmaceutical Dosage Form. In this section, the determination of felodipine and metoprolol was achieved by calculation of ratio difference after obtaining first ratio spectra despite their spectral overlap in zero-order measurements. The proposed method was adopted for the simultaneous estimation of both drugs in the range of 0.30- 15.00 µg/mL for FDP and 0.40- 22.00 µg/mL for MTP in their pure forms, laboratory prepared mixtures, and in their pharmaceutical dosage form. The statistical comparison of the results obtained with those of a reported HPLC method was made. Section D: Dual Wavelength Spectrophotometric Method for Determination of Felodipine and Metoprolol in their Pure and Pharmaceutical Dosage form. In this section, the determination of felodipine and metoprolol was achieved by the dual-wavelength method in the zero-order spectra by calculating the difference between two wavelengths for both drugs despite their spectral overlap in zero-order measurements. The proposed method was adopted for the simultaneous estimation of both drugs in the range of 0.30- 15.00 µg/mL for FDP and 0.40- 22.00 µg/mL for MTP in their pure forms, laboratory prepared mixtures, and in their pharmaceutical dosage form. The statistical comparison of the results obtained with those of a reported HPLC method was made. Part III: Simultaneous Estimation of Cardiovascular Drugs in Bulk, Pharmaceutical Dosage Forms, and spiked human plasma by Different HPLC Methods. This part is divided into three sections. Section A: Eco-friendly, Reversed Phase High Performance Liquid Chromatography (RP-HPLC) Method with UV-detection for Simultaneous Estimation of Felodipine and Metoprolol in their Pure Powder and Pharmaceutical Dosage Form. In this section, simultaneous determination of felodipine and metoprolol was performed using high-performance liquid chromatography coupled with a UV detector using a C18 column and gradient programming adjusted at (70:30, v/v) of potassium dihydrogen phosphate: ethanol then shifted to (20:80, v/v) at 4 minutes till the end of the run at pH 2.5. Olopatadine HCL was used as an internal standard. UV detection was performed at 237 nm for felodipine and 221nm for metoprolol and olopatadine. The proposed method was further applied to analyze both drugs in their pure forms, laboratory prepared mixtures as well as their pharmaceutical dosage form. The results were statistically compared to those obtained from a reported HPLC method. Section B: Eco-friendly, Bioanalytical Reversed Phase High Performance Liquid Chromatography (RP-HPLC) Method Coupled with Fluorescence Detection for Simultaneous Estimation of Felodipine and Metoprolol. In this Section, simultaneous determination of felodipine and metoprolol was performed using high-performance liquid chromatography coupled with a Fluorescence detector using C18 column and using isocratic elution with flow rate of the mobile phase at 1 mL/min adjusted at (40:60, v/v) of potassium dihydrogen phosphate: ethanol at pH of 2.5. Fluorescence detection was programmed to measure felodipine, metoprolol, and tadalafil at excitation wavelengths of 230 nm, 275 nm, and 367 nm and emission wavelengths of 300 nm, 335 nm, and 440 nm, respectively. The proposed method was further applied to analyze both drugs in their pure forms, laboratory-prepared mixtures, pharmaceutical dosage form, and spiked human plasma. Bioanalytical method validation was applied to confirm the method's applicability to human plasma. The results were statistically compared to those obtained from a reported HPLC method. Section C: Reversed Phase High Performance Liquid Chromatography (RP HPLC) Method Coupled with UV Detection for the Simultaneous Estimation of Bisoprolol, Rosuvastatin, and Clopidogrel. In this section, simultaneous determination of the co-administered drugs bisoprolol, rosuvastatin, and clopidogrel along with an internal standard olopatadine HCL using high-performance liquid chromatography coupled with UV detector using C18 column and gradient programming adjusted at (70:30, v/v) of potassium dihydrogen phosphate: acetonitrile then shifted to (20:80, v/v) at 6.5 minutes till the end of the run at pH 3. UV detection was programmed to measure bisoprolol, rosuvastatin, and clopidogrel at wavelengths 225 nm, 240 nm, and 230 nm, respectively. The proposed method was further applied to analyze co-administered drugs in their pure forms, laboratory-prepared mixtures, and pharmaceutical dosage forms. The results were statistically compared to those obtained from a reported HPLC method.Item Restricted Design, synthesis, and biological evaluation of novel arylpyrrole derivatives with antibacterial activity /Qandeel, Basma Magdy,The increasing prevalence of antimicrobial resistance poses an enormous burden and threat to the global public health. Infections caused by multidrugresistant bacteria are associated with serious morbidity and mortality, with at least 1.27 million deaths recorded per year. Conventional antibiotics are becoming ineffective against various Gram-negative and Gram-positive bacterial strains, especially the gram-positive methicillin-resistant S. aureus (MRSA). Since 1990 and up till today, MRSA infections presented a stressing global problem, and the development of new antimicrobial agents to combat MRSA infections is of utmost importance. According to the WHO, it is necessary to introduce novel chemical scaffolds, target novel pathways, and demonstrate wide-spectrum activity versus multidrug-resistant strains. Our research objectives were to design, synthesize, and biologically evaluate new antibacterial leads with broad antibacterial activity and potential anti-MRSA activity. This thesis consists of two parts. Part One focuses on the design, synthesis, and biological evaluation of novel arylpyrrole derivatives with antibacterial activity. Upon investigating literature for active chemical moieties that exhibit potent antibacterial activity, we came across a highly active phenylthiazole scaffold that exhibited notable antibacterial activity against gram-positive bacteria, including 18 MRSA strains. Several rational modifications of the phenylthaizole lead compound were proposed, and three series of novel N-arylpyrrole derivatives were suggested (Hydrazinecarboximidamide, carbothioamide, and carboxamide). Molecular modelling studies were performed to preliminary evaluate our newly designed compounds using consecutive computer-aided drug design protocols. The 3D QSAR pharmacophore generation protocol was utilized to generate a valid predictive pharmacophore model; then, the designed compounds were mapped via the ligand pharmacophore mapping protocol to predict their activity. Furthermore, the designed compounds were docked into the binding site of their proposed target, Undecaprenyl diphosphate phosphatase (UPPP), using the CDOCKER protocol in Discovery Studio 4.1 software, which allowed studying their binding modes and affinities. The designed compounds were synthesized, purified, and structurally confirmed by different analytical and spectral techniques. The study involved the synthesis of the following unavailable reported intermediate: 1) 2,5-Dimethyl-1-phenyl-1H-pyrrole (IIIa). 2) 1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrole (IIIb). 3) 1-([1,1'-Biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrole (IIIc). 4) 2,5-Dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (IVa). 5) 1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (IVb). 6) 1-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethanone (IVd). 7) 1-[1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]ethanone (IVe). Also, it comprised the synthesis of the following new intermediates: 1) 1-([1,1'-Biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (IVc). Furthermore, the study involved the synthesis and characterization of the following new final compounds: 1) 2-((2,5-Dimethyl-1-phenyl-1H-pyrrol-3yl)methylene) hydrazinecarboximidamide (Va). 2) 2-((1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3yl)methylene) hydrazinecarboximidamide (Vb). 3) 2-((1-([1,1'-Biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene) hydrazinecarboximidamide (Vc). 4) 2-(1-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarboximidamide (Vd). XIX 5) 2-(1-(1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarboximidamide (Ve). 6) 2-((1-([1,1'-Biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene) hydrazinecarbothioamide (VIc). 7) 2-(1-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarbothioamide (VId). 8) 2-(1-(1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarbothioamide (VIe). 9) 2-((1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene) hydrazinecarboxamide (VIIb). 10) 2-((1-([1,1'-Biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene) hydrazinecarboxamide (VIIc). 11) 2-(1-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarboxamide (VIId). 12) 2-(1-(1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)ethylidene) hydrazinecarboxamide (VIIe). Also, it comprised the synthesis of the following reported final compounds: 1) 2-((2,5-Dimethyl-1-phenyl-1H-pyrrol3yl)methylene) hydrazinecarbothioamide (VIa). 2) 2-((1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrol-3- yl)methylene)hydrazinecarbothioamide (VIb). 3) 2-((2,5-Dimethyl-1-phenyl-1H-pyrrol-3yl)methylene)hydrazinecarboxamide (VIIa). All the synthesized compounds were tested for their biological activity by determining their minimum inhibitory concentrations (MIC) against a panel of susceptible and drug-resistant gram-positive and gram-negative bacterial strains using the broth microdilution method. The gram-positive panel includes the methicillin-susceptible S. aureus (ATCC 29213) and clinical isolates of methicillinresistant S. aureus (MRSA). The gram-negative panel includes the enteric bacterial strains E. coli (ATCC 25922) and K. pneumoniae (ATCC 700603) and the nonenteric bacterial strains P. aeruginosa (ATCC 27853) and clinical isolates of A. baumannii. In addition, all compounds were tested for their antitubercular activity against clinical isolates of Mycobacterium phlei. The antimicrobial evaluation of the new N-aryl-pyrrole derivatives revealed that the hydrazinecarboximidamide series Va-e was the most active. Compounds Vb, Vc, and Ve outperformed our standard reference Levofloxacin inhibitory activity against MRSA (MIC= 8 μg/ml) with a MIC of 4 μg/ml, while Vd had a MIC of 8 μg/ml, which is equivalent to the MIC of Levofloxacin, thus revealing promising activity against MRSA. In addition, compound Vc had MIC values of 4 μg/ml and 8 μg/ml against E. coli and K. pneumoniae, respectively. Compound Vc also showed promising activity against A. baumannii with a MIC of 8 μg/ml, which is equivalent to the MIC of Levofloxacin when tested against the same strain, and the compound also displayed some activity against P. aeruginosa with a MIC of 32 μg/ml. Vc also showed good inhibitory activity against clinical isolates of Mycobacterium phlei with a MIC value of 8 μg/ml. Compound Vb displayed the same promising activity as compound Vc. However, Vb exhibited one-fold higher MIC values against E. coli (8 μg/ml), A. baumannii (16 μg/ml), and Mycobacterium phlei (16 μg/ml) and onefold lower MIC value against P. aeruginosa (16 μg/ml). Compound Ve displayed one-fold higher MIC values than Vb, except for the MIC value against MRSA, which remained the same (4 μg/ml). The hydrazinecarbothioamide, and hydrazinecarboxamide series VIa-e and VIIa-e mostly displayed minimal antimicrobial activity. The cytotoxicity of the four most potent compounds (Vb, Vc, Vd, Ve) was evaluated by MTT assay against normal mammalian cell line VERO (African Green Monkey Kidney cells). Compounds Vc and Vb manifested great selectivity for bacterial over mammalian cells (Vero) and demonstrated an excellent safety profile (non-toxic up to 15μg/ml). Compounds Vd and Ve displayed moderate to weak selectivity against MRSA with mean SI values of 0.27, 2.55, and CC50 values of 2.8 ± 0.35 and 10.33± 0.49 µg/ml, respectively. Part Two of the thesis focuses on the lead generation of UPPS inhibitors targeting MRSA using 3D QSAR pharmacophore Modelling, virtual screening, molecular docking, and molecular dynamic simulations. Undecaprenyl Pyrophosphate Synthase (UPPS) is a vital target enzyme in the early stages of bacterial cell wall biosynthesis. UPPS inhibitors have antibacterial activity against resistant strains such as MRSA and VRE. In this study, we used several consecutive computer-based protocols to identify novel UPPS inhibitors. The 3D QSAR pharmacophore model generation (HypoGen algorithm) protocol was used to generate a valid predictive pharmacophore model using a set of UPPS inhibitors with known reported activity. The developed model consists of four pharmacophoric features: one hydrogen bond acceptor, two hydrophobic, and one aromatic ring. It had a correlation coefficient of 0.86 and a null cost difference of 191.39, reflecting its high predictive power. Hypo1 was proven to be statistically significant using Fischer's randomization at a 95% confidence level. The validated pharmacophore model was used for the virtual screening of several databases. The resulting hits were filtered using SMART and Lipinski filters. The hits were docked into the binding site of the UPPS protein, affording 70 hits with higher docking affinities than the reference compound (6TC, -21.17 kcal/mol). The top five hits were selected through extensive docking analysis and visual inspection based on docking affinities, fit values, and key residue interactions with the UPPS receptor. Moreover, molecular dynamic simulations of the top hits were performed to confirm the stability of the protein-ligand complexes, yielding five promising novel UPPS inhibitors.Item Restricted Design, synthesis and biological evaluation of novel indole derivatives as Anti-Cancer agents /Ghobish, Sarah Ammar Ali Ibrahim,; Supervisor : Nahla A. H. Farag, Khaled Omar Ahmed Mohamed, Doaa Boshra farag.Item Restricted Synthesis, molecular modeling and biological evaluation of Indole-Containing novel Structures as anticancer agents /Mohamed, Nesreen Mohamed Hassan,; Supervisor : Adel Abbas Elgendy, Khaled Omar Ahmed Mohamed, Doaa Boshra.Item Restricted Analytical study of selected multicomponent pharmaceutical preparations in different matrices /Anis, Monica Sherif Anwar,; Supervisor : Ahmed Emad Elgendy, Samah Sayed Abbas, Lubna Ahmed Kormod.Item Restricted Applicability of advanced analytical techniques for the monitoring and detection of Anti-epileptic drugs; in dosage forms and Bio-Fluids /Sonbol, Heba Hassan Ali,; Supervisor : Samy El-Sayed Sayed Ahmed Emara, Ghada Mekawy Hadad Tawfeik, Ahmed Shawky.Item Restricted Applicability of advanced analytical techniques for monitoring and detection of antibiotics in dosage forms and Bio-Fluids /Ebrahim, Hager Mohamed Saad Mahmoud,; Supervisor : Samy El-Sayed Sayed Ahmed Emara, Ghada Mekawy Hadad Tawfeik, Walaa Zarad.Item Restricted Traceability of different pharmaceutical residues in environmental samples and food product using different analytical techniques.Elsharkawy, Loubna Moustafa Ibrahim,; Supervisor : Ahmed Emad Elgendy, Maha Abdel-Monem Hegazy, Rasha Mahmoud Ahmed.Item Restricted Molecular design and synthesis of new thienopyrimidine based compounds as a potential anti-angiogenesis agentsShatat, Asmaa Raafat Mohammed,; Supervisor : Nahla A.H. Farag, Marwa A. Fouad Samar M.A. Mowafy.