| Titre : | Theoretical study of the regioselectivity of the transetherification reaction and in silico prediction of pharmacological properties of 2-nitroanilines |
| Auteurs : | MELLAS NARIMANE, Auteur ; Nadjib Melkemi, Directeur de thèse |
| Type de document : | Mémoire magistere |
| Editeur : | Biskra [Algérie] : Faculté des Sciences Exactes et des Sciences de la Nature et de la Vie, Université Mohamed Khider, 2025 |
| Format : | 1VOL.(59p) / ill.couv.ill.en coul / 30cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Mots-clés: | 2-nitroaniline, Regioselectivity, Transetherification reaction, DFT, SIRT6, Molecular docking/Dynamics simulations, ADME. |
| Résumé : |
Type 2 diabetes affects over 350 million people worldwide. Even with the availability of medications, regulating blood sugar levels remains difficult. In order to enhance metabolic balance and lower the incidence of problems, novel and efficient treatments are being investigated. SIRT6 is considered an attractive biological target for the development of new type 2 diabetes drugs. Our research work focuses on two main themes. First, the regioselectivity of the transetherification reaction of 4,5-dialkoxy-2-nitroanilines was theoretically studied using reactivity concepts from the DFT approach. The findings indicate that the carbon atom C4 is the best site for aromatic nucleophilic substitution (ArSN). The second study aims to identify the binding mechanism of SIRT6 as a potential target for the therapy of type 2 diabetes. Molecular docking was used to explore the interaction of 5-(4methylpiperazin-1-yl)-2-nitroaniline and its five analogs with the SIRT6 pocket. Molecular docking/Dynamics simulations revealed high binding affinity for ligands L4 and L18, as well as stable interactions with the pocket of the SIRT6 (PDB ID: 3K35). This affinity was confirmed by high negative score values and the establishment of several non-covalent interactions with the active site residues of the receptor. Furthermore, drug-likeness and ADME prediction analyses showed favourable absorption and oral bioavailability characteristics for ligands L4 and L18, suggesting their potential as precursor compounds for antidiabetic drug development. These analyses have led to a better understanding of the experimentally observed chemical behaviour and open up promising prospects in the field of pharmaceutical compound design. |
| Sommaire : |
LIST OF MAIN ABBREVIATIONS .........IX LIST OF FIGURES .....................X LIST OF TABLES ....................XII GENERAL INTRODUCTION ................1 References………………………………………………………………………3 CHAPTER I: OVERVIEW OF DIABETES AND NITROANILINE COMPOUNDS PART 1: OVERVIEW OF DIABETES ..................5 I.1.1. INTRODUCTION ...........................5 I.1.2 DIABETES DEFINITION .....................6 I.1.3. CLASSIFICATION AND PATHOPHYSIOLOGY .......6 I.1.4. DIAGNOSIS AND TREATMENT ..................7 I.1.5. PHARMACEUTICAL RESEARCH AND INNOVATION ...8 PART 2: OVERVIEW OF NITROANILINE COMPOUNDS ......9 I.2.1. DEFINITION .............................9 I.2.2. NITROANILINE - STRUCTURE AND MOLECULAR PROPERTIES ...............9 I.2.3. PHYSICO-CHEMICAL PROPERTIES ................10 I.2.4. CHEMICAL REACTIVITY.........................10 I.2.5. TOXICITY AND SAFETY.........................10 I.2.6. INDUSTRIAL AND SCIENTIFIC APPLICATIONS.....10 I.2.7. AROMATIC SUBSTITUTION REACTIONS ..........11 I.2.8. CLASSICAL NUCLEOPHILIC AROMATIC SUBSTITUTION ................11 I.2.9. MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION..............12 References…………………………………14 CHAPTER II:THEORETICAL STUDY ON THE REGIOSELECTIVITY OF THE TRANSETHERIFICATION OF 4,5-DIALKOXY-2-NITROANILINE II.1. INTRODUCTION ..............17 II.2. COMPUTATIONAL METHODS: ....18 II.3. FRONTIER MOLECULAR ORBITALS (HOMO AND LUMO) ...............18 II.4. GLOBAL AND LOCAL REACTIVITY DESCRIPTORS ...................20 II.4.1. Global HSAB (Hard and Soft Acids and Bases) principle ...................20 II.4.1.1. Definitions ..............20 II.4.1.2. Statement of the HSAB principle .........................21 II.4.2 Chemical concepts and reactivity indices derived from DFT ..........22 II.4.2.1 Global Indices derived from conceptual DFT ..............22 a) Electronic Chemical Potential ......................23 b) Global Hardness and Softness .......................23 c) Global Electrophilicity Index ......................23 d) Global Nucleophilicity Index .......................23 II.4.2.2 Local reactivity indices derived from conceptual DFT ............25 a)Fukui Indices ..................26 b)Condensed Form of Fukui Functions ..............26 II.5. MOLECULAR ELECTROSTATIC POTENTIAL (MEP) ....29 a)3D-Molecular Electrostatic Potential ...........29 b)2D-Contours of the Molecular Electrostatic Potential.............29 II.6. CONCLUSION ......31 Reference……………………………………32 CHAPTER III:IN SILICO STUDY OF THE ANTIDIABETIC PROPERTIES OF 5-(4-METHYLPIPERAZIN-1-YL)-2NITROANILINE AND ITS ANALOGS. III.1. INTRODUCTION .............................................35 III.2. BRIEF OVERVIEW OF IN SILICO METHODS IN DRUG DISCOVERY .......35 III.2.1. Molecular docking............................................................................................. 35 III.2.2. Types of molecular docking .............................................................................. 36 III.2.3. Molecular docking procedure ............................................................................ 37 a. Ligand preparation ............................................................................................................................... 37 b. Target preparation ................................................................................................................................ 37 c. Active site recognition ........................................................................................................................ 37 d. Docking .................................................................................................................................................... 38 e. Validation and evaluation .................................................................................................................. 38 III.2.4. Molecular Dynamics (MD) simulations ............................................................. 38 III.2.5. Bioisosteric Conversion ..................................................................................... 39 III.3. MOLECULAR DOCKING/DYNAMICS SIMULATIONS OF 5-(4-METHYLPIPERAZIN-1-YL)-2NITROANILINE AND ITS ANALOGS AS SIRT6 INHIBITORS ..................................................... 39 III.3.1. Materials and methods ....................................................................................... 39 III.3.1.1 Ligands preparation ................................................................................................................ 39 III.3.1.2. Target preparation.................................................................................................................. 40 III.3.1.3. Molecular docking protocol ............................................................................................... 42 Active site residues of target .................................................................................. 42 Method validation .................................................................................................. 43 III.3.1.3. Molecular Dynamicss simulation .................................................................... 43 III.3.1.4. ADME prediction and physicochemical properties .................................................. 44 III.3.2. Results and discussion ....................................................................................... 44 III.3.2.1. Molecular docking analysis ............................................................................................... 44 III.3.2.2. Molecular Dynamicss analysis ......................................................................................... 50 III.3.2.3. Protein-ligand interactions after MD simulations ..................................................... 52 III.3.2.4. Evaluation of the ADME-T properties and drug-likeness: ............................... 54 References…………………………………………………………………………………….57 GENERAL CONCLUSION………………………………………………………..59 |
| Type de document : | Mémoire master |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| MCH/655 | Mémoire master | bibliothèque sciences exactes | Consultable |
