| Titre : | Structural exploration and study of the QSAR properties of several series of macrolide antibiotics. |
| Auteurs : | Karima Zitouni, Auteur ; Salah Belaidi, Directeur de thèse |
| Type de document : | Thése doctorat |
| Editeur : | Biskra [Algérie] : Faculté des Sciences Exactes et des Sciences de la Nature et de la Vie, Université Mohamed Khider, 2021 |
| Format : | 1 vol. (176 p.) / couv. ill. en coul / 30 cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Résumé : |
In this work a fundamental and original research on the 14- membered macrolide, the aim is to predict the reactivity and biological activity of the compound studied and its derivatives. The molecular modeling methods used in our work are: MM+, PM3 and ab initio/HF(STO- 3G). These methods were used to determine the structural parameters, electronics and energy associated with molecules studied. The nature of such substituent (donor, acceptor) affects the electronic and energy parameters of basic core of the 14- membered macrolide. Indeed, this qualitative study allows us to predict the chemical reactivity of derivatives of the 14- membered macrolide and also the ketolides. A study of structure - property relationships (SPR) forthe 14- membered macrolide derivatives has been carried out for a series of bioactive derivatives of the 14- membered macrolide. QSAR studies have been performed on fifty molecules of the 14- membered macrolide as the antibiotics, multiple linear regression analysis was performed to derive QSAR models which were further evaluated internally for the prediction of activity. The developed models were cross-validated by the ‘leave one out’ technique as well as by the calculation of statistical parameters LOO. High correlation between experimental and predicted activity values was observed, indicating the validation and the good quality of the derived QSAR models |
| Sommaire : |
Acknowledgements…………………………………………………………………….… 2 Table of contents………………………………………………………………………… 4 List of Figures………………………………………………………………...………...… 9 List of Tables………………………………………………………………………...…… 11 List of Abbreviations……………………………………………………………...……… 12 General Introduction………………………………………………………….………… 14 References……………………………………………………………………………..… 19 CHAPTER 1: Classification and pharmacological properties of macrolides and ketolides 1. The macrolides……………………………………………………………………………… 23 1.1 Introduction………………………………………………………………………………… 23 1.2. Nomenclature of macrolides……………………………………………………………..… 24 1.3 Chemical structure of macrolide and classification………………………………………… 26 1.4 The need for novel antibacterial agents…………………………………………………… 29 1.5 Macrolide-binding site in the ribosome…………………………..……………………….. 29 1.6 Modes of inhibition of protein synthesis by macrolides……………… …………………… 30 1.7 Antibiotic Resistance ……………………………………………………………………….. 31 1.7.1 Macrolide action and drug resistance:……………………… ……………………………. 33 2. Discovery and physicochemical properties of ERYTHROMYCIN…………………………….. 34 2.1 Discovery…………………………………………………………………………………….. 34 2.2 Chemistry……………………………………………………………………………………. 34 2.3 Physical Properties………………………………………………………………………….... 35 2.4 Stability…………………………………………………………………………………......... 375 2.5 Erythromycin derivatives……………………………………………………………………. 40 2.6 Clinical pharmacology……………………………………………………………………… 42 2.6.1 Spectrum of antimicrobial activity………………………………………………………. 42 2.6.2 Mode of action……………………………………………………………………………... 45 2.6.3 Resistance………………………………………………………………………………….. 45 2.7 Pharmacokinetics of ERYTHROMYCIN……………………………………………………... 46 2.7.1 Absorption and bioavailability…………………………………………………………… 47 2.7.2 Metabolism ……………………………………………………………………………….. 47 3. The ketolides…………………………………………………………………….…………….. 48 3.1 Introduction………………………………………………………………………………….. 48 3.2 From macrolides to ketolides (Chemistry and structure–activity relationship)……………. 49 3.3 Mechanism of action………………………………………………………………………… 51 3.4 Antibacterial activity………………………………………………………………………… 53 3.5 Resistance…………………………………………………………………………………….. 54 i. Target site modification………………………………………………………………… 54 ii. Efflux pumps …………………………………………………………………………… 55 iii. Production of antibiotic inactivating enzymes ……………………….………………... 55 3.6 Stability………………………………………………………………………………………. 55 3.7 Metabolism and drug interaction…………………………………………………………… 56 4. REFERENCES ………………………………………………………………………………….. 56 CHAPTER 2. Molecular Modeling 1. Introduction…………………………………………………………………………………… 64 2. Quantum Mechanical Methods………………………………………………………………. 65 2.1 Schrödinger equation………………………………………………………………………... 65 2.2 The Born-Oppenheimer Approximations:……………………………… …………………. 66 3. Hartree-Fock Self-Consistent Field Method…………………………………………………. 67 3.1 Post-HF Methods…………………………………………………………………………….. 67 3.2 Moller-Plesset perturbation theory (MP)…………………………..………………………... 686 3.3 Density-Functional Theory (DFT)……………………………………..…………………….. 68 3.4 Quantum methods: Ab initio :………………………………………………………………. 69 4. Semi-empirical method…………………………………………….……………..………….. 70 5. Molecular Mechanics (MM)………………………………………………………………….. 72 5.1 Steric Energy…………………………………………………………….…………………… 72 5.2 Examples of MM force fields…………………………………………………….………….. 74 5.3 Energy Minimization and Geometry Optimization……………… …………………………. 76 6. Research Methods of Global Minimum………………………… …………………………….. 77 6.1 The Steepest Descent Method……………………………………………………... 77 6.2 The Conjugate Gradient Method……………………………………………………………. 78 6.3 The Newton-Raphson Methods……………………………………………….…………….. 78 7. Types of Calculations………………………………………………………….………………. 79 7.1 Molecular Geometry……………………………………...... 79 7.2 Geometry Optimization…………………………………………………………………….. 79 7.3 Single Point Calculations……………………………………………………………………. 80 7.4 Transition State Calculations………………………………………………………………... 80 7.5 Electronic Density and Spin Calculations, Graphical Models and Property Maps…………. 80 7.6 Chemical Reactivity…………………………………………………………………………. 81 7.7 IR, UV and NMR spectra…………………………………………………………………….. 81 8. Scope of application of molecular modeling ……… …………………….…………………... 81 8.1 QSAR Methods :……………………………………………………………………………... 82 8.1.1 Introduction:………………………………………………..……………………………… 82 8.1.2 Historical Development of QSAR :………………………………………………………... 82 8.1.3 Tools and techniques of QSAR:……………………………………………………………. 84 8.1.3 .1 Biological parameters:………………………………………………………………….... 84 8. 1.3. 2. Molecular descriptors :……………………………………………………………....…. 84 8. 1. 3. 3. Statistical methods :………………………………………………………...………….. 85 8. 1. 3. 4. Multi-linear regression :……………………………………………………………… 867 ❖ Description of the method………………………………………………………………. 86 ❖ Test of the total significance of the regression :…………………………..……………... 87 a. Determination coefficient (R2) :…………………………………………………….... 87 b. Correlation coefficient (R)…………………………………………………………… 88 c. Test Fisher-Snedecor (F) …………………………………………………………….. 88 d. Standard deviation (s)……………………………………………………………….. 88 e. Prediction coefficient (Q2)………………………………….………………………... 89 8.1.4 Models Validations ……………………………………….……………………….………. 89 9. Programs and materials used ………………………………………………………………... 90 10. REFERENCES ………………………………………………………………………………… 91 CHAPTER 3: Geometric, Electronic Structure and Substituent effects of 14- Membered α, β -Unsaturated Macrolides. 1. Introduction………………………………………………………………………………. 98 2. Mulliken population analysis (MPA)……………………………………………………. 98 3. Electrostatic Potential Surface(MESP)……………………………………………………….. 99 4. Dipole Moment……………………………………………………………………………….. 100 5. Heat of Formation (∆Hf)………………………………………………………………………. 100 6. Energies of the Frontier Molecular Orbitals HOMO and LUMO…………………………… 101 7. Substituent Effects on the Electronic Structure……………………………………………… 101 8. Material and methods………………………………………………………………………… 103 9. Results and discussion…………………………………………………………………….. 103 9.1 Conformational Analysis of 14-Membered α, β -Unsaturated Macrolides……………… 103 9.2 Geometric and Electronic Structure of Basic Structure of Symmetric 14-membered Macrolide Type 6 (T6)………………………………………………………………………… 105 9.3 The molecular electrostatic potential MESP of basic structure (T6)… ………………… 107 9.4 Substituent effects on the electronic structure in symmetric 14-membered macrolides…………… 108 10. Conclusion…………………………………………………………………………………….. 112 11. REFERENCES………………………………………………………………………………. 1128 CHAPTER 4: Drug-likeness properties and Structure activity Relationships of 14- Membered Macrolides. 1. Introduction………………………………………………………………………………. 117 2. Structure-Property Relationships (SPR) Properties…………………………………………… 119 2.1 Molecular Volume And Surface Area………………………………………………………. 119 2.2 Molecular Refractivity (MR)………………………………………………………………… 120 2.3 Molecular Polarizability (Pol)………………………………………………………………. 120 2.4 Molecular Weight (MW)…………………………………………………………………… 121 2.5 Hydration Energy (HE)……………………………………………………………………… 121 2.6 Partition Coefficient (Log P)………………………………………………………………… 122 2.7. Number of Hydrogen Bond Donors and Bond Acceptors…………………………………. 124 2.8. Druglikeness………………………………………………………………………………. 124 2.9. Lipinski Rules……………………………………………………………………………….. 125 3. Results and Discussion……………………………………………………………………….. 126 3.1 Study of Structure - activity Relationships for 14-membered Macrolides………………. 126 3.2 Structural Comparison of the 14-membered Macrolide Derivatives……………………… 127 3.3 Structure Property/Activity Relationships…………………………………………………….. 134 3.4 Drug likeness screening of 14-membered macrolide derivatives…………..…………….. 138 4. Quantitative structure-activity relationships studies ……………………………..………… 141 5. Conclusion…………………………………………………………………………………….. 143 6. REFERENCES………………………………………………………………………………. 144 General Conclusion………………………………………………………….….……… 145 Appendix A…………………………………………………………………………………….. 148 Appendix B………………………………………………………………………………… |
| Type de document : | Thése doctorat |
| En ligne : | http://thesis.univ-biskra.dz/5480/1/these.pdf |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/87 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
