ΙΑΤΡΙΚΗ ΧΗΜΕΙΑ

MEDICINAL CHEMISTRY

Lesson Code:	BE0200

Professor in charge:	Mylonis Ilias, Associate Professor

Other Teachers:	G. Simos, P. Liakos, G. Hahami

ECTS:	5.00

Type\|Type of Course:	YP \| BACKGROUND

Teaching Semester:	1st Semester

Hours per week:	5 Hours

Total Time (Teaching Hours + Student Workload)	135 Hours

Prerequisites:	NO

Language of Instruction:	Greek

Available for Erasmus:	YES

Semester Lectures:	Details/Lectures

Teaching Method:	Face-to-face and specific: The teaching of the "Medicinal Chemistry" course consists of lectures, tutorials, seminars and laboratory exercises. Attendance at tutorials and laboratory exercises is mandatory. The lectures develop the material described above. In the tutorials, the theoretical background of the laboratory exercises, the theoretical basis and the applications of the techniques that are currently used in biomedical research and laboratory medicine are developed. In the seminars, the course material is analyzed in the form of questions and answers. The laboratory exercises aim to familiarize the students with the use of techniques and instruments to carry out an experimental / research work. After completing the laboratory exercises, the student must have acquired some general skills of experimental work, i.e. be able to: 1. plan and conduct an experiment, 2. receive and process experimental data, 3. judge the results and reveal possible experimental errors, 4. draw the conclusions, 5. handle the basic laboratory equipment – spectrophotometer, pH-meter, electrophoresis device, etc. 6. to know and observe laboratory safety rules, 7. to follow instructions, 8. to work in a team. Attendance is mandatory in all tutorials and laboratory exercises. • POWERPOINT: for preparing lecture material and viewing slides and videos. • E-class: • The study guide (explanatory material & additional bibliography), the theory and protocols of the laboratory exercises, the slides of the presentations after each lesson as well as videos and scientific articles related to the taught material are made available online to students through the e-class. • The evaluation of the course by the students is done online. • Communication with the students is done through the e-class platform or by e-mail • Laboratory exams are done online with the simultaneous use of the e-class and teams platform

Evaluation Method:	The assessment language of the students is Greek. The evaluation of the students' performance in the course is done: 1. with an evaluation of the results of each laboratory exercise presented in the form of a written assignment after each laboratory exercise. 2. by electronic means (e-class and MS Teams) for end-of-semester lab exams with multiple choice, true-false, matching, layout questions. In the Laboratory exams, the material to be examined is the theory, methodology and methods of processing results included in the Laboratory Exercises Guide or developed by the teachers during the workshops and the corresponding tutorials. 3. with written examinations of the theory of the course "Medicinal Chemistry" in the examination period of the winter semester with free development, multiple choice, true-false and matching questions. In the theory exams of the course, the material to be examined is the material of the lectures and tutorials according to the analytical material of the course. 4. Only those students who have passed the Laboratory exams have the right to participate in the course exams. The final grade of the course is formed by the contribution of the laboratory grade (20%) and theory (80%) with performance in theory 50% as a prerequisite. All of the above can be accessed by the students as they are contained in the Course Guide that is distributed to all students in print, and is posted in the e-class.

Objective Objectives/Desired Results:	The general purpose of the course "Medicinal Chemistry" is to introduce students to selected chapters of general, physical, organic and biological chemistry with the ultimate goal of forming a knowledge base and enabling them to design and analyze the application of chemical processes in the interpretation biomedical phenomena, the chemical structure and properties of basic biomolecules (carbohydrates, lipids, amino acids, proteins and enzymes) as well as the effect of environmental chemistry on human health. Furthermore, the course seeks to provide students with the basic elements necessary to understand and assimilate courses of subsequent semesters, such as Biochemistry, Physiology, Pharmacology, Clinical Biochemistry, and laboratory medicine chapters applied daily to diagnosis. The specific objectives of the course are specialized in the following intended learning outcomes: Upon successful completion of the course, the student will be able to: He/she will be able to use the acquired knowledge in order to: • be able to describe the chemical basis of biomedical phenomena, the structure, properties, roles and action of basic chemical elements and compounds of biological importance as well as the toxicity of xenobiotic substances, the structure, properties and roles of basic biomolecules such as carbohydrates, lipids, amino acids, proteins and enzymes, conducting laboratory analyzes and assessing the correctness of the results. • to make use of the knowledge acquired in the course as a basis for understanding the courses of the longer semesters: Biochemistry, Physiology, Pharmacology, Clinical Biochemistry and Toxicology. • have the ability to analyze data with a critical approach and be able to search and analyze information relevant to Medicinal Chemistry from various sources. • use the basic equipment of a chemical laboratory and carry out basic chemical analyses. • collaborate with fellow students in a laboratory environment to perform basic chemical analyzes and process their results. General Skills • Search, analysis and synthesis of data and information, using the necessary technologies • Adaptation to new situations • Decision making • Autonomous work • Teamwork • Exercise criticism and self-criticism • Promotion of free, creative and inductive thinking

Course URL :	https://eclass.uth.gr/courses/MED_U_169/

Course Description:	<br /> Η ύλη του μαθήματος Ιατρικής Χημείας έχει διαμορφωθεί ως εξής:<br /> 1. εξεταστέα ύλη – «αυτό που πρέπει να ξέρουν καλά»,<br /> 2. σχετικές γνώσεις που στοχεύουν στην ευρύτερη παιδεία του φοιτητή ως επιστήμονα – «αυτό που πρέπει να έχουν ακούσει»</p> <p>COURSE ANALYTICAL MATERIAL – STUDY CHART</p> <p>Unit 1. PERIODIC TABLE – ELEMENTS OF BIO-INORGANIC CHEMISTRY<br /> What students should know well:<br /> • Periodic properties of the elements and the relationship of these properties with the electronic configuration of the atom: ionization energy, electron affinity, electronegativity, size of atoms, size of ions, redox properties.<br /> • Oxidation-reduction reactions, oxidation state, redox and biological systems, membrane potential.<br /> • Periodic table from a medical point of view: basic and trace elements of the human body. Toxic trace elements and examples of their effect on human health<br /> • Life-giving elements and their selection by nature. Relevance of the biological role and chemical properties of the vital elements.<br /> • Examples of the involvement of trace elements in certain pathological conditions. Element deficiency and excess.<br /> What students should have heard:<br /> • Law of periodicity according to Mendeleev and according to Mosley and its relationship with the electronic structure of the atom.<br /> • Toxic trace elements and environmental contamination problems.</p> <p>Unit 2. CHEMICAL BONDING AND NON-HOMEPOLAR INTERMOLECULAR INTERACTIONS<br /> What students should know well:<br /> • Chemical bonds – Theory of molecular orbitals. Sigma and pi bonds.<br /> • Hybridization of atomic orbitals and stereochemical structure of molecules.<br /> • Dipole, dipole moment, induction dipole, polarity of the molecule.<br /> • Non-covalent interactions and their nature: Van der Waals forces, London, hydrogen bonding. The role of non-covalent interactions in biomolecules.<br /> What students should have heard:<br /> • Electronic structure for the homonuclear diatomic molecules of the 1st and 2nd periods. Bond class.<br /> • Physico-chemical and pharmaceutical properties of chemical compounds and non-covalent interactions.<br /> • Non-covalent interactions and the action of drugs.</p> <p>Unit 3. COMPLEX ASSOCIATIONS AND COMPLEX THERAPY<br /> What students should know well:<br /> • Definition of complex compounds or splicing compounds.<br /> • Substituents (ligands), polyactive/ monoactive/ chemical substituent and chemical complexes.<br /> • Stability of complexes. Stability of complexes based on the theory of hard and soft acids and bases.<br /> • Stability of chemical compounds.<br /> • Examples of complexes with biological significance: iron complexed to heme, , carbonic anhydrase.<br /> • Complex therapy (chelation therapy) and the pathological conditions applied. Complexing agents that find use in complex therapy and corresponding pharmaceutical preparations.<br /> What students should have heard:<br /> • Nature of bonding in complexes: bond-valence theory, crystal field theory.<br /> • Spectroscopic and magnetic properties of the complexes and their interpretation based on bond-valence and crystal field theories.<br /> • Stereochemical structure of the complexes</p> <p>Unit 4. ACID-BASE BALANCE AND REGULATORY SYSTEMS OF THE BODY<br /> What students should know well:<br /> • Properties of electrolytic solutions.<br /> • Electrolytes of the extracellular and intracellular fluid.<br /> • Lewis acid-bases.<br /> • Blood pH and its fluctuations.<br /> • Buffers, buffer capacity.<br /> • Henderson-Hasselbalch equation and preparation of the buffer solutions.<br /> • Blood regulatory systems.<br /> • Effects of CO2, HCO-3 and H2CO3 on blood pH.<br /> What students should have heard:<br /> • Ionization and absorption of drugs</p> <p>Section 5. DISTRIBUTION SYSTEMS<br /> What students should know well:<br /> • Dispersion systems: mixtures, colloidal systems, solutions.<br /> • Solubility, unsaturated, saturated and supersaturated solutions. Ways of expressing concentration.<br /> • Hydrophilicity / hydrophobicity / lipophilicity of chemical compounds and prediction of these properties from the study of the chemical structure of the compound. Hydrophilic functional groups.<br /> • Additive properties of solutions: osmosis. Hypotonic, isotonic and hypertonic solutions. Plasmolysis and hemolysis.<br /> • Colloid systems: aerosol, emulsion, suspension.<br /> • Colloid systems in water: hydrophobic and hydrophilic colloids. Colloid thrombosis and its mechanisms.<br /> • Increasing water solubility of a xenobiotic substance as a way to detoxify the body.</p> <p>Unit 6. INTRODUCTION TO ORGANIC CHEMISTRY<br /> What students should know well:<br /> • Marital systems.<br /> • Electronic phenomena and distribution of the electronic cloud in molecules: Inductive (I) and conjugate (R) effect. Coordination.<br /> • Classification of reactions and reagents in organic chemistry. Nucleophilic and electrophilic reagents, free radicals.<br /> • Reactive oxygen compounds, oxidative stress and human health.<br /> • Functional groups of organic compounds and their role in the design of new drugs.<br /> What students should have heard:<br /> • Carbanions and carbocations<br /> • Basic steps in the development of new drugs: identification of initial bioactive structures (hit compounds), transition to lead compounds</p> <p>Section 7. STEREOCHEMISTRY OF ORGANIC COMPOUNDS<br /> What students should know well:<br /> • Stereochemistry and stereoisomerism.<br /> • Mirror image isomers / enantiomers / optical antipodes<br /> • Chiral/ achiral compounds<br /> • Asymmetric (chiral, stereogenic) center<br /> • Optical activity, (+) – right-handed and (-) – left-handed enantiomer.<br /> • Racemic mixture, racemization.<br /> • Views against Fischer<br /> • Description of the absolute stereochemical structure of the enantiomers with symbols D,L.<br /> • Stereotype description of the chiral centers of the molecule according to the CHAN-INGOLD-PRELOG rules and RS symbols.<br /> • Diastereoisomerism, mesoforms.<br /> • Geometric isomerism : CIS – TRANS, ZE, priority of substituents.<br /> • Mechanisms of SN1, SN2 nucleophilic substitution reactions.<br /> What students should have heard:<br /> • Special rotational capacity.<br /> • Separation and isolation of enantiomers.<br /> • Thalidomide case – typical example of a substance whose two enantiomers exhibit completely different pharmacological activity.<br /> • Stereoselectivity of enzymes.</p> <p>Section 8. HYDROCARBONS-AROMATIC COMPOUNDS-STEROIDS<br /> What students should know well:<br /> • General properties and most important reactions of hydrocarbons. Electrophilic addition reactions, hydrogenation, hydrogenation, hydration of unsaturated hydrocarbons.<br /> • Aromatic hydrocarbons: aromatic character, HUCKEL's rule. Electrophilic substitution – characteristic reaction of aromatic hydrocarbons.<br /> • Examples of hydrocarbons in biological systems.<br /> • Resonance energy, aromatic stabilization.</p> <p>Section 9. SIMPLE OXYGEN, SULFUR & NITROGEN COMPOUNDS<br /> What students should know well:<br /> • Alcohols: properties (water solubility, acidity), production (by reduction of aldehydes, ketones, by hydration of alkenes), reactions (oxidation, dehydration, esterification, nucleophilic substitution).<br /> • Phenols: Properties: water solubility, acidity<br /> • Thiols: properties (water solubility, acidity), reactions (mild and strong oxidation), disulfide bond and its biological significance.<br /> • Sulfonic acids and 4-aminobenzenesulfonic acid derivatives – sulfonamide drugs.<br /> • Aliphatic amines: primary, secondary, tertiary. General properties – their basic character. Characteristic reactions.<br /> • Aromatic amines: general properties and the comparison of their properties with the properties of aliphatic amines.<br /> • Aliphatic quaternary ammonium salts.<br /> • Amides. Imines, amino alcohols.</p> <p>Section 10. CARBONYL COMPOUNDS & CARBOXYLIC ACIDS<br /> What students should know well:<br /> • Carbonyl physicochemical properties, polarizability, electrophilic and nucleophilic attack<br /> • Enol – ketone tautomerism, tautomers.<br /> • Nucleophilic addition reactions. Hemiacetals, hemiketals, acetals, ketals. Condensation reactions with amines (R-NH2). Imines – Schiff's bases.<br /> • Aldol condensation.<br /> • Ketoacids, urinary ketones, ketoacidosis. Causes of ketoacidosis and ketonuria.<br /> • General properties of carboxyl group: ionization, coordination.<br /> • Acyl derivatives of acids: acyl halides, anhydrides, esters, amides.<br /> • Mechanism of formation and hydrolysis of carboxylic acid esters.<br /> • Dicarboxylic acids, hydroxy acids, ketone acids and unsaturated acids: Special properties and members of biological interest.<br /> What students should have heard:<br /> • Toxic effect of formaldehyde and acetaldehyde, treatment of poisoning with methanol (xyl alcohol).</p> <p>Section 11. HETEROCYCLIC COMPOUNDS – NUCLEOTIDES<br /> • Definition of heterocyclic compounds.<br /> • Five-membered heterocyclic compounds with one heteroatom and their derivatives: pyrrole (proline, porphyrin), imidazole (histidine), thiophene (biotin). Chemical properties: aromaticity, participation in nucleophilic or electrophilic substitution reactions, acid-base properties.<br /> • Five-membered heterocyclic compounds with two heteroatoms: imidazole and its derivatives histidine and histamine, thiazole (thiamine – vitamin B1)<br /> • Heterocyclic compounds with one heteroatom and their derivatives: pyridine (NAD+, NADP+, pyridoxal). Chemical properties of pyridine: aromaticity, participation in nucleophilic or electrophilic substitution reactions, acid-base properties.<br /> • Heterocyclic compounds with two heteroatoms and their pyrimidine derivatives (uracil, thymine, cytosine).<br /> • Condensed heterocyclic rings and their derivatives: indole (tryptophan), purine (adenine, guanine), isoalloxazine (riboflavin, FAD, FMN), pteridine (folic acid).<br /> • Structure and properties of nucleosides and nucleotides</p> <p>Unit 12. STRUCTURE AND BIOLOGICAL ROLE OF AMINO ACIDS AND PEPTIDES<br /> What students should know well:<br /> • Biological functions of amino acids<br /> • Common chemical structure, stereochemistry, common chemical properties, ionization<br /> • Chemical structure of the 20 proteinogenic amino acids: Hydrophobic, Polar, Charged<br /> • Essential amino acids, amino acid modifications & derivatives<br /> • Spectroscopic properties and biologically important reactions<br /> • Detection & analysis<br /> • Peptides & peptide bond, important peptides<br /> What students should have heard:<br /> • Diagnostic value of amino acid analysis</p> <p>Section 13. STRUCTURE AND BIOLOGICAL ROLE OF PROTEINS<br /> What students should know well:<br /> • General functions of proteins<br /> • Molecular interactions that determine protein structure and function<br /> • Levels of molecular organization<br /> • Primary structure<br /> • Physicochemical properties – Solubility<br /> • 3D Structure – Limitations<br /> • Secondary structure: α-helix, β-fold, turns & loops<br /> • Tertiary structure<br /> The role of hydrophobic interactions<br /> The example of myoglobin<br /> The role of disulfide bonds<br /> • Quaternary structure<br /> • Protein structure representation<br /> • Experimental determination of protein structure<br /> • Protein folding<br /> The experiment of C. Anfinsen<br /> The role of amino acids, Cumulative selection, Molecular chaperones<br /> Fatal errors: Amyloidosis, encephalopathies, prion diseases<br /> The student who will attend the course should have heard<br /> • for the Rachamandran diagram and the possible values of the angles φ and ψ of the peptide bond<br /> • for the super-secondary structures (motifs) and structural domains of proteins<br /> • for intrinsically unstructured & metamorphic proteins<br /> • for protein information banks<br /> • for protein folding models and computational methods</p> <p>Unit 14. STRUCTURE AND BIOLOGICAL ROLE OF CARBOHYDRATES & LIPIDS<br /> What students should know well:<br /> • Basic chemical structure, functions, classes and stereo-isomerism of carbohydrates<br /> • Common monosaccharides:<br /> Circular structures & polystorfism<br /> Reducing sugars, Glycated hemoglobin<br /> Exogenous derivatives<br /> • Glycosidic bond<br /> • Common disaccharides<br /> • Polysaccharides: Starch/Glycogen, Cellulose, Chitin<br /> • Glycoproteins, Proteoglycans, Glycosaminoglycans, Glycolipids<br /> • Biological role & Classes of lipids<br /> • Fatty acids: Chemical structure, properties, Nomenclature<br /> • Triacylglycerols: Chemical structure, properties<br /> • Phospholipids: Chemical structure, properties of Phosphoglycerides & Sphingolipids<br /> • Glycolipids & Ethereal lipids<br /> • Steroids: Cholesterol & derivatives, Vitamin D<br /> The student who will attend the course should have heard<br /> • for lectins<br /> • for blood groups</p> <p>Unit 15. CHEMICAL THERMODYNAMICS AND CHEMICAL EQUILIBRIUM<br /> What students should know well:<br /> • What questions does chemical thermodynamics answer?<br /> • Enthalpy, entropy and free energy of a chemical or biochemical reaction. Work and free energy. Standard free energy. Exothermic / endothermic reaction. Exergonic / endergonic reactions<br /> • Equilibrium constants of a reaction. Factors affecting the equilibrium constant – VAN'T HOFF equation.<br /> • Free energy and equilibrium constant ΔGo = – RT ln Kequor<br /> • HESS's law, LE CHATELIER's principle.<br /> • Coupling of chemical and biochemical reactions. What is a chemical intermediate and its role in coupling?<br /> • Experimental determination of enthalpy, entropy and free energy<br /> The student who will attend the course should have heard<br /> • Open, closed and isolated thermodynamic system.<br /> • Statistical interpretation of entropy.<br /> • Chemical potential.</p> <p>Unit 16. CHEMICAL KINETICS – MECHANISMS OF CHEMICAL REACTIONS<br /> What students should know well:<br /> • Rate of chemical reactions, rate law, order of the reaction.<br /> • Zero, first and second order reactions and their mathematical description with differential or integral equations. Half-life (double doubling) time and initial concentration dependence.<br /> • Molecularity of chemical reactions.<br /> • Theory of molecular collisions. Activation energy of a reaction. Arrhenius equation. Examples of nucleophilic - electrophilic reactions.<br /> What they must have heard:<br /> • Experimental determination of velocity law. Relationship between rate law and mechanism of a chemical reaction.<br /> • Experimental determination of activation energy and the rate constant of a chemical reaction.<br /> • Parallels of chemical kinetics and pharmacokinetics.</p> <p>Unit 17. ENZYMES AND KINETICS OF ENZYME REACTIONS<br /> What students should know well:<br /> • General characteristics, clinical applications, function, enzyme cofactors<br /> • Classification & Nomenclature of enzymes<br /> • Thermodynamics & Transition state of Enzyme reaction<br /> • Enzyme Active Center: Characteristics, Models, Binding Energy<br /> • The steady state model in enzyme kinetics<br /> • The Michaelis-Menten equation<br /> • The importance of Vmax, KM and the Michaelis-Menten curve<br /> • Vmax and KM values, Conversion number, Specificity constant<br /> • Experimental determination of Vmax and KM<br /> • Double inverse chart<br /> • Physiological Significance of Vmax and KM: Alcohol Sensitivity, Fate of Glucose, Diagnosis – Treatment</p> <p>Section 18. REGULATION OF ENZYMES.<br /> • Basic principles of enzyme activity regulation:<br /> • Allosteric regulation:<br /> Characteristics of allosteric enzymes<br /> V vs [S] sigmoid curve, Two forms (R and T), Models<br /> Allosteric modifiers<br /> Synergistic properties<br /> Feedback inhibition<br /> Catalytic/Regulatory subunits<br /> • Isoenzymes<br /> • Regulation by covalent modification<br /> • Proteolytic cleavage – Zymogens</p> <p>Section 19. CATALYTIC MECHANISMS AND ENZYME INHIBITORS<br /> • Basic principles of catalysis<br /> Equivalent, General acid-base, metal ion, with approx<br /> • Effect of temperature and pH<br /> • Enzyme inhibitors<br /> Types of inhibition and motor discrimination<br /> Inhibitors as tools to study enzymes<br /> Inhibitors as drugs<br /> • Serine protease catalysis strategies<br /> Chymotrypsin, Trypsin, Elastase<br /> Specificity, Role of active center serine, Catalytic triad<br /> Tetrahedral transition state<br /> • Catalysis strategies of other proteases<br /> • High speed enzymes: Carbonic anhydrases<br /> • Enzymes with high specificity: Restriction endonucleases</p> <p>TUTORIALS<br /> Section Φ1. INSTRUMENTAL ANALYSIS<br /> What students should know well:<br /> • Visible and ultraviolet spectroscopy – physicochemical basis of the method. LAMBERT – BEER law. Molar absorption coefficient. Principles of qualitative and quantitative analysis using visible and ultraviolet spectroscopy: standard solutions, instrument calibration, reference curve.<br /> • Chromatography – physicochemical basis of the method. Gas and liquid chromatography. Distribution, ion exchange, gel chromatography. Examples of applications in clinical chemistry and the study of proteins.<br /> • Mass spectroscopy – physicochemical basis of the method, its role in combined chromatography-mass spectroscopy techniques. Examples of applications in clinical chemistry/biochemistry and toxicology.<br /> • Evaluation of measurements and results: precision, repeatability, random and systematic errors.</p> <p>Section Φ2. PROTEIN ANALYSIS METHODOLOGY<br /> What students should know well:<br /> • the basic principles of protein isolation, purification and analysis methods: differential centrifugation, fractional sedimentation, dialysis, thin layer chromatography, column chromatography, electrophoresis, isoelectric focusing, ultracentrifugation, mass spectroscopy.<br /> • Electrophoresis, physicochemical basis of the method and application examples.<br /> • the basic principles of the amino acid sequence determination methodology<br /> • the basic principles of immunological techniques used in protein analysis (ELISA, immunoblotting, immuno-fluorescence microscopy).<br /> The student who will attend the course should have heard<br /> • on the definition and importance of the proteome and its relationship with the genome<br /> • about the basic structure and properties of antibodies<br /> • on the importance and method of preparation of monoclonal antibodies<br /> • for the methodology of structure determination by X-ray crystallography and NMR.

Recommended reading:	• Notes from deliveries – Posted in e-class. • A. Tsakalov "Medicinal Chemistry in questions and answers" - posted for free on the KALLIPOS platform: https://repository.kallipos.gr/handle/11419/8447?&locale=en • Berg JL, Tymoczko JM & L. Stryer: BIOCHEMISTRY – BASIC PRINCIPLES, PASCHALIDIS EDITIONS. • Varvoglis A. G.: Epitomical organic chemistry, Ziti Publications. • GA TAYLOR: Organic Chemistry for Medical and Biological Sciences. • Raymond Chang: “Physical Chemistry for the Chemical and Biological Sciences”, University Science Books. • Caret Robert L., Denniston Katherine J., Topping Joseph J.: "Principles & applications of inorganic, organic & biological chemistry" Paschalidis Publications.

MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRY

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