91025 - Medicinal and Toxicological Chemistry I

Learning outcomes

Students acquire fundamental knowledge for the understanding of the drug, its structure and activity in relation to the interaction with biomolecules at the cellular and systemic levels, as well as for the necessary design activities, of its molecular mechanism of action and in particular of the types of bonds and steric factors involved in the drug-molecular target interaction, the modifications operated by metabolic reactions, the mechanisms of elimination, and the possible formation of toxic species. They know the main classes of drugs capable of selectively targeting foreign microorganisms to the human organism (chemotherapy), and also those capable of acting at the level of the central nervous system. They are able to apply their knowledge to understand their general synthesis, physicochemical properties, mechanisms of action, structure-activity relationships, utilization, and chemical-toxicological aspects, including through database research.

Course contents

GENERAL PART.

Molecular mechanism of action of a drug. Elements of pharmacokinetics: absorption, distribution, metabolism (phase I reactions and phase II reactions), excretion, drug pollution. Drug-receptor interaction: types of binding involved. Steric factors affecting drug activity: optical, geometrical and conformational isomery. Bioisostery. Enzyme inhibition: competitive and noncompetitive inhibition. Antimetabolites. Enzyme inhibitors by suicide. Analogs of transition structures.

Receptors: elements of receptor theory. Intracellular receptors and membrane receptors.

DESCRIPTIVE PART.

Chemotherapeutics: definition, generalities.

Antibiotics that interfere with cell wall synthesis: β-lactam antibiotics (structure and nomenclature; mechanism of action). Penicillins: natural, acid-resistant, β-lactamase-resistant, broad-spectrum penicillins. Cephalosporins: I, II, III and IV generation, SAR.

Tienamycins, Imipenem, Nocardicins, Monobactams, Clavulanic acid, Sulbactam, Phosphomycin, Glycopeptides.

Antibiotics that interfere with transcription: Ansamycins (Rifamycins).

Antibiotics that interfere with translation: Macrolides, Chloramphenicol (classical synthesis), Aminoglycosides, Tetracyclines (natural and semisynthetic, physicochemical properties, degradation pathways), Oxazolidinones.

DNA gyrase inhibitors: Quinolones (Structure and mechanism of action. Generation I, II and III derivatives. SAR).Dihydropteroate synthetase inhibitors: Sulfonamides (Structure and physicochemical properties; SAR).

Dihydrofolate reductase inhibitors: Structure and functions of folic acid, classical and nonclassical inhibitors, selective toxicity. SAR.

Antimalarial drugs: Plasmodium cycle. China alkaloids and analogues. 4-Aminoquinolines, 8-aminoquinolines, 9-aminoacridines, (mechanism of action, therapeutic use), other benzonaftiridine core derivatives, Artemisinins.

Antifungal drugs: Natural antifungals: Griseofulvin, Macrolide-Polyenes (Structures and mechanism of action). Synthetic antifungals: Azoles (Mechanism of action), Allylamines, Thiocarbamates, 5-Fluorocytosine.

Antiviral drugs: Purine derivatives. Pyrimidine derivatives. Neuraminidase inhibitors. Protease inhibitors.

Antitumor drugs: Alkylating agents. Antimetabolites. Intercalators. Topoisomerase I and II inhibitors. Mitotic inhibitors.
 
Arachidonic acid cascade: prostaglandins, thromboxane, and leukotrienes.

Nonsteroidal anti-inflammatory drugs: mechanism of action, SAR, pharmacological profile (selectivity toward COX 1 and COX 2).

Drugs active on the cardiovascular system: Cardiac action potential, ion channels. Cardiac glucosides: Structure, SAR, receptor hypothesis, mechanism of action. Antiarrhythmic drugs: classification, mechanisms of action. Main exponents of each class. Calcium modulators, examples, SAR. Antianginal drugs, examples. Antihypertensive drugs: direct vasodilators, examples, general characteristics. Inhibitors of the renin-angiotensin system: generalities, converting enzyme inhibitors, examples, SAR. Angiotensin II antagonists: discovery, development of losartan and the sartan class, structure, SAR

Steroid Hormones: Structure, biosynthesis, steroid receptors. Estrogens: structures, SAR, natural and synthetic estrogens.Antiestrogens: receptor antagonists, triphenylethylene derivatives, tamoxifen, raloxifene and analogs, SAR.Steroidal and nonsteroidal aromatase inhibitors, examples and SARs.Progestatives: structures, SAR, semisynthetic derivatives.Mifepristone. Androgens and anabolics: structures, SAR. Antiandrogens: receptor antagonists: cyproterone, flutamide. Biosynthesis inhibitors: liarozole and finasteride.Corticosteroids: mineralcorticoids, glucocorticoids, examples, SAR.

PRACTICAL PART.
Synthesis of: 6-aminopenicillanic acid (6-APA); minocycline; nalidixic acid; trimethoprim; mefloquine; fluconazole; diclofenac; nifedipine; verapamil; captopril; enalapril; diethylstilbestrol.

Readings/Bibliography

Foye's Principles of Medicinal Chemistry (English Edition)

Teaching methods

The course is taught in English and involves frontal theoretical activities. All examination topics will be covered

Assessment methods

The examination consists of an oral discussion, the aim of which is to test the acquisition of the knowledge set out in the course objectives. A written illustration of the chemical synthesis of two of the drugs covered during the course and specifically indicated in the syllabus will also be required, followed by two questions on more general topics, and will be deemed passed by the correct answer to the questions posed, with particular regard to the relationships between chemical structure and biological activity and drug-target interaction. It is therefore relevant that the candidate has acquired knowledge from previous years' courses, in particular organic chemistry and biochemistry.

Teaching tools

The slides presented in class are made available to University of Bologna students via the Virtual platform.

Office hours

See the website of Andrea Milelli

See the website of Roberto Mandrioli