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 mechanisms of Drug action. Principles of drug pharmacokinetics: drug absorption, drug distribution, drug metabolism (Phase I and Phase II reactions), drug excretion, drugs pollution. Drug target interactions: description of different chemical bonds involved in. Influence of steric factors on drugs activity: optical (chirality), geometric and conformational isomery. Bioisosterism. Enzymatic inhibition: competitive and non-competitive inhibition. Antimetabolites. Suicide enzymatic inhibitors. Transition-state analogues.

Receptors: basic principles of receptor theory. Intracellular and membrane receptors.

SPECIFIC TOPICS
Chemioterapeutics: definition, general aspects
Antibiotics which interfere with the biosynthesis of the cellular wall : beta-lactams antibiotics (chemical structure and nomenclature; mode of action). Penicillins: natural penicillins, acid-resistants, betalactamase-resistants, and wide spectrum penicillins. Cephalosporins: I, II, III e IV generation, SAR.
Thyenamycins, Imipenem, Nocardicins, Monobactams, clavulanic acid, Sulbactam, Fosfomycin, Glicopeptides.
Antibiotics which interfere with the protein transcription : Ansamycins (Rifamycins).
Antibiotics which interfere with the protein transduction : Macrolides, Chloramphenicol (classical synthesis), aminoglycosides, Tetracyclines (natural and semysinthetic, chemical physical properties, matabolic degradation), Oxazolidinones.
DNA gyrase inhibitors : Quinolones (Chemical structures and mode of action. Derivatives of I, II e III generation. SAR.).
Ihnibitors of the dihydropteroate synthase : Sulphamidics (general structure and chemical-phisical properties; SAR).
Ihnibitors of the dihydrofolate reductase : Structure and biological role of the folic acid, classical and non-classical inhibitors, selective toxicity. SAR.

Antimalaric drugs: Plasmodium life cycle. Quinine alkaloids and analogues. 4-Aminoquinolines, 8-aminoquinolines, 9-amminoacridines, (mode of action, therapeutic use), other derivatives with benzonaftiridinic nucleus, Artemisinines.
Antimycotics drugs: natural antimycotics : Griseofulvin, Macrolides Polyenes (Structure and mode of action). Chemical antymicotics: Azoles (mode of action), Allylammines, thiocarbammates, 5-Fluorocitosine.
Antiviral drugs : Derivatives of purines and pyrimidines. Neuraminidase inhibitors. Protease inhibitors.
Anticancer drugs : Alkylating drugs. Antimetabolites. Intercalators. Topoisomerase I and II inhibitors. Mitotic inhibitors.

Drugs acting on CNS.
Sedative-hypnotics: Benzodiazepines (structure, mode of action, therapeutic use, metabolism, SAR). Antagonists. Ansiolitics endowed with non-benzodiazepinic structure. Barbiturates (structure, mode of action, therapeutic use, SAR).
Antiepileptics drugs: Barbiturates. Primidone. Other drugs acting on GABAergic system. Hydantoines. Oxazolidindiones. Succinimides. Other derivatives.
General anesthetics : gaseous, volatiles and endovenous (modes of action). Dopaminergic agonist (antiparkinson): Biological role of dopamine and acetylcholine. Dopaminergic agonists, Dopa-decarboxylase inhibitors, MAO-B inhibitors, COMT inhibitors.
Dopaminergic antagonists (neuroleptics): Phenothiazines (Structure, mode of action, SAR, analogues). Butyrophenones. Benzamides. Reserpine and analogues. Atypical antipsychotics.
Antidepressant drugs : MAO inhibitors (classification, structure, synthesis of iproniazide). Tricyclic antidepressants endowed with 6,6,6 and 6,7,6 cycle (structure, mode of action). Selective biological amines reuptake inhibitors.
Opioid analgesics: morphine, oripavines derivatives, morphinanes, benzomorphans, 4-phenylpiperidines and diphenylpropylamines (mode of action, therapeutic use, SAR); partial agonists and antagonists.
Arachidonic acid cascade: prostaglandins, thromboxanes and leukotrienes.
Non steroidal antinflammatory drugs: mode of action, SAR, pharmacological profile, (COX 1 and COX 2 selectivity).

PRACTICE PART

Synthesis of: 6-aminopenicillanic acid; minocycline; nalidixic acid; trimetoprim; mefloquine; fluconazole; general synthesis of barbiturates; oxazepam and general synthesis of benzodiazepines; carbidopa; chlorpromazine and fluphenazine; imipramine and amitriptyline; oximorphone, oxycodone, methadone; diclofenac.

 

Readings/Bibliography

VICTORIA F. ROCHE, S. WILLIAM ZITO, THOMAS L. LEMKE, DAVID A. WILLIAMS, Foye's Principles of Medicinal Chemistry, Wolters Kluwer Health, 2019, ISBN: 13:978-1-4963-8502-4

The slides will be available on the web site of the course

Teaching methods

During the lessons will be treated all the different drugs classes with relative mechanisms of action, and the required synthesis as reported in the course program.

Assessment methods

The final class grade is based on an oral examination. In order to pass this exam the description of the chemical synthesis of two drugs, reported in the course program, will be required followed by an oral description of at least three drugs classes with the aim to verify the level of the acquisition of the different topics as reported in the outcomes of the course.

Registration on-line on AlmaEsami is mandatory.

Teaching tools

All the teaching program wiil be explained by PC power point presentation and, when necessary, by using the 3D molecular models and Chemoffice software.

Office hours

See the website of Vincenzo Tumiatti