04318 - Pharmaceutical and Toxicological Chemistry

Learning outcomes

By the end of the course, the student should have a good understanding of the mechanistic aspects of how drugs work (mode of action) and about the chemical stability, metabolism and the chemical-toxicological behaviour of the drugs.

Course contents

INTRODUCTION

Molecular mechanisms of Drug action. Principles of drug pharmacokinetics: drug absorption, drug distribution, drug metabolism (Phase I and Phase II reactions), drug excretion. 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: cephalosporins of I, II, III e IV generation, SAR. Monobactams, Clavulanic acid, Sulbactam.
Antibiotics which interfere with the protein transduction: Macrolides, Chloramphenicol, Tetracyclines (natural and semysinthetic, chemical physical properties, matabolic degradation).
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), Artemisinines.
Antimycotics drugs. Natural antimycotics: Griseofulvin, Macrolides Polyenes (Structure and mode of action). Chemical antymicotics: Azoles (mode of action).
Antiviral drugs: Derivatives of purines and pyrimidines. Ribavirin. Foscarnet. 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).
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. Atypical antipsychotics.
Antidepressant drugs: MAO inhibitors (classification, structure). 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.
Non steroidal antinflammatory drugs: mode of action, SAR, pharmacological profile, (COX 1 and COX 2 selectivity). 
The discovery of new drugs: Serendipity, clinical observations, Random Screening, rational drug design, from the lead compound to drug.

Readings/Bibliography

W.O. FOYE, T.L. LEMKE, D.A. WILLIAMS, Principi di Chimica Farmaceutica, Piccin Ed. 2010
GRAHAM L. P., Chimica Farmaceutica Ed. italiana, Edises, 2010

A. GRINGAUZ, Introduction to Medicinal Chemistry   How Drugs act and why,  Wiley – VCH, 1997E. SCHROEDER, C. RUFER, R. SCHMIECHEN, Chimica Farmaceutica, Voll. 1,2, SES 1990

C. HANSCH, Comprehensive Medicinal Chemistry, Voll.1-4, Pergamon Press, 1990

All displayed material is available on amsCampus

Teaching methods

During the lessons will be treated all the drugs classes reported in the program and their related chemical aspects such as stability, reactivity, toxicity and metabolism.

Assessment methods

The final class grade is based on an oral examination. In order to pass this exam the illustration and a discussion of at least three drugs classes, as reported in the course contents, is required. The aim is to verify the level of the acquisition of the different topics as described 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 molecular models.

Office hours

See the website of Vincenzo Tumiatti