00126 - Medicinal and Toxicological Chemistry I;

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 in particular about the different kind of bonds and the steric factors involved in the drug-target interactions. During the course will be dealed the principal drugs families which interact both with targets located in the host cell and with neurotransmitters receptors. Furthermore, their chemical synthesis, structure-activity relationships, therapeutical utilization, and their related chemical-toxicological aspects should be known by the students.

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. 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: synthesis of the 6-APA; natural penicillins, acid-resistants, betalactamase-resistants, and wide spectrum penicillins. Cephalosporins: synthesis of 7-ACA; cephalosporins of I, II, III e IV generation, SAR. (Conversion of penicillins in cephalosporins).
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 and stereospecific synthesis), aminoglycosides, Tetracyclines (natural and semysinthetic, chemical physical properties, matabolic degradation, synthesis of mynocicline), Oxazolidinones.
DNA gyrase inhibitors : Quinolones (Chemical structures and mode of action. Derivatives of I, II e III generation. SAR. Synthesis of nalidixic acid).
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. Synthesis of trimetoprim.
Antimalaric drugs: Plasmodium life cycle. Quine alkaloids and analogues. 4-Aminoquinolines, 8-aminoquinolines, 9-amminoacridines, (mode of action, therapeutic use, synthesis of chloroquine and mefloquine), other derivatives with benzonaftiridinic nucleus, Artemisinines.
Antimycotics drugs: natural antimycotics : Griseofulvin, Macrolides Polyenes (Structure and mode of action). Chemical antymicotics: Azoles (mode of action, synthesis of ketoconazole and fluconazole ), Allylammines, thiocarbammates, 5-Fluorocitosine.
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, synthesis of chlordiazepoxide, oxazepam and general synthesis). Antagonists. Ansiolitics endowed with non-benzodiazepinic structure.  Barbiturates (structure, mode of action, therapeutic use, SAR, general synthesis ).  
Antiepileptics drugs: Barbiturates. Primidone. Other drugs acting on GABAergic system. Hydantoines (synthesis of  diphenylhydantoine). 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. Synthesis of carbidopa.
Dopaminergic antagonists (neuroleptics): Phenothiazines (Structure, mode of action, SAR, analogues). Butyrophenones. Benzamides. Reserpine and analogues. Atypical antipsychotics. ( synthesis of chlorpromazine and fluphenazine).
Antidepressant drugs : MAO inhibitors (classification, structure, synthesis of iproniazid and tranylcypromine). Tricyclic antidepressants endowed with 6,6,6  and 6,7,6 cycle (structure, mode of action, synthesis of  imipramine e amitriptiline). Selective biological amines reuptake inhibitors.
Opioid analgesics: morphine, oripavines derivatives, morphinanes, benzomorphans, 4-phenylpiperidines and diphenylpropylamines (mode of action, therapeutic use, SAR, synthesis of levorphanol, oximorphone, oxycodone and ethorphine, meperidine, methadone, dextropropoxyphene, pentazocine); 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). General synthesis of arylacetics and arylpropionics, synthesis of diclophenac, indomethacin, sulindac and general synthesis of oxycams.

Readings/Bibliography

LEMKE T.L., WILLIAMS DA., Foye's Principi di chimica farmaceutica, PICCIN, 2010.

GRAHAM L. P., Chimica Farmaceutica Ed. italiana, Edises, 2004

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

Teaching methods

During the lessons will be treated all the drugs classes and the synthesis as reported in the course program.

Assessment methods

In order to pass this exam it will be required the chemical synthesis of two drugs reported in the course program, followed by an oral description of at least three drugs classes.

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