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 the drugs 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. About these drugs will be described their chemical synthesis, structure-activity relationships, therapeutical utilization, and their related chemical-toxicological aspects.

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 inhibitors. Transition-state analogues.
Receptors: basic principles of receptor theory. Intracellular and membrane receptors.

Laxatives and purgatives.

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.
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).
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.
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 ), 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 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. Oxazolidindiones. Succinimides. Other derivatives.
General anesthetics : gaseous, volatiles and endovenous (modes of action). Dopaminergic agonist (antiparkinson): Biological role of dopamine. Dopaminergic agonists, Dopa-decarboxylase inhibitors, MAO-B inhibitors, COMT inhibitors.
Dopaminergic antagonists (neuroleptics): Phenothiazines (Structure, mode of action, SAR, analogues, synthesis). Butyrophenones. Benzamides. Reserpine and analogues. Atypical antipsychotics.
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). 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); partial agonists and antagonists.
Endocannabinoids.
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 e general synthesis of oxycams.

Readings/Bibliography

W.O. FOYE, T.L. LEMKE, D.A. WILLIAMS, Principi di Chimica Farmaceutica, Piccin Ed. 2008.
Beale J.M, Block J.H, WILSON & GISVOLD, Chimica Farmmaceutica, CEA ED, 2014
E. SCHROEDER, C. RUFER, R. SCHMIECHEN, Chimica Farmaceutica, SES 1990.
C. HANSCH, Comprehnsive Medicinal Chemistry, Voll.1-4, Pergamon Press, 1990.

GRAHAM L. PATRICK Introduzione alla Chimica Farmaceutica EdiSES, 2004.

Teaching methods

Lectures in class.

Assessment methods

The exam consists of an oral examination on both modules. It is designed to verify the knowledge acquired (as detailed in the objectives of the course) and will be passed through the correct answer to multiple questions related to course topics, and also includes an illustration of the chemical synthesis of the main medications. It  is very important that the candidate is familiar with the information derived from the previous years courses (prerequisites), particularly with regard to the knowledge of organic chemistry and biochemistry.

Teaching tools

All the teaching program wiil be explained by PC Powerpoint presentations.

Office hours

See the website of Mirella Rambaldi

See the website of Angela Rampa