MEDICINAL AND TOXICOLOGICAL CHEMISTRY

Educational goals: to provide the fundamental know-how used in medicinal chemistry for the “Drug Discovery”, starting from the first step of the development of the molecule until it evolve to a medication. To provide knowledge of the route of the drugs in the human body starting from the administration to the elimination “clearance” evaluating all the conditioning properties related to the interaction of drug-biophase. To provide knowledge of the main classes of active drugs in the treatment of diseases caused by infectious agents, and for each of these classes, the most representative of the components used, their physico-chemical properties and biological synthesis and structure-activity relationships.

MODULO A (4 CFU): the course includes 28 hours of classroom lectures (first semester).

MODULO B (4 CFU): the course includes 28 hours of classroom lectures (second semester).

Classroom attendance is mandatory. The maximum limit of absences allowed is 30% of the total hours of lessons.

MODULE A – Lez. 30 h; CFU 4

GENERAL ASPECTS

Unity 1

Introduction. Production of drugs. Pharmaceutical research. Access ways to new drug substances. Development phases of a new drug. Development of a drug into a pharmaceutical agent. Pre-clinic studies: chemical, analytical and galenical development, pharmacodynamics, pharmacokinetics, toxicity, carcinogenicity and mutagenicity. Clinical tests. Patent protection. Good Clinical Practice (GCP). Ethics Committee. Off-label, generic equivalent, Me-too drugs. Innovation. Orphan drugs. Stability.

Unity 2

Phases of a drug action:

- pharmaceutical phase, administration pathways and characteristics.

- pharmacokinetic phase with absorption mechanisms, transport in the bloodstream, distribution, pathways of xenobiotic metabolism, phase I reactions (oxidation, reduction, hydrolysis), phase II (methylation, acetylation, conjugation), enzymatic inhibition and induction, elimination and excretion pathways. Pro-drugs, advantages and combinations. Mutual pro-drugs. Soft-drugs, advantages and soft analogues.

- pharmacodynamic phase: drug-receptor interaction, chemical bonding and theories about the drugs mechanism of action. Dose-response relationships. Antagonism.

Unity 3

Haptophoric and pharmacophoric groups. Structural features and pharmacological activity, optical and geometric isomerism, conformational isomerism and eudismic index, influence of stereoselectivity and stereospecificity on drug-receptor interaction, molecular modifications, chemical isosterism, bioisosterism classical and nonclassical bioisosteres. International drug abbreviations, DC.IT, INN, importance to monitoring and scientific information. Pharmacosurveillance. ATC classification.

MODULE B – Lez. 36 h; CFU 5

SPECIFIC TOPICS

Unity 4

ANTIBIOTICS AND ANTIMICROBIAL AGENTS: general principles, classifications.

BACTERIAL CHEMOTHERAPY: antibacterial classification and mechanism of action. Bacterial resistance.

Sulfonamides: short historical outlines, classification, action spectrum, association, mode of action, synthesis of N-heterocyclic, N-acyl and acylamino derivatives, structure-activity relationships.

- classical: sulfathiazole, sulfamethazine, sulfamethizole, sulfisomidine,sulfisoxazole.

- semiretard: sulfadiazine, sulfamethoxazole, sulfamerazine.

- retard: sulfamethoxypyridazine, sulfadimethoxine, sulfamethoxydiazine.

- ultraretard: sulfadoxine.

- topical action: sulfacetamide, sulfanilamide, sulfaguanidine, phthalylsulfathiazole, succinylsulfathiazole, sulfasalazine.

Nitrofurans: short historical outlines, activity, action spectrum, mode of action, synthesis, structure-activity relationships. Nitrofurazone, nifuroxime, nitrofurantoin, furazolidone, nifuratel.

Nitroimidazoli: short historical outlines, action spectrum, mode of action, metronidazole.

Quinolones: fluoro- and difluoroquinolones, synthesis, mode of action, structure-activity relationships.

- I generation: nalidixic acid, piromidic acid, oxolinic acid.

- II generation: pipemidic acid, cinoxacin.

- III generation: ofloxacin, norfloxacin, ciprofloxacin, enoxacin, pefloxacin mesylate.

Unity 5

ANTIMYCOBACTERIAL AGENTS: general principles, mode of action, synthesis, antimycobacterial therapy.

Diaminodiphenylsulfones: dapsone, acedapsone.

Carboxylic acids and derivatives: 4-aminosalicylic acid, isoniazid, pyrazinamide.

Thioamides: etionamide, protionamide.

Ethylenediamines: ethambutol.

Antibiotics: cycloserine, rifamycin SV, rifampicin,rifabutin, streptomycin.

Unity 6

ANTIBIOTICS: short historical outlines, production pathways: fermentation, synthesis, semisynthesis.

Beta-lactam antibiotics: structure, nomenclature, properties, synthesis, mode of action, antimicrobial spectrum, bacterial resistance.

penicillins: stability, acid lability, acid stability, production of 6-APA, structure-activity relationships, depot penicillins, penicillinase-stable penicillins, broad-spectrum penicillins, antipseudomonas penicillins, ureidopenicillins.

Unity 7

- Cefalosphorins: short historical outlines, activity, production of cephalosporin C, production of 7-ACA, structure-activity relationships, classification. I generation, cefacetrile, cefalotin, cefapirin, cefaloridine; perorally cephalosporins, cefalexin, cefaclor; II generation, cefamandole, cefuroxime, cephamycins, cefoxitin; III generation, cefotaxime, IV generation, cefpirome, cefepime, cefclidine.

- 2-penem: structural features

- carbapenem: structural features, antimicrobial spectrum, thienamycin, imipenem.

- monobactams: chemical and structural features, synthesis, aztreonam, carumonam

Unity 8

Tetracyclines: therapeutic and structural features, classification, structure-activity relationships, chemical properties, stability, synthesis, oxytetracycline, metacycline, doxycycline, minocycline, prodrugs, rolitetracycline, lymecycline, mepicycline.

Amphenicols: therapeutic features, synthesis, structure-activity relationships, Chloramphenicol, thiamphenicol.

Unity 9

Macrolide antibiotics: structural features, classification, mode of action, erythromycin, roxithromycin, azithromycin, oleandomycin, spiramycin.

Carbohydratic antibiotics: lincosamides, lincomycin, structure-activity relationships, clindamycin.

Aminoglycosides: structural and therapeutic features, bacterial resistance, kanamycin B, streptomycin, amikacin, synthesis, gentamicin.

Ansamycins: rifamycins, mode and spectrum of action, structural features, structure-activity relationships, rifampicin, rifapentin.

Polypeptides: classification, mode of action, bacitracin.

Lipopeptides: mode of action, polymyxin, colistin.

Unity 10

ANTIFUNGAL AGENTS: pathogenicity of fungus, mycosis, therapy, classification.

Antibiotics: griseofulvin, nystatin, anphotericin.

Imidazoles: therapeutic features, mode of action and synthesis, clotrimazole, miconazole, econazole, isoconazole, ketoconazole.

Triazoles: terconazole, fluconazole.

Unity 11

ANTIVIRAL AGENTS: features of viruses, viral replication steps, antiviral therapy, chemoterapy, mode of action, spectrum and synthesis.

Thiosemicarbazones: methisazone.

Aminoadamantanes: amantadine, tromantadine.

Nucleosides: pyrimidine, azole, purine analogues, idoxuridine, cytarabine, ribavirin, acyclovir, gancyclovir.

NEW THERAPEUTIC APPROACHES FOR THE TREATMENT OF HIV INFECTIONS: co-receptor inhibitors, fusion inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, protease inhibitors.

DRUGS FOR HCV INFECTIONS: NS3 / 4A protease inhibitors, NS5A phosphoprotein inhibitors, NS5B polymerase inhibitors, therapeutic combinations.

Unity 12

CANCER CHEMOTHERAPY: cancer generalities, classification, carcinogenesis, treatment of cancer, alkylating agents, cisplatin, carboplatin; procarbazine, antibiotics, antimetabolites, Vinca alkaloids.

NEW STRATEGIES IN ANTITUMORAL CHEMOTHERAPY: kinase, histone deacetylases, farnesil transferase inhibitors.

1. Materiale Didattico fornito dal docente: http://studium.unict.it/dokeos/2016/index.php?category=409a732f04b0
2. FOYE’S PRINCIPI DI CHIMICA FARMACEUTICA - VI ediz. italiana (2014) - Piccin.
3. PATRICK G.L. - Introduzione alla Chimica Farmaceutica – II ed. (2010) - EdiSES.
4. Wilson & Gisvold -Chimica Farmaceutica- I Ed. (2014) - Casa Editrice Ambrosiana
5. Gasco A. Gualtieri F. Chimica Farmaceutica- I Ed. (2015) - Casa Editrice Ambrosiana
6. G. GRECO - Farmacocinetica e Farmacodinamica su basi chimico-fisiche - (2007) – Loghìa
7. G. GRECO – Farmaci antibatterici - (2009) - Loghìa

Letture consigliate:

- BURGER’S - Medicinal Chemistry and Drug Discovery, vol I - Ed. M.E. Wolff - J. Wiley & Sons.