Industrial pharmacy REPLICA LATINA

Program. 1. Introduction to Medicinal Chemistry Organic Chemistry and Biochemistry for Medicinal Chemistry: recognition of functional groups, amino acids, nitrogenous bases, sugars, mixed structures from 2D and 3D structures, representation of organic molecules in 1D, 2D and 3D. Definitions: Drug. History. Fields of Medicinal Chemistry and Medicinal Chemistry. Origin of Drugs: Drugs of Natural Origin, Semi-Synthetic Drugs, Synthetic Drugs, Combinatorial Synthesis. 2. Macromolecules of Chemical Pharmaceutical Interest Proteomics and Genomics in Drug Discovery. Structure of Protein and Nucleic Macromolecules (tertiary structure of DNA and structure and functions of RNA). 3. Pharmaceutical Phases Definitions. Pharmacokinetics: Routes of Drug Administration (Enteral, Rectal, Parenteral, Topical), Drug Absorption (chemical factors, biological factors). Absorption by Passive Diffusion and by the oral route (Lipinski's Rule). Drug Distribution. Bioavailability. Binding to Plasma Proteins. Drug Metabolism: First Pass Metabolism, Phase I Metabolism (Structure and Reactions of Cytochromes P450, Oxidative Cycle, Oxidative Reactions Catalyzed by Other Enzymes, Reduction Reactions, Hydrolysis Reactions, Metabolic Activation), Phase II Metabolism (Conjugation Reactions, Conjugation Cofactors, Glucuronidation, Sulfoconjugation, Glutathione Conjugation, Methylation and Acetylation, Dopamine Metabolism, Hippuric Conjugation), Example of Phase I and II Metabolism: Case of Aspirin, Metabolic Stability, Hard and Soft Drugs, Metabolism of the Antiviral Agent: Indinavir. Drug Elimination. 4. Pharmacodynamic Phase Drug/Macromolecule Interactions, Types of Interaction, Covalent Bonds, Ionic Bonds, Ion-dipole and dipole-dipole Interactions, Hydrogen Bonds, Charge-Transfer Complexes, Hydrophobic Interactions, Cation-π Interactions, Halogen Bonding, Van der Waals or London Forces, Non-bonding Interaction, Numerical Determination of Interactions. Enzymes as Drug Targets (Types of Inhibitors, Enzyme Kinetics). Receptors (Classification, Orphan Receptors, Design of Agonist Ligands, Antagonists, Partial Agonists and Inverse Agonists, Desensitization and Sensitization, Tolerance and Dependence, Receptor Types and Subtypes, Affinity, Efficacy and Potency). Nucleic Acids as Drug Targets. Other Drug Targets. 5. Drug Discovery and Drug Design Identification of the Prototype (Hit), Hit to Lead, Lead Compounds. Optimization of interactions with the target. Structure-Activity Relationships (SAR). Identification of a pharmacophore. Strategies adopted in Drug Design (Variation of substituents, extension of the structure, linear and cyclic homology, variation of the nature of the cycles, fusion of cycles, isosteres and bioisosteres, structural simplifications, stiffening of the structure, drug design based on the structure of the interaction site and molecular modeling, multi-target drugs (MTDD)). 6. Antibacterials/Antibiotics The bacterial cell. Classification by mechanism of action. Inhibitors of metabolite synthesis. Inhibitors of folate synthesis. Sulfonamides: Origin, mechanism of action, structure-activity relationships, pharmacokinetics, applications. Prontosil, metabolism of prontosil. Trimethoprim: structure, mechanism of action and association with sulfonamides. Inhibitors of bacterial cell wall biosynthesis. Penicillins: Origin, mechanism of action, resistance, methods of preparation of penicillins: 6-APA. [S], structure-activity relationships, structural analogues of penicillin. Benzylpenicillin (G). Phenoxymethylpenicillin (V). Sensitivity to acids. Acid-resistant penicillins. Beta-Lactamase Resistant Penicillins (Methicillin, Nafcillin, Temocillin, Oxacillin, Cloxacillin, Flucloxacillin, Dicloxacillin). Broad-Spectrum Penicillins (Penicillin N, Penicillin T, Ampicillin, Amoxicillin, Pivampicillin, Talampipicillin, Bacampicillin). Penicillin Prodrugs. Carboxypenicillins (Carbenicillin, Carfecillin, Indanylcarbenicillin, Ticarcillin). Ureidopenicillins (Azlocillin, Mezlocillin, Piperacillin). Clinical Aspects. Cephalosporins: History and Overview. Properties of Cephalosporin C and SAR. Methods of Preparation of 7-ACA [S] for the Synthesis of Cephalosporins. First Generation Cephalosporins (Cephalothin, Cephaloridine, Cefalexin [3-Methylated Cephalosporin Synthesis], Cefazolin), Second Generation Cephamycin C, Cefoxitime and Oximinocephalosporins [Cefuroxime], Ceftazidime), Third Generation Cefotaxime, Ceftizoxime, Ceftriazone, Fourth Generation Cefepime, Cefpirome, Fifth Generation Ceftaroline, Ceftaroline Fosamil), Clinical Aspects. Carbapenems and Monobactams: Thienamycin, Imipenem, Meropenem, Ertapenem, Nocardicin A, Aztreonam. Beta-Lactamase Inhibitors: Clavulanic Acid, Sulbactam, Tazobactam, Olivanic Acids. Other Bacterial Cell Wall Inhibitors: General Information and Mechanism of Action. Cycloserine, Bacitracin, Glycopeptides (Vancomycin). Bacterial Protein Biosynthesis Inhibitors. Aminoglycosides: General Information, Mechanism of Action and Structure-Activity Relationships. Streptomycin, Gentamicin. Tetracyclines: General Information, Mechanism of Action and Structure-Activity Relationships. Tetracycline, Aureomycin, Doxycycline, Demeclocycline. Chloramphenicol: General Information and Mechanism of Action. Macrolides: General Information, Mechanism of Action. Erythromycin, Clarithromycin, Azithromycin, Telithromycin. Lincosamides. General Information, Mechanism of Action. Lincomycin, Clindamycin, Clindamycin phosphate. Oxazolidinones: General Information, Mechanism of Action and Structure-Activity Relationships. Linezolid, Radezolid. Drugs that affect the transcription and replication of nucleic acids. Quinolones and Fluoroquinolones. General Information, Mechanism of Action, Structure-Activity Relationships and Adverse Effects. Nalidixic Acid, Enoxacin, Ciprofloxacin [S], Levofloxacin, Moxifloxacin, Besifloxacin. Rifamycins: General Information, Mechanism of Action and Structure-Activity Relationships. Rifamycin B, Rifampicin, Rifaximin. 7. Antivirals General information. History and pathogenic viruses for humans. Structure of viruses and replication cycle. Antiviral drugs against DNA viruses. General information, Mechanism of action, Structures and Clinical aspects. Aciclovir [S], Valaciclovir [S], Desciclovir, Ganciclovir [S], Valganciclovir, Penciclovir, Famciclovir, Cidofovir, Idoxuridine, Trifluridine, Vidarabine, Foscarnet. Drugs against RNA viruses. Anti-HIV: General information, replication cycle of the virus and targets for drugs. Reverse transcriptase inhibitors: Nucleosides (NRTI). Mechanism of action, Structures, Resistance and Clinical aspects. Zidovudine [S], Stavudine, Zalcitabine, Didanosine and metabolic activation, Emtricitabine, Lamivudine, Abacavir and metabolic activation, Adefovir dipivoxil, Tenofovir disoproxil and metabolic activation. Non-Nucleoside Receptor Blockers (NNRTI): Mechanism of Action, Structures, Resistance and Clinical Aspects. Butterfly-like model. Nevirapine, Efavirenz, Rilpivirine, Etravirine, Delavirdine. Protease inhibitors: Design, Mechanism of Action, Structures, Structure-Activity Relationships and Clinical Aspects. Saquinavir, Ritonavir, Lopinavir, Indinavir, Nelfinavir, Palinavir, Amprenavir, Darunavir, Atazanavir. Integrase and fusion inhibitors: Mechanism of Action, Structures and Structure-Activity Relationships. Raltegravir, Enfurtivide, Maraviroc. Anti-Influenza: General information, virus replication cycle and drug targets. Ion channel blockers: Mechanism of Action and Structures. Adamantanes (Amantadine, Rimantadine). Neuraminidase inhibitors: Design, Mechanism of Action, Structures and Structure-Activity Relationships. Mechanism of sialic acid hydrolysis. Zanamivir, Laninamivir, Oseltamivir. Anti-HCV: General, virus replication cycle and drug targets. Boceprevir, Telaprevir, Narlaprevir, Setrobuvir. Broad-spectrum antiviral agents: Mechanism of action and Structures. Cyclopentenyl Cytosine, 3-Deazaneplanocin A, Ribavirin. Interferons. 8. Antifungals Antifungal drugs and their molecular targets. Classes of drugs used as antifungals and their structures. Echinocandins: General Information, Mechanism of Action, Structure-Activity Relationships, Resistance. Caspofungin, Micafungin, Anidulafungin. Polyene Antibiotics: General Information, Mechanism of Action and Structure-Activity Relationships. Amphotericin B, Nystatin. Biosynthesis of ergosterol. Azole Antifungals: General Information, Mechanism of Action, Structure-Activity Relationships and Resistance. Imidazoles: Miconazole [S], Tiaconazole, Clotrimazole, Ketoconazole [S]. Triazoles: Fluconazole [S], Itraconazole, Voriconazole, Posaconazole [S], Ravuconazole. Allylamines: General Information, Mechanism of Action and Structure-Activity Relationships. Terbinafine, Naftifine, Butenafine. Morpholines: General Information, Mechanism of Action and Structure-Activity Relationships. Amorolfine, Fenpropimorph. Inhibitors of microtubule function: General Information, Mechanism of Action and Structure-Activity Relationships. Griseofulvin. Inhibitors of DNA/RNA synthesis and function: General Information, Mechanism of Action and Structure-Activity Relationships. Flucytosine. 9. Antimycobacterials Types of mycobacteria pathogenic to humans. Tuberculosis: Implications of tuberculosis in the world and history of antituberculosis. Selection of resistant strains MDR, XDR and TDR. Therapeutic approaches: first, second and third line. First-line anti-tuberculosis drugs: General information, Structures, Mechanism of Action and Structure-Activity Relationships. Isoniazid, Pyrazinamide, Rifampicin, Ethambutol. Second-line anti-tuberculosis drugs: General information, Structures, Mechanism of Action and Structure-Activity Relationships. Ciprofloxacin, Kanamycin, Cycloserine, Linezolid. Leprosy: Pathology. Antileprotic drugs: General information, Structures, Mechanism of Action and Structure-Activity Relationships. Dapsone, Thiambutosin, Clofazimine. 10. Antiparasitics Protozoa and classification. Amoebiasis: General Information. Pharmacological Treatment: Mechanism of Action and Structures. Emetine, Dehydroemetine, Metronidazole [S], Tinidazole, Chloroquine, Paromomycin, Iodoquinol, Carbarsone, Diloxanide Furoate. Other intestinal protozoan infections and their pharmacological treatment: Giardiasis, Balantidiasis, Toxoplasmosis, Cryptosporidiosis and Isosporiasis. Pharmacological Treatment for Giardiasis: Furazolidone, Quinacrine, Nitazoxanide. Genitourinary Infections: Trichomoniasis. General Information, Metronidazole, Tinidazole. Pulmonary Infections: Pneumocystis Jirovecii Pneumonia. Treatment of Pneumonia: Mechanism of Action, Structures and Structure-Activity Relationships. Trimethoprim, Sulfamethoxazole, Dapsone, Pentamidine diisethionate [S], Atovaquone, Trimetrexate, Leucovorin. Leishmania. General Information, Vector and Pharmacological Treatment. Sodium stibogluconate, Meglumine antimoniate, Amphotericin B, Miltefosine, Imiquimod, Sitamaquina. African trypanosomiasis. General Information, Vector and Pharmacological Treatment. Sodium suramin, Melarsoprol, Eflornithine. American trypanosomiasis. General Information, Vector and Pharmacological Treatment. Nifurtimox, Benznidazole. Malaria. General Information, Vector and Pharmacological Treatment. Quinoline antimalarials: Mechanism of action, Structure-activity relationships and resistance. History and derivatives of natural origin: cinchona extracts and alkaloids (Quinine, Quinidine, Cinchonine, Cinchonidine). 8-Aminoquinoline Derivatives: Pamaquine, Primaquine [S], Tafenoquine. 4-Aminoquinoline Derivatives: Chloroquine [S], Amodiaquine, Isoquine. Quinoline Methanolic Derivatives: Mefloquine [S], Halofantrine, Lumefantrine. Antimalarials Artemisinin Derivatives. Mechanism of Action and Structure-Activity Relationships. History and Discovery of Artemisinin. Semi-Synthetic Artemisinin Derivatives: Dihydroartemisinin, Artemether, Arteether, Sodium Artesunate, Artelinic Acid. Inhibitors of De Novo Pyrimidine Synthesis: Pyrimethamine [S], Proguanil, Cycloguanil, Sulfadoxine, Atovaquone. 11. Antitumor drugs Introduction. Causes and hallmarks of cancer. Drugs that act directly on nucleic acids: Mechanism of action, Structures, Structure-Activity Relationships and Clinical Aspects. Anthracyclines (Doxorubicin, Epirubicin, Daunorubicin, Idarubicin), Mitoxantrone, Amsacrine, Dactinomycin. Non-intercalating agents that inhibit the action of topoisomerases on DNA: Mechanism of action, Structures, Structure-Activity Relationships and Clinical Aspects. Podophyllotoxins (Podophyllotoxin, Etoposide, Teniposide), Camptothecins (Camptothecin, Topotecan, Irinotecan, SN-38). Alkylating and metallating agents: Mechanism of action, Structures, Structure-Activity Relationships and Clinical Aspects. Nitrogen mustards: Chlormethine, Melphalan, Chlorambucil, Estramustine, Bendamustine, Ifosfamide, Cyclophosphamide, TH-302. Cis-Platinum and Analogues: Cisplatin, Carboplatin, JM 216, Oxaliplatin. Other Alkylating Agents: Dacarbazine, Procarbazine, Lomustine, Carmustine, Temozolomide. Drugs that act on enzymes. Antimetabolites: Mechanism of Action, Structures, Structure-Activity Relationships and Clinical Aspects. Dihydrofolate Reductase Inhibitors: Methotrexate, Pralatrexate, Pemetrexed. Thymidylate Synthase Inhibitors: 5-Fluorouracil, Raltitrexed, ZD 9331. Adenosine Deaminase Inhibitors: Pentostatin. DNA Polymerase Inhibitors: Cytarabine, Are-CTP, Gemcitabine, Fludarabine. Purine Antagonists: 6-Mercaptopurine, 6-Thioguanine. Poly(ADP-ribose) Polymerase Inhibitors: Olaparib, Rucaparib, Niraparib, Talazoparib. Hormone Therapies: Mechanism of Action, Structures, Structure-Activity Relationships, and Clinical Aspects. Ethinyl Estradiol, Diethylstilbestrol, Fosfestrol, Medroxyprogesterone Acetate, Megestrol Acetate, Fluoxymesterone, Testosterone Propionate, Dihydrotestosterone. LHRH Agonists: Leuprolide, Goserelin. Antiestrogens: Tamoxifen, 4-Hydroxytamoxifen, Toremifene, Raloxifene, Fulvestrant. Antiandrogens: Flutamide, Cyproterone Acetate, Abiraterone. Aromatase Inhibitors: Aminoglutethimide, Anastrozole, Letrozole, Formestane. Antitumor Drugs Acting on Structural Proteins: Mechanism of Action, Structures, Structure-Activity Relationships, and Clinical Aspects. Tubulin Polymerization Inhibitors: Vinblastine, Vincristine, Vindesine, Vinorelbine, Combrestatins (Combrestatin A-4), Taxoids (Paclitaxel, Docetaxel). Signal Transduction Pathway Inhibitors: Mechanism of Action and Types of Inhibitors, Structures, Structure-Activity Relationships, and Clinical Aspects. Protein Kinase Inhibitors. Epidermal Growth Factor Receptor (EGF-R) Kinase Inhibitors: Gefitinib [S], PKI-166, Erlotinib. EGF-R, ErbB2, VEGF-R Kinase Inhibitors: Lapatinib, Vandetanib. Abelson c-Kit, PDFG-R, and SRC Tyrosine Kinase Inhibitors: Imatinib [S], Nilotinib, Dasatinib, Tozasertib, Bosutinib, GNF-2, ON012380. Other Kinase Targets: Vemurafenib, Ruxolitinib, Vismodegib. Multiple Receptor Tyrosine Kinase Inhibitors: Sunitinib, Vatalanib, Pazopanib, Sorafenib, Regorafenib. Naturally Derived Kinase Inhibitors: Sirolimus, Temsirolimus, Everolimus. Matrix Metalloprotease Inhibitors: Mechanism of Action. Marimastat, CGS 27023A, Prinomastat, BAY 12-9655. Proteasome Inhibitors: Mechanism of Action, Structures, Structure-Activity Relationships and Clinical Aspects. Bortezomib, MG-132. 12. Antiulcer drugs H+/K+ ATPase proton pump and its regulation, histamine and histamine receptors, histamine ionization. Discovery of histamine H2 antagonists: development of cimetidine, cimetidine analogues: ranitidine, famotidine, nizatidine. Discovery of proton pump inhibitors: development of omeprazole. Omeprazole analogues: pantoprazole, lansoprazole, rabeprazole sodium, esomeprazole and dexlansoprazole. Mechanism of action of proton pump inhibitors, synthesis of omeprazole.

Indispensable: knowing the notions of Organic Chemistry I and II and Biochemistry Important: know the notions of Anatomy, Biology, Physiology, Microbiology and Pharmacology

Reference books: Chimica Farmaceutica di Graham L. Patrick III^ Edizione Foye's. Principi di chimica farmaceutica di O. Foye Edizione 6 Additional books: An Introduction to Medicinal Chemistry - Graham Patrick 5a Edizione in Inglese (2013) The Practice of Medicinal Chemistry - 4th Ed (2015) Silverman - The Organic Chemistry of Drug Design and Drug Action 3th Ed (2015) Comprehensive Medicinal Chemistry III (2017) Medicinal Chemistry for Practitioners (2021)

Attendance to frontal teaching will not be compulsory but recommended

The course evaluation method is characterized by a final evaluation scheduled in the various exam sessions in which the teacher will ask a series of questions aimed at establishing whether the student has acquired mastery of the subject matter, skills and competences. The student responds to the questions, both general and specific, in both written and oral form.

The teaching will be carried out with lectures in the classroom through the use of a computer with which slides in Power Point / PDF presentations will be projected. The teacher will also use the internet for any further information on the different contents covered, when he deems it appropriate