Programme

**Antiviral Drugs.** Drugs active against RNA viruses. **Anti-HIV agents:** General principles, viral replication cycle, and pharmacological targets. **Reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitors (NRTIs):** Mechanism of action, chemical structures, resistance, and clinical aspects. Zidovudine [S], Stavudine, Zalcitabine, Didanosine and its metabolic activation, Emtricitabine, Lamivudine, Abacavir and its metabolic activation, Adefovir dipivoxil, Tenofovir disoproxil and its metabolic activation. **Non-nucleoside reverse transcriptase inhibitors (NNRTIs):** Mechanism of action, chemical structures, resistance, and clinical aspects. “Butterfly-like” model. Nevirapine, Efavirenz, Rilpivirine, Etravirine, Delavirdine. **Protease inhibitors:** Drug design, mechanism of action, chemical structures, structure–activity relationships (SAR), and clinical aspects. Saquinavir, Ritonavir, Lopinavir, Indinavir, Nelfinavir, Palinavir, Amprenavir, Darunavir, Atazanavir. **Integrase and fusion inhibitors:** Mechanism of action, chemical structures, and structure–activity relationships. Raltegravir, Enfurtivide, Maraviroc. **Anti-HCV agents:** General principles, viral replication cycle, and pharmacological targets. Boceprevir, Telaprevir, Narlaprevir, Setrobuvir. **Broad-spectrum antiviral agents:** Mechanism of action and chemical structures. Cyclopentenyl cytosine, 3-Deazaneplanocin A, Ribavirin. Interferons. Anti-SARS-CoV-2 agents.

**Anticancer Drugs.**

Introduction. Causes and hallmarks of cancer. **Drugs acting directly on nucleic acids:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. Anthracyclines (Doxorubicin, Epirubicin, Daunorubicin, Idarubicin), Mitoxantrone, Amsacrine, Dactinomycin. **Non-intercalating agents that inhibit DNA topoisomerases:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. Podophyllotoxins (Podophyllotoxin, Etoposide, Teniposide), Camptothecins (Camptothecin, Topotecan, Irinotecan, SN-38). **Alkylating and metal-based agents:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. Nitrogen mustards: Mechlorethamine, Melphalan, Chlorambucil, Estramustine, Bendamustine, Ifosfamide, Cyclophosphamide, TH-302. **Cisplatin and analogues:** Cisplatin, Carboplatin, JM 216, Oxaliplatin. **Other alkylating agents:** Dacarbazine, Procarbazine, Lomustine, Carmustine, Temozolomide.

**Drugs acting on enzymes. Antimetabolites:** Mechanism of action, chemical 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-based therapies:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. Ethinylestradiol, 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.

**Anticancer drugs acting on structural proteins:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. **Tubulin polymerization inhibitors:** Vinblastine, Vincristine, Vindesine, Vinorelbine, Combretastatins (Combretastatin A-4), Taxoids (Paclitaxel, Docetaxel).

**Signal transduction pathway inhibitors:** Mechanism of action and classes of inhibitors, chemical structures, structure–activity relationships, and clinical aspects. **Protein kinase inhibitors. Epidermal growth factor receptor (EGFR) kinase inhibitors:** Gefitinib [S], PKI-166, Erlotinib. **EGFR, ErbB2, and VEGFR kinase inhibitors:** Lapatinib, Vandetanib. **Abelson tyrosine kinase, c-Kit, PDGFR, and SRC 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 metalloproteinase inhibitors:** Mechanism of action. Marimastat, CGS 27023A, Prinomastat, BAY 12-9655. **Proteasome inhibitors:** Mechanism of action, chemical structures, structure–activity relationships, and clinical aspects. Bortezomib, MG-132.

**Antihistamines.** General principles. Overview of classical H1 antihistamines. General chemical structure, Mepyramine, Antazoline, Diphenhydramine, Promethazine.

**Phenothiazine Neuroleptics.** Hypotheses concerning schizophrenia. Discovery of chlorpromazine. Chlorpromazine: synthesis and structure–activity relationships (SAR). Perazines and phenazines. Trifluoperazine, Thioridazine, Mesoridazine, Perphenazine, Prochlorperazine, Fluphenazine, Trifluoperazine. Chlorprothixene (synthesis), Thiothixene. Depot formulations of phenothiazine and thioxanthene neuroleptics. Metabolism of phenothiazine neuroleptics. Atypical antipsychotics. Clozapine (synthesis), Clotiapine, Loxapine, Perlapine.

**Butyrophenone Neuroleptics.** Discovery of haloperidol. Haloperidol: synthesis and SAR. Trifluperidol, Spiperone, Droperidol, Penfluridol, Fluspirilene, Pimozide.

**Benzamide Neuroleptics.** From local anesthetics to benzamide neuroleptics: Benzocaine, Procaine, Procainamide, Metoclopramide, Sulpiride, Amisulpride. Rauwolfia alkaloids: overview.

**Anxiolytics.** Discovery of benzodiazepines (Chlordiazepoxide). The GABA(_A) receptor for GABA; the benzodiazepine receptor (BZR). BZR: full agonists (e.g., Diazepam, Flunitrazepam), inverse agonists (e.g., β-carbolines), antagonists (e.g., Flumazenil). Therapeutic activities of benzodiazepines. Chlordiazepoxide, Diazepam (synthesis), Nordazepam, Bromazepam, Nitrazepam, Clonazepam, Flunitrazepam, Potassium clorazepate, Lorazepam, Oxazepam, Alprazolam, Triazolam (synthesis). SAR of benzodiazepines. Benzodiazepine metabolism. Non-benzodiazepine BZR agonists (Z-drugs): Zolpidem, Zaleplon, Zopiclone. Partial BZR agonists: Imidazenil, Bretazenil. Non-benzodiazepine anxiolytics not acting through GABA: Buspirone.

**Hypnotic–Sedative Drugs.** Physiology of sleep. Barbiturates: mechanism of action at the GABA(_A) receptor, general chemical structure, synthesis. Lipophilicity/hydrophilicity requirements and SAR. Amobarbital, Aprobarbital, Butabarbital, Pentobarbital, Secobarbital, Thiopental, Phenobarbital, Mephobarbital, Cyclobarbital, Hexobarbital. Sodium thiopental. Barbiturate metabolism. Chloral hydrate. Melatonin receptor agonists: Ramelteon.

**Anticonvulsants.** Excitatory (glutamate) and inhibitory (GABA) amino acids: biosynthesis and catabolism. Ionotropic and metabotropic receptors. **Drugs acting on GABA:** Sodium valproate, Gabapentin, Tiagabine, Barbiturates, Primidone, Benzodiazepines, Felbamate, Topiramate. **Drugs acting on glutamate:** Felbamate, Topiramate, Lamotrigine. **T-type Ca(^{2+}) channel blockers:** Succinimides (Ethosuximide, Methsuximide, Phensuximide), Oxazolidinediones (Trimethadione), Sodium valproate, Zonisamide. **K(^+) channel activators:** Retigabine. **Na(^+) channel blockers:** Hydantoins (Phenytoin, Mephenytoin, Ethotoin), Iminostilbenes (Carbamazepine, Oxcarbazepine). Synthesis of phenytoin and phenobarbital.

**Antiparkinsonian Drugs.** Biosynthesis and catabolism of dopamine and noradrenaline. Hypotheses concerning the etiology of Parkinson’s disease (PD). L-DOPA, Carbidopa, Benserazide. **MAO inhibitors:** Selegiline, Rasagiline. **COMT inhibitors:** Tolcapone, Entacapone. Amantadine, Memantine. Bromocriptine and ergot alkaloids. **Anticholinergic agents:** Trihexyphenidyl, Procyclidine, Biperiden.

**Antidepressants.** Monoamine hypothesis. **NSRIs (non-selective reuptake inhibitors):** *Tricyclic agents:* Imipramine (synthesis), Clomipramine, Trimipramine, Amitriptyline (synthesis), Doxepin, Dosulepin; *non-tricyclic agents:* Venlafaxine, Duloxetine, Milnacipran. **Noradrenaline-selective reuptake inhibitors:** *Tricyclic and tetracyclic agents:* Desipramine, Nortriptyline, Butriptyline, Amoxapine, Maprotiline, Mianserin; *non-tricyclic agents:* Nisoxetine, Atomoxetine, Reboxetine. **SSRIs (serotonin-selective reuptake inhibitors):** Zimelidine and norzimelidine, Fluoxetine (synthesis) and norfluoxetine, Paroxetine, Talopram and Talsupram, Citalopram and Desmethylcitalopram, Sertraline and Desmethylsertraline, Fluvoxamine. **DNRIs (dopamine/noradrenaline reuptake inhibitors):** Bupropion, Mazindol, Amitifadine. Trazodone. Mirtazapine. **MAO inhibitors:** Iproniazid, Phenelzine, Tranylcypromine, Moclobemide. Lithium salts.

**Analeptics.** Strychnine, Prethcamide, Nikethamide, Pentylenetetrazole (synthesis). Xanthine alkaloids (synthesis of caffeine), theophylline salts.

**General Anesthetics.** Stages of central nervous system depression. Meyer–Overton theory and the ion-channel and protein-receptor hypotheses. Thiopental, Ketamine. Nitrous oxide, Diethyl ether, Chloroform, Halothane, Enflurane, Isoflurane.

**Local Anesthetics.** Cocaine. Pharmacophore structure. Benzocaine, Procaine, Tetracaine. Lidocaine, Mepivacaine, Bupivacaine. Dyclonine. Pramoxine.

**Opioid Analgesics.** Opium alkaloids: Morphine, Codeine, Thebaine, Papaverine. Endogenous opioids: enkephalins and endorphins. Molecular mechanism of μ-opioid receptor agonists. Neurochemical basis of the mechanisms of abuse and dependence (unitary hypothesis): Cocaine, Amphetamine, μ-opioid agonists, κ-opioid agonists. Opioid receptors (μ, κ, δ, NOR). Morphine: structure, stereochemistry, SAR studies. Beckett and Casy model. Importance of pharmacokinetics: Morphine, 6-Acetylmorphine, Heroin, Codeine. Hydromorphone and Hydrocodone; Oxymorphine, Oxymorphone, and Oxycodone. **N17 substitution (agonists and antagonists):** Naloxone and Naltrexone, Nalorphine, Nalbuphine, *N*-Phenethylmorphine.

**Molecular simplification:** *Morphinans:* *N*-Methylmorphinan, Levorphanol and Dextromethorphan, Levallorphan, N-Phenethyllevorphanol, Butorphanol; *benzomorphans:* Metazocine, Phenazocine (synthesis), Pentazocine, Bremazocine; *4-phenylpiperidines and 4-anilinopiperidines:* Meperidine (synthesis), Ketobemidone, Fentanyl, Sufentanil, Alfentanil, Remifentanil; *3-phenylpropylamines:* Methadone (synthesis), Acetylmethadol, Dextropropoxyphene and Levopropoxyphene, Loperamide, Diphenoxylate. **Molecular complication:** *Oripavines:* Etorphine (synthesis), Diprenorphine, Buprenorphine. Models of the μ-opioid receptor: Beckett and Casy (1954 and 1971), Portoghese (1965 and 1981), Snyder (1976).

**Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).** Salicylic acid, Acetylsalicylic acid. Arachidonic acid cascade. Diflunisal. **Fenamates:** Mefenamic acid, Meclofenamic acid. **Profens and related agents:** Indomethacin (synthesis), Sulindac, Diclofenac (synthesis), Ketoprofen (synthesis), Ibuprofen, Flurbiprofen, Naproxen, Etodolac, Ketorolac. **Pyrazolidinediones and pyrazolones:** Phenylbutazone, Aminophenazone, Dipyrone. **Oxicams:** Piroxicam (synthesis), Sudoxicam, Isoxicam, Meloxicam. Paracetamol, Acetanilide, Phenacetin. **Selective COX-2 inhibitors:** Nimesulide, Celecoxib (synthesis), Rofecoxib, Valdecoxib, Lumiracoxib.

**Drugs Acting on the Cholinergic Nervous System.** Nicotinic and muscarinic receptors. **Cholinergic agonists:** Acetylcholine, Acetyl-α-methylcholine, Methacholine, Carbachol, Bethanechol, Pilocarpine. **Indirect cholinomimetics: reversible acetylcholinesterase (AChE) inhibitors:** *Carbamoylating agents:* Physostigmine, Neostigmine, Pyridostigmine, Rivastigmine; *non-carbamoylating agents:* Tacrine, Donepezil, Galantamine. **Irreversible AChE inhibitors:** Sarin, Malathion, Parathion, Paraoxon. Antidotes for organophosphate poisoning: 2-PAM. **Muscarinic antagonists:** Atropine, Scopolamine, Homatropine; pharmacophore development: Adiphenine, Glycopyrrolate, Trihexyphenidyl. **Nicotinic antagonists:** d-Tubocurarine, Decamethonium, Succinylcholine, Hexamethonium.

**Drugs Acting on the Adrenergic Nervous System.** Noradrenaline and adrenaline: SAR and adrenergic receptors. **Selective β-agonists:** Isoprenaline, Orciprenaline, Isoetharine, tert-Butylnoradrenaline, Terbutaline, Salbutamol. Structural modification of the catecholamine scaffold: Synephrine, Phenylephrine, Metaraminol; Ephedrine, Norephedrine; Amphetamine, Methamphetamine. **Selective α-agonists:** Naphazoline (synthesis), Clonidine (synthesis), α-Methyldopa. **Selective α-antagonists:** Prazosin (synthesis), Terazosin, Doxazosin; Mirtazapine; Dihydroergocristine, Dihydroergotoxine. **Selective β-antagonists:** Dichloroisoprenaline, Pronethalol, Propranolol (synthesis). Differences between arylethanolamines and aryloxypropanolamines. Oxprenolol, Timolol, Pindolol, Nadolol. **Selective β1-blockers:** Acebutolol, Atenolol, Metoprolol, Betaxolol. Xamoterol. **Non-selective α/β blockers:** Labetalol and Carvedilol.

**Cardiovascular Drugs.** **Antiarrhythmic agents:** Quinidine, Procainamide, Lidocaine, Phenytoin, Propranolol, Oxprenolol, Nadolol, Acebutolol. **Calcium-channel blockers:** Verapamil, Diltiazem, Bepridil, 1,4-Dihydropyridines (DHPs). Nifedipine (synthesis and SAR), Nitrendipine, Nimodipine, Isradipine. **Coronary vasodilators:** β-Blockers, Ca(^{2+})-channel blockers, organic nitrates (Nitroglycerin, Isosorbide dinitrate). **Antihypertensive agents:** Adrenergic and antiadrenergic drugs (Prazosin, Clonidine, α-Methyldopa, β-Blockers); direct-acting vasodilators (Hydralazine, Minoxidil, Diazoxide); **ACE inhibitors:** Captopril, Enalapril and Enalaprilat (SAR), Fosinopril and Fosinoprilat; **angiotensin II receptor blockers (ARBs):** Losartan, Eprosartan. **Diuretics:** Osmotic diuretics (Mannitol, Sorbitol, Isosorbide); carbonic anhydrase inhibitors (Acetazolamide); loop diuretics (Furosemide, Ethacrynic acid); thiazide diuretics (Chlorothiazide, Hydrochlorothiazide, Trichlormethiazide, Hydroflumethiazide); potassium-sparing diuretics (Spironolactone, Canrenone, Potassium canrenoate; Triamterene, Amiloride). **Lipid-lowering agents:** Fibrates (Clofibrate, Fenofibrate, Ciprofibrate), bile acid sequestrants (Cholestyramine), statins (Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin).

**Steroids.** Stereochemistry. α-Gonane and β-Gonane. **Androgens:** Testosterone and its esters as depot formulations, Androsterone, Methyltestosterone. **Progestins:** Progesterone, Ethisterone. **Estrogens:** Estrone, Estradiol, Ethinylestradiol, Mestranol, Quinestrol. **Corticosteroids:** Mineralocorticoids (Corticosterone, Aldosterone), Glucocorticoids (Hydrocortisone, Cortisone).

Core Documentation

Medicinal Chemistry (G. Costantino, G. Sbardella)
Medicinal Chemistry (G.L. Patrick)
Foye's Principles of Medicinal Chemistry
Medicinal Chemistry (A. Gasco, F. Gualtieri, C. Melchiorre)

Attendance

Attendance at the course lectures is mandatory.

Type of evaluation

The assessment method of the course is characterized by five possible oral exam appeals. The teacher offers full willingness to organize any postponement for each appeal in order to meet the requests of the students. This is to give the students the widest possibilities to optimize the outcome of the exam. During the oral examination the teacher verifies the knowledge and learning that the student has acquired on all parts of the exam program. The topics presented should be treated with a language appropriate to a professional operating in the world of pharmacy. The elements taken into consideration for the evaluation are: the knowledge of the subject in all the parts described in the program, the use of an appropriate scientific language, the active participation during the lectures and the laboratory exercises, the ability of reasoning demonstrated in the examination interview, the ability to study autonomously on the suggested texts. Sufficient knowledge of the topics covered, in the various parts of the program, is required for passing the exam with minimum grades. To achieve a score of 30/30 cum laude instead, the student must demonstrate that he has acquired excellent knowledge of all the topics covered during the course, being able to connect them in a logical and consistent way. He/she has also to demonstrate that it has mastered the subject, moving through it with security, appropriateness and naturalness.