Molecular Biology, Medicinal Chemistry and Computer Science for Pharmaceutical Applications

Program of Examination of Medicinal Chemistry (Prof. A. Mai, Dr. F. Fiorentino) Antihistamines General overview. Notes on classic anti-H1 antihistamines. General formula, mepyramine, antazoline, diphenhydramine, promethazine. Phenothiazine Neuroleptics Etiological hypotheses on schizophrenia. Discovery of chlorpromazine. Chlorpromazine: structure-activity relationships (SAR). Perazine and phenazine. Trifluoperazine, thioridazine, mesoridazine, perphenazine, prochlorperazine, fluphenazine, trifluoperazine. Chlorprothixene, thiothixene. Depot forms of phenothiazine and thioxanthene neuroleptics. Atypical antipsychotics: clozapine, clotiapine, loxapine, perlapine. Butyrophenone Neuroleptics Discovery of haloperidol. Haloperidol: SAR. Trifluperidol, spiperone, droperidol, penfluridol, fluspirilene, pimozide. 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, nordiazepam, bromazepam, nitrazepam, clonazepam, flunitrazepam, potassium clorazepate, lorazepam, oxazepam, alprazolam, triazolam. SAR of benzodiazepines. Metabolism of benzodiazepines. Non-benzodiazepine BZR agonists (Z-drugs): zolpidem, zaleplon, zopiclone. Partial BZR agonists: imidazenil, bretazenil. Hypnotic-Sedatives Barbiturates: mechanism of action on GABA_A receptor, general formula. Lipophilicity/hydrophilicity requirements and SAR. Amobarbital, aprobarbital, butabarbital, pentobarbital, secobarbital, thiopental, phenobarbital, mephobarbital, cyclobarbital, esobarbital. Sodium thiopental. Metabolism of barbiturates. Melatonin agonists: ramelteon. Anticonvulsants Excitatory (glutamate) and inhibitory (GABA) amino acids: biosynthesis and catabolism. Ionotropic and metabotropic receptors. GABA-targeting drugs: sodium valproate, gabapentin, tiagabine, barbiturates, primidone, benzodiazepines, felbamate, topiramate. Glutamate-targeting drugs: felbamate, topiramate, lamotrigine. T-type Ca²⁺ channel blockers: succinimides (ethosuximide, methosuximide, phensuximide), oxazolidinediones (trimethadione), sodium valproate, zonisamide. K⁺ channel activators: retigabine. Na⁺ channel blockers: hydantoins (phenytoin, mephenytoin). Anti-Parkinson Agents Biosynthesis and catabolism of dopamine and noradrenaline. Hypotheses on Parkinson’s disease (PD) etiology. L-DOPA, carbidopa, benserazide. MAO inhibitors: selegiline, rasagiline. COMT inhibitors: tolcapone, entacapone. Amantadine, memantine. Bromocriptine, pergolide and dopamine agonists. Anticholinergics: trihexyphenidyl, procyclidine, biperiden. Antidepressants Monoamine hypothesis. NSRI (non-selective reuptake inhibitors): • Tricyclics: imipramine, clomipramine, trimipramine, amitriptyline, doxepin, dothiepin • Non-tricyclics: venlafaxine, duloxetine NSRI (noradrenaline-selective reuptake inhibitors): • Tricyclics/tetracyclics: desipramine, nortriptyline, butriptyline, amoxapine, maprotiline, mianserin • Non-tricyclics: nisoxetine, atomoxetine, reboxetine SSRI (serotonin-selective reuptake inhibitors): zimelidine and nor-zimelidine, fluoxetine and nor-fluoxetine, paroxetine, talopram and talsupram, citalopram and desmethylcitalopram, sertraline and desmethylsertraline, fluvoxamine DNRI (dopamine/noradrenaline reuptake inhibitors): bupropion, mazindol, amitifadine SARI (serotonin antagonist reuptake inhibitor): trazodone NaSSA (noradrenaline/serotonin selective antagonist): mirtazapine MAO inhibitors: iproniazid, phenelzine, tranylcypromine, moclobemide Hypercholinergic hypothesis: mecamylamine Melatonergic hypothesis: agomelatine Glutamatergic hypothesis: ketamine Opioid Analgesics Opium alkaloids: morphine, codeine, thebaine, papaverine. Endogenous opioids: enkephalins and endorphins. Mechanism of µ-opioid receptor agonists. Opioid receptors: µ, κ, δ, NOR. Morphine: structure, stereochemistry, SAR. Beckett and Casy model. Pharmacokinetics: morphine, 6-acetylmorphine, heroin, codeine. Hydromorphone and hydrocodone; oxymorphone, oxycodone. N17 substitution (agonists and antagonists): naloxone, naltrexone, nalorphine, nalbuphine, N-phenethylmorphine. Molecular simplification: morphinans: N-methylmorphinan, levorphanol, dextromethorphan, levallorphan, N-phenethyllevorphanol, butorphanol; benzomorphans: metazocine, phenazocine, pentazocine, bremazocine; 4-phenylpiperidines and 4-anilinopiperidines: meperidine, ketobemidone, fentanyl, sufentanil, alfentanil, remifentanil; 3-phenylpropylamines: methadone, acetylmethadol, dextro- and levo-propoxyphene, loperamide, diphenoxylate. Molecular complication: oripavines: etorphine, diprenorphine, buprenorphine. µ-opioid receptor models: Beckett & Casy (1954 & 1971), Portoghese (1965 & 1981), Snyder (1976). Adrenergic Nervous System Drugs Noradrenaline and adrenaline: SAR, adrenergic receptors. β-selective agonists: isoprenaline, orciprenaline, isoetharine, tert-butyl-noradrenaline, terbutaline, salbutamol. Catecholamine structure simplification: synephrine, phenylephrine, metaraminol; ephedrine, norephedrine; amphetamine, methamphetamine. α-selective agonists: naphazoline, clonidine, α-methylDOPA. α-selective antagonists: prazosin, terazosin, doxazosin; mirtazapine. β-selective antagonists: dichloroisoprenaline, pronethalol, propranolol. Arylethanolamines vs arylpropylamines. Oxprenolol, pindolol, nadolol. β1-selective blockers: acebutolol, atenolol, metoprolol, betaxolol. “Smart” β1-blockers: xamoterol. Antihypertensive Drugs Adrenergics and antiadrenergics: prazosin, clonidine, α-methylDOPA, β-blockers. ACE inhibitors: ACE vs Carboxypeptidase A catalysis and inhibition, development of the first lead compounds starting from teprotide, captopril, enalapril and enalaprilat (SAR), lisinopril, fosinopril and fosinoprilat. Sartans: structural comparison between angiotensin II and S-8308, losartan, eprosartan. Antibacterial Drugs The bacterial cell and the modes of action of antibacterial agents. Antibacterial drug resistance strategies. Antibacterial agents that inhibit cell wall synthesis. Penicillins: mechanism of action, resistance to penicillins, structure-activity relationships, acid sensitivity, Penicillin G, penicillin V, acid-resistant penicillins, β-lactamase-resistant penicillins (methicillin, nafcillin, oxacillin, cloxacillin, flucloxacillin, and dicloxacillin), aminopenicillins (ampicillin, amoxicillin, bacampicillin, pivampicillin), ureidopenicillins (azlocillin, mezlocillin, piperacillin). Cephalosporines: cephalosporin C, SAR and structural modifications, first-generation cephalosporins (cephalotin, cefalexin and cefadroxil), second-generation cephalosporines (cephamycin C, cefoxitin, cefuroxime, cefuroxime axetil), third and fourth generation cephalosporines (Ceftazidime, cefotaxime, ceftizoxime, ceftriaxone, cefepime, cefpirome). Carbapenems (Thienamycin, imipenem, meropenem, ertapenem). β-lactamase inhibitors (mode of action, clavulanic acid, sulbactam, sulbactam pivoxal and tazobactam). Antibacterial agents that inhibit protein synthesis. Chloramphenicol, macrolides (Erythromycin, clarithromycin, azithromycin). Drugs that act on the transcription and replication of nucleic acids: quinolones and fluoroquinolones (nalidixic acid, enoxacin, ciprofloxacin, levofloxacin, moxifloxacin, besifloxacin). Antiviral Drugs: the example of anti-HIV compounds Viruses and viral diseases, general structure of viruses, structure of the HIV virus. The reverse transcriptase and the development of reverse transcriptase inhibitors. Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Didanosine (metabolic activation steps), zidovudine, lamivudine, emcitrabine, abacavir (metabolic activation steps), stavudine, zalcitabine, adefovir dipivoxil, tenofovir disoproxil (metabolic activation steps). Non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, efavirenz , etravirine , rilpivirine. HIV Protease inhibitors: the HIV protease enzyme (including substrate binding mode and mechanism of catalysis), the rationale behind the design of HIV protease inhibitors, saquinavir (including its development starting from the Phe-Pro dipeptide), ritonavir, lopinavir, indinavir, nelfinavir, palinavir, amprenavir, darunavir (including their drug design and development), atazanavir. Inhibitors of viral entry into cells and integrase: enfuvirtide, maraviroc. Anticancer Drugs Introduction and causes of cancer, oncogenes and proto-oncogenes, genetic defects, alteration of signalling pathways and cell cycle regulation, apoptosis and p53, telomers. Drugs acting directly on nucleic acids: anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), mitoxantrone, amsacrine. Alkylating and metallating agents: chlormethine, melphalan, chlorambucil, ifosfamide, cyclophosphamide, cisplatin, carboplatin, oxaliplatin. Antimetabolites. Dihydrofolate reductase inhibitors: reactions catalyzed by DHFR and the role of folic acid, methotrexate, pemetrexed. Inhibitors of thymidylate synthase: reactions catalyzed by thymidylate synthase, 5-fluorouracil (metabolic activation steps). DNA polymerase inhibitors: cytarabine, gemcitabine, fludarabine. Purine antagonists: 6-mercaptopurine and 6-thioguanine. Protein kinase inhibitors: ATP binding to the EGFR. Gefitinib (including drug design and development), erlotinib, lapatinib, vandetanib, imatinib (including drug design and development), nilotinib, dasatinib, sorafenib (including drug design and development). ________________________________________ Central Nervous System Drugs: 24 hours Opioid analgesics: 8 hours Adrenergic nervous system and antihypertensive drugs: 8 hours Antibacterial drugs: 12 hours Antiviral drugs: 10 hours Anticancer drugs: 10 hours

**Essential:** To understand the lectures in *Pharmaceutical and Toxicological Chemistry 2*, knowledge of **organic chemistry**, **biochemistry**, **human anatomy**, and **physiology** is essential. **Important:** It is important to have acquired knowledge of **pathology**, **pharmacology**, **pharmacognosy**, and **toxicology**. **Useful:** It is useful to have prior knowledge of **general chemistry** and **drug analysis**.

Foye, Essential Principles of Medicinal Chemistry

not mandatory

Assessment Methods The course evaluation is based on an oral exam session scheduled each month of the year, excluding August. For each scheduled session, the instructor is also available to offer a deferred session (upon student request), held 15 days after the official date listed on Infostud. This is intended to provide students with the widest possible range of opportunities to take the exam—provided they are well-prepared. Indeed, students who do not pass the exam in the “standard” session will not be allowed to retake it during the deferred session, and their eligibility to attend the following session will be at the instructor’s discretion. The oral exam lasts approximately one hour per student, during which the instructor thoroughly examines the candidate’s knowledge across all parts of the syllabus. The goal of the exam is to assess the student’s knowledge of major drug classes, their identification, structure-activity relationships, molecular mechanisms, and biological effects. Topics must be discussed using language appropriate for a professional in pharmaceutical sciences. The evaluation is based on the following criteria: Knowledge of the subject across all therapeutic areas covered by the syllabus Use of appropriate scientific language Active participation during lectures Demonstrated reasoning skills during the oral exam Ability to study independently using the recommended textbooks A sufficient understanding of the topics in all areas of the syllabus is required to pass the exam with the minimum grade. To achieve the highest grade (30/30 with honors), the student must demonstrate excellent knowledge of all topics, the ability to connect concepts logically and coherently, and show that they have truly internalized and mastered the subject matter, navigating through it with confidence and fluency. In short, they must demonstrate something beyond mere memorization—a level of understanding that exceeds 100% of standard expectations.

The course Pharmaceutical and Toxicological Chemistry 2 consists of lectures delivered in person, occasionally complemented by one or two specific seminars. All lectures are interactive, with the instructor actively engaging students by asking questions that they are expected to answer based on knowledge acquired in previous courses. This approach helps highlight connections between the current course and prior coursework, whose foundational concepts are crucial for understanding the new material. These frequent references to earlier subjects aim to encourage students not to treat this course as an isolated topic, merely to be studied for the final exam and then forgotten. Instead, the goal is to promote a multidisciplinary study approach, which students must be trained for—especially by the fourth year, as they near the end of their academic journey. Slides and study materials (exam syllabus, recommended textbooks) will be made available on the e-learning platform to aid exam preparation. However, the slides are meant only as a guideline and cannot replace the recommended textbooks or the lectures themselves. Attendance is not mandatory but strongly recommended.