Molecular Biology, Medicinal Chemistry and Computer Science for Pharmaceutical Applications

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: For understanding the lessons in Medicinal Chemistry, knowledge of organic chemistry, biochemistry, and biology is essential. Important: Acquiring knowledge of pathology and pharmacology is important. Useful: Having acquired knowledge of general chemistry is useful.

Essentials Of Foyes Principles Of Medicinal Chemistry - Thomas L. Lemke, Victoria F. Roche - Wolters Kluwer An Introduction to Medicinal Chemistry - Graham L- Patrick - Oxford University Press

Attendance at the course is optional but recommended.

The course assessment consists of an oral examination scheduled once a month throughout the year, excluding August. For each scheduled exam session, the instructor is also available to offer a postponed session (upon student request) 15 days after the official exam 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. In fact, students who do not pass the exam during the official session are not allowed to take the postponed session, and their eligibility to attend the next exam session will be at the instructor’s discretion. The oral exam typically lasts about one hour per student, during which the instructor thoroughly explores the candidate's knowledge across all parts of the exam syllabus. The aim of the exam is to verify the student’s understanding of the main drug classes, their identification, structure–activity relationships, molecular mechanisms, and biological effects. The topics must be discussed using language appropriate to a pharmaceutical professional. The elements considered in the evaluation include: knowledge of the subject across all therapeutic areas covered in the syllabus; the use of appropriate terminology; active participation during lectures; reasoning skills demonstrated during the oral exam; and the ability to study independently using the recommended textbooks. A sufficient understanding of the topics in the various parts of the syllabus is required to pass the exam with the minimum grade. To achieve a score of 30/30 with honors, the student must demonstrate an excellent command of all topics covered in the course, and be able to connect them logically and coherently. The student must show that they have fully absorbed and internalized the subject matter, navigating it with confidence and fluency. In short, they must demonstrate that extra something that goes beyond mere memorization.

The Medicinal Chemistry course is delivered through in-person lectures. All lectures are interactive, with the instructor actively engaging students by asking questions that they are expected to answer based on knowledge from previously completed courses. This approach allows the instructor to highlight the connections between the current course and earlier coursework, whose concepts play a key role in understanding the material being taught. Frequent references to prior knowledge are intended to train students not to treat the subject matter as a self-contained block aimed solely at passing the final exam and then quickly forgotten. Instead, the goal is to promote a multidisciplinary approach to learning—an essential habit for third-year students of a Bachelor’s degree. Students will find lecture slides and supporting materials (exam syllabus, recommended textbooks) on the e-learning platform to help them prepare for the exam. It is understood, however, that the slides serve only as a guide to the exam topics and can never replace the recommended textbooks or the in-person lectures given by the instructor.