General Objectives.
The general objective of the MEDICINAL AND TOXICOLOGICAL CHEMISTRY I course is to provide students with the rational foundations of modern medicinal chemistry, providing the specific chemical knowledge underlying the therapeutic action of drugs. The course is divided into two parts, including general medicinal chemistry and systematic medicinal chemistry. The general medicinal chemistry section analyzes the concepts and strategies for rational drug discovery and design, as well as the rules used in drug nomenclature. Knowledge of the pharmaceutical and pharmacokinetic phases allows for an understanding of the drug's pathway within the human body, from absorption to distribution to elimination through the excretory system. The study of the pharmacodynamic phase covers the various types of drug molecular targets, the interactions involved, and the consequences of these interactions. The systematic medicinal chemistry section covers the main classes of natural and synthetic antibacterial drugs (sulfonamides, quinolones, nitrochemotherapeutics, peptidoglycan synthesis-inhibiting antibiotics, penicillins, cephalosporins, carbapenems, ribosome-inhibiting antibiotics, aminoglycosides, macrolides, tetracyclines, chloramphenicol, and ansamycins), antimycobacterial, antifungal, antiviral, anticancer, disinfectant, and topical anti-infective agents. Within each class, particular emphasis is placed on drug discovery and development, molecular mechanisms of action, the relationship between chemical structure and biological activity, the study of pharmacokinetic properties, the main therapeutic uses, toxicity profiles, potential interactions with other xenobiotics, and the synthesis of representative drugs. Upon completion of the course, students will possess the chemical knowledge underlying the therapeutic action of drugs. Students will be able to follow the drug design and development phases, understand drug absorption and distribution in the body, target interaction, metabolism, and excretion. The course will provide students with the chemical basis of the mechanism of action of each drug class covered and an understanding of the molecular modifications that influence the duration of action, routes of administration, and spectrum of action, and can improve clinical efficacy and safety. Students will also gain knowledge of the synthetic pathways leading to the production of some of the drugs covered in the course, especially with regard to production costs.
Specific Objectives
1. Student Knowledge and Understanding (Dublin Descriptor 1) The student will know and be able to understand all the main issues and strategies of drug discovery and rational design, the pharmaceutical, pharmacokinetic, and pharmacodynamic phases of drug action, the synthetic issues in drug preparation, and the main classes of antibacterial, antimycobacterial, antifungal, antiviral, antitumor, disinfectant, and topical anti-infective drugs.
2. Ability to Apply Knowledge and Understanding (Dublin Descriptor 2) At the end of the course, the student, applying the knowledge acquired, will be able to recognize a drug and classify it into one of the above categories, evaluate the structural variations within a drug class that improve or worsen its activity, and modulate absorption and duration of action. The student will be able to plan the synthesis of a specific drug or biologically active molecule. He or she will be able to apply this knowledge to hypothesize the interaction modes of a specific drug with its molecular target.
(Dublin descriptors 3, 4, 5 – soft skills)
3. Critical thinking and judgment skills (lab tests, written reports, etc.) By the end of the course, students will be able to evaluate the choice of a drug based on its chemical structure. This critical thinking and judgment will be developed through the ongoing interactivity offered during the course. The instructor will continuously ask students questions to stimulate them and develop their critical thinking. These questions will also serve to evaluate and encourage students to make connections with everything previously studied, avoiding considering the study of the material an exercise, but integrating the material in light of the knowledge already acquired.
4. Ability to communicate what has been learned. The student's evaluation will be assessed solely through an oral exam, which will cover all the topics of the program, testing the student's ability to communicate what they have learned.
5. Ability to continue studying independently. Students will find in-depth coverage of what they learned in class in the recommended textbooks and in scientific literature and will be able to use them to continue their studies independently. This will help them recall the topics covered even in the future, even when their memory of the concepts taught in class has faded. The textbooks will remain a point of reference for the student, who will know where to go to revisit in detail the concepts acquired in the past, some of which have inevitably been forgotten.
The general objective of the MEDICINAL AND TOXICOLOGICAL CHEMISTRY I course is to provide students with the rational foundations of modern medicinal chemistry, providing the specific chemical knowledge underlying the therapeutic action of drugs. The course is divided into two parts, including general medicinal chemistry and systematic medicinal chemistry. The general medicinal chemistry section analyzes the concepts and strategies for rational drug discovery and design, as well as the rules used in drug nomenclature. Knowledge of the pharmaceutical and pharmacokinetic phases allows for an understanding of the drug's pathway within the human body, from absorption to distribution to elimination through the excretory system. The study of the pharmacodynamic phase covers the various types of drug molecular targets, the interactions involved, and the consequences of these interactions. The systematic medicinal chemistry section covers the main classes of natural and synthetic antibacterial drugs (sulfonamides, quinolones, nitrochemotherapeutics, peptidoglycan synthesis-inhibiting antibiotics, penicillins, cephalosporins, carbapenems, ribosome-inhibiting antibiotics, aminoglycosides, macrolides, tetracyclines, chloramphenicol, and ansamycins), antimycobacterial, antifungal, antiviral, anticancer, disinfectant, and topical anti-infective agents. Within each class, particular emphasis is placed on drug discovery and development, molecular mechanisms of action, the relationship between chemical structure and biological activity, the study of pharmacokinetic properties, the main therapeutic uses, toxicity profiles, potential interactions with other xenobiotics, and the synthesis of representative drugs. Upon completion of the course, students will possess the chemical knowledge underlying the therapeutic action of drugs. Students will be able to follow the drug design and development phases, understand drug absorption and distribution in the body, target interaction, metabolism, and excretion. The course will provide students with the chemical basis of the mechanism of action of each drug class covered and an understanding of the molecular modifications that influence the duration of action, routes of administration, and spectrum of action, and can improve clinical efficacy and safety. Students will also gain knowledge of the synthetic pathways leading to the production of some of the drugs covered in the course, especially with regard to production costs.
Specific Objectives
1. Student Knowledge and Understanding (Dublin Descriptor 1) The student will know and be able to understand all the main issues and strategies of drug discovery and rational design, the pharmaceutical, pharmacokinetic, and pharmacodynamic phases of drug action, the synthetic issues in drug preparation, and the main classes of antibacterial, antimycobacterial, antifungal, antiviral, antitumor, disinfectant, and topical anti-infective drugs.
2. Ability to Apply Knowledge and Understanding (Dublin Descriptor 2) At the end of the course, the student, applying the knowledge acquired, will be able to recognize a drug and classify it into one of the above categories, evaluate the structural variations within a drug class that improve or worsen its activity, and modulate absorption and duration of action. The student will be able to plan the synthesis of a specific drug or biologically active molecule. He or she will be able to apply this knowledge to hypothesize the interaction modes of a specific drug with its molecular target.
(Dublin descriptors 3, 4, 5 – soft skills)
3. Critical thinking and judgment skills (lab tests, written reports, etc.) By the end of the course, students will be able to evaluate the choice of a drug based on its chemical structure. This critical thinking and judgment will be developed through the ongoing interactivity offered during the course. The instructor will continuously ask students questions to stimulate them and develop their critical thinking. These questions will also serve to evaluate and encourage students to make connections with everything previously studied, avoiding considering the study of the material an exercise, but integrating the material in light of the knowledge already acquired.
4. Ability to communicate what has been learned. The student's evaluation will be assessed solely through an oral exam, which will cover all the topics of the program, testing the student's ability to communicate what they have learned.
5. Ability to continue studying independently. Students will find in-depth coverage of what they learned in class in the recommended textbooks and in scientific literature and will be able to use them to continue their studies independently. This will help them recall the topics covered even in the future, even when their memory of the concepts taught in class has faded. The textbooks will remain a point of reference for the student, who will know where to go to revisit in detail the concepts acquired in the past, some of which have inevitably been forgotten.
teacher profile teaching materials
Definitions: drug and medicinal product. Brief history of drugs. Scope of medicinal chemistry and the role of the medicinal chemist in the modern drug discovery and development process. Origins of drugs: naturally derived drugs, semisynthetic drugs, synthetic drugs, biotechnology-derived drugs/biopharmaceuticals (overview), and cell therapies (overview).
# 2. Essential Concepts of Organic Chemistry and Biochemistry for Medicinal Chemistry
Organic chemistry and biochemistry as applied to medicinal chemistry: recognition of functional groups, amino acids, nucleobases, and sugars. Fundamental concepts of stereochemistry. Structure of protein and nucleic acid macromolecules, including the structure and functions of DNA and RNA.
# 3. Pharmaceutical and Pharmacokinetic Phases
Definitions. Pharmaceutical phase: routes of drug administration, including enteral, sublingual, rectal, parenteral, and topical routes. Bioavailability.
Pharmacokinetic phase and ADMET properties. Drug absorption: major physicochemical and biological factors. Absorption by paracellular diffusion or filtration, convective diffusion, simple passive diffusion, facilitated passive diffusion, primary or secondary active transport, endocytosis/pinocytosis, and transcytosis.
Intrinsic partition coefficient, P (logP and clogP), and methods for its determination. Apparent partition or distribution coefficient (logD). Oral absorption and Lipinski’s Rule of Five. Drug–drug interactions. Drug–food interactions. Interactions with the microbiota. Pulmonary and percutaneous/dermal absorption.
Drug distribution. Major factors affecting biodistribution. Plasma protein binding. Volume of distribution, loading dose, and elimination rate.
Drug metabolism: first-pass metabolism; Phase I metabolism, including the structure and reactions of cytochrome P450 enzymes, the oxidative cycle, oxidative reactions catalysed by other enzymes, reduction reactions, hydrolysis reactions, and metabolic activation; Phase II metabolism, including conjugation reactions, conjugation cofactors, glucuronidation, sulfation, glutathione conjugation, methylation and acetylation, and amino acid conjugation.
Prodrugs and bioprecursors. Examples of Phase I and Phase II metabolism: norepinephrine, benzo[a]pyrene, and paracetamol. Metabolic stability. *Hard* and *soft drugs*. Metabolism of the antiviral agent indinavir.
Drug excretion. Routes of excretion. Characteristics and major factors affecting renal and biliary excretion. Major pharmacokinetic parameters—plasma half-life, clearance, and volume of distribution—and their interrelationships. Repeated-dose administration.
# 4. Pharmacodynamic Phase
Drug–macromolecule interactions and types of interactions: covalent bonds, ionic interactions, ion–dipole and dipole–dipole interactions, hydrogen bonds, *charge-transfer complexes*, hydrophobic interactions, cation–π interactions, π–π interactions, amide–π interactions, *halogen bonding*, van der Waals forces, and London dispersion forces.
Enzymes as drug targets: types of inhibition, enzyme kinetics, Ki, and IC50.
Receptors: classification; orphan receptors; major characteristics of ligands acting as agonists, antagonists, partial agonists, and inverse agonists; receptor desensitisation and sensitisation; tolerance and dependence; receptor types and subtypes; affinity, efficacy, and potency.
Nucleic acids as drug targets. Lipids as drug targets. Drugs lacking a macromolecular target.
# 3. Drug Discovery and Development
Identification of a prototype compound (*hit* or *lead*) and prototype optimisation (*hit-to-lead* and *lead optimisation*).
Identification of prototype compounds through extensive screening; random screening; high-throughput screening (HTS); virtual screening (VS); isolation, testing, and investigation of the effects of naturally occurring substances derived from microorganisms, plants, and animals; screening of libraries of synthetic intermediates, products, and by-products; modification of existing drugs, including “*me-too*” and “*me-better*” drugs, *chiral switching*, amplification and selective optimisation of side activities (*Selective Optimization of Side Activity*, SOSA), and investigation of the metabolism of known drugs.
Use of endogenous natural ligands or modulators as prototype compounds, including natural receptor ligands, substrates, intermediates and products of enzymatic reactions, and allosteric modulators of receptors and enzymes.
Fortuitous or accidental discovery (*serendipity*). Identification of prototype compounds from molecular fragments (*fragment-based drug discovery*). *Computer-aided drug design* (CADD) using structure-based and ligand-based approaches.
Optimisation of interactions with the biological target. Structure–Activity Relationships (SAR) and Quantitative Structure–Activity Relationships (QSAR). Role of the major functional groups in interactions with pharmacological targets.
The principle of isosterism: historical development and major examples of classical and non-classical (bio)isosteres. Identification of a pharmacophore.
Strategies used in drug design and in the optimisation of pharmacodynamic and pharmacokinetic properties: modification of substituents, including alkyl substituents and substituents on aromatic rings; molecular variations within homologous series, including linear and cyclic homology; isosteres and bioisosteres; vinylogues and benzologues; molecular simplification or disjunctive approaches (*molecular striptease*); analogue-based approaches (*benzo cracking*, ring opening and fusion, and modification of ring systems); and molecular complication or conjunctive approaches, including the addition of fused or condensed rings, structural extension, conformational rigidification, molecular duplication, and multi-target drugs or *multi-target-directed ligands* (MTDLs) obtained through molecular addition, molecular hybridisation, and the development of chimeric drugs.
Structure-based drug design using the structure of the interaction/binding site and molecular modelling.
Design of prodrugs or bioprecursors to achieve different objectives: improving membrane permeability, including enhancement of oral absorption/bioavailability or biodistribution to specific organs; prolonging duration of action; improving chemical and/or enzymatic stability; reducing toxicity and adverse effects; improving patient acceptability and compliance; increasing aqueous solubility; and targeting the drug to its intended site of action.
# 4. Antibacterial Agents
General principles of anti-infective or antimicrobial drugs. Classification of anti-infective drugs. General principles of antibacterial drugs. Bactericidal and bacteriostatic agents. Brief historical overview of antibacterial drugs. Mechanisms of bacterial resistance. Clinically important bacteria: the 2024 WHO Bacterial Priority Pathogens List and ESKAPE pathogens.
The bacterial cell. Gram-positive and Gram-negative bacteria. Classification of antibacterial drugs according to their mechanism of action.
## Inhibitors of Bacterial Cell Metabolism: Antimetabolites
Inhibitors of folate biosynthesis.
Sulfonamides: origin, including Prontosil and its metabolism; mechanism of action; SAR; spectrum of activity; resistance mechanisms; pharmacokinetics; classification; and therapeutic uses. Synthesis of sulfanilamide and sulfacetamide and general synthetic scheme for sulfonamides [S].
Trimethoprim: structure, mechanism of action, activity, spectrum of activity, combination with sulfonamides as co-trimoxazole, and major therapeutic applications.
## Inhibitors of Bacterial Cell-Wall Biosynthesis
Penicillins: origin, structure, biosynthesis, mechanism of action, mechanisms of resistance, overview of β-lactamase classification, benzylpenicillin (Penicillin G), adverse effects of penicillins, structure–activity relationships of penicillins, and major limitations of Penicillin G, including acid sensitivity, susceptibility to penicillinases, limited spectrum of activity, and short half-life.
Acid-resistant penicillins. Phenoxymethylpenicillin (Penicillin V).
Natural penicillins and production of penicillins by fermentation and semisynthesis [S].
Classification of penicillins: narrow-spectrum, β-lactamase-sensitive penicillins, including benzylpenicillin and benzathine benzylpenicillin; naturally occurring orally active penicillins; penicillinase-resistant penicillins, including methicillin, nafcillin, and the isoxazolyl penicillins oxacillin, cloxacillin, flucloxacillin, and dicloxacillin; and broad-spectrum penicillins, including aminopenicillins (ampicillin, amoxicillin, bacampicillin), carboxypenicillins (ticarcillin), and ureidopenicillins (piperacillin).
General characteristics of penicillins. Clinical aspects. Ambler classification of β-lactamases.
β-Lactam β-lactamase inhibitors: clavulanic acid, sulbactam, and tazobactam. Combinations of penicillins with β-lactamase inhibitors and the mutual prodrug sultamicillin.
Cephalosporins: history and general principles. Structural properties of cephalosporin C, comparison with Penicillin G, and SAR of cephalosporins. Biocatalytic and chemical methods for the preparation of 7-ACA [S] for cephalosporin synthesis.
Classification of cephalosporins into five generations. Major chemical, pharmaceutical, pharmacological, and clinical characteristics of first-generation cephalosporins (cephalothin, cefazolin, cephalexin, cefadroxil); second-generation cephalosporins (cefaclor, Cefoxitima, cefuroxime, cefamandole, cefonicid); third-generation cephalosporins (cefotaxime, ceftazidime, cefixime, cefoperazone, cefpodoxime proxetil, ceftriaxone); fourth-generation cephalosporins (cefepime); and fifth-generation cephalosporins (ceftaroline fosamil and ceftobiprole medocaril).
Summary of the general characteristics of cephalosporins.
Carbapenems and monobactams: thienamycin, imipenem, meropenem, ertapenem, nocardicin A, and aztreonam.
Non-β-lactam β-lactamase inhibitors: avibactam, including mechanism of action and use in combination therapy.
Non-β-lactam inhibitors of bacterial cell-wall biosynthesis: general information and mechanisms of action. Fosfomycin. *D*-Cycloserine.
(Lipo)glycopeptide antibiotics: vancomycin, teicoplanins, and second-generation lipoglycopeptides, including dalbavancin, oritavancin, and telavancin.
Polypeptide antibiotics: bacitracins, polymyxins, and tyrothricin, including gramicidins and tyrocidines.
## Inhibitors of Bacterial Protein Biosynthesis Acting at the Translational Level
Oxazolidinones: general information, mechanism of action, and SAR. Linezolid [S] and tedizolid phosphate.
Tetracyclines: general information, mechanism of action, and SAR.
Naturally occurring tetracyclines: acid–base equilibria, chelating properties, spectrum of activity, mechanisms of resistance, chemical instability, and pharmacokinetic characteristics. Tetracycline, chlortetracycline (Aureomycin), demeclocycline, and oxytetracycline.
Semisynthetic tetracyclines and their advantages over naturally occurring compounds: methacycline, meclocycline, doxycycline, minocycline, and tigecycline.
Tetracycline prodrugs: rolitetracycline and lymecycline.
Amphenicols—chloramphenicol and thiamphenicol: general information, stereochemistry, mechanism of action, SAR, activity, spectrum of activity, resistance mechanisms, therapeutic uses, and toxicity.
Macrolides: general information, structures, mechanism of action, activity, spectrum of activity, resistance mechanisms, drug interactions, and chemical instability. Erythromycin, clarithromycin, flurithromycin, azithromycin, roxithromycin, josamycin, miocamycin, and spiramycins.
Lincosamides: general information and mechanism of action. Lincomycin, clindamycin, and clindamycin phosphate.
Aminoglycosides: general information, structural classes, mechanisms of action, SAR, spectrum of activity, resistance mechanisms, pharmacokinetic characteristics, toxicity, and therapeutic applications. Gentamicin, kanamycin, tobramycin, amikacin, netilmicin, neomycin, paromomycin, and streptomycin.
## Drugs Acting on Nucleic Acid Replication and Transcription
Quinolones and fluoroquinolones: general information; development through four generations; mechanism of action; SAR and pharmacophore; activity and spectrum of action; mechanisms of resistance; pharmacokinetic characteristics; adverse effects; and therapeutic applications.
Nalidixic acid, pipemidic acid, enoxacin, norfloxacin, ciprofloxacin [S], lomefloxacin, ofloxacin, levofloxacin, rufloxacin, moxifloxacin, prulifloxacin, and delafloxacin.
Brief overview of rifamycins; see antimycobacterial drugs.
Nitrofurans: nitrofurazone, nifuratel, nitrofurantoin, and nifurtimox.
# 4. Antimycobacterial Agents
Mycobacteria: general information, structure of the mycobacterial cell wall, and structure of mycolic acids. Types of mycobacteria pathogenic to humans.
Tuberculosis: current global tuberculosis situation and brief history of antitubercular drugs. First-line, second-line, and more recently approved antitubercular drugs.
Antitubercular chemotherapy: drug-susceptible strains, multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant tuberculosis (XDR-TB).
First-line antitubercular drugs: general information, structures, stereochemistry, mechanisms of action, resistance mechanisms, SAR, metabolism, and toxicity. Isoniazid [S], pyrazinamide [S], rifampicin (rifampin), and ethambutol.
Rifamycins: general information, structural characteristics, mechanism of action, SAR, spectrum of activity, pharmacokinetic properties, toxicity, and therapeutic uses. Rifamycin B, rifamycin SV, rifampicin (rifampin), rifabutin, rifapentine, and rifaximin.
Second-line antitubercular drugs: general information, structures, mechanisms of action, and SAR. Streptomycin, para-aminosalicylic acid (PAS), amikacin, kanamycin, polypeptide antibiotics, *D*-cycloserine, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), linezolid, clofazimine, and thioamides (ethionamide and prothionamide).
More recently approved antitubercular drugs: general information, chemical structures, mechanisms of action, essential SAR, and major therapeutic indications. Bedaquiline, delamanid, and pretomanid.
Novel antitubercular treatment regimens and recent clinical guidelines.
Leprosy: disease overview. Antileprosy drugs: general information, structures, mechanisms of action, and SAR. Dapsone, rifampicin (rifampin), and clofazimine.
# 5. Antifungal Agents
Fungi, mycoses, and the major fungal infections affecting humans. Classification of antifungal agents. Antifungal drugs and their principal molecular targets.
## Antifungal Antibiotics
Echinocandins: general information, mechanism of action, SAR, and resistance. Caspofungin, anidulafungin, and micafungin.
Polyene antibiotics: general information, mechanism of action, SAR, and therapeutic applications. Amphotericin B and nystatin.
Inhibitors of microtubule function: general information, mechanism of action, and SAR. Griseofulvin.
## Synthetic Antifungal Agents
Ergosterol biosynthesis and the major therapeutic targets of antifungal agents.
Azole antifungal agents, including imidazoles and 1,2,4-triazoles: general information, structural characteristics, stereochemistry, mechanism of action, SAR, mechanisms of resistance, pharmacokinetics, toxicity, drug interactions, and therapeutic applications.
Imidazoles: clotrimazole, bifonazole, isoconazole, econazole, miconazole, tiaconazole, fenticonazole, sertaconazole, and ketoconazole [S].
1,2,4-Triazoles: itraconazole, posaconazole, fluconazole [S], voriconazole, and isavuconazole.
Allylamines: general information, mechanism of action, and SAR. Terbinafine, naftifine, and butenafine.
Morpholines: general information, mechanism of action, and SAR. Amorolfine.
Inhibitors of DNA/RNA synthesis and function: general information, activity, spectrum of activity, bioactivation, mechanism of action, resistance, SAR, and therapeutic applications.
Pyrimidine antifungal agents: flucytosine.
Pyridine antifungal agents: ciclopirox.
# 6. Antiprotozoal Agents
Protozoa and their classification. Pathogenic protozoa, protozoal infections, and the principal mechanisms of infection transmission.
## Malaria
Current global burden of malaria; general information; vector; clinical manifestations; vaccines; the *Plasmodium* life cycle; and pharmacological treatment, including causal prophylaxis, radical cure, clinical cure, and interruption of disease transmission.
Naturally derived antimalarial drugs: Cinchona alkaloids and artemisinins.
Cinchona and Cinchona alkaloids: history, extraction, structures, stereochemistry, mechanism of action, SAR, resistance, pharmacokinetics, toxicity, and therapeutic applications. Quinine, quinidine, cinchonine, and cinchonidine. *Gin & tonic*.
Artemisinin and semisynthetic derivatives: history, structures, mechanisms of action, resistance, SAR, ADMET properties, and therapeutic applications. Dihydroartemisinin (DHA), artemether, arteether, and sodium artesunate.
Synthetic antimalarial drugs: structures, stereochemistry, mechanisms of action, resistance, SAR, ADMET properties, and therapeutic applications.
4-Aminoquinoline derivatives: chloroquine [S] and hydroxychloroquine.
Quinolinemethanol derivatives: mefloquine.
8-Aminoquinoline derivatives: primaquine [S] and tafenoquine.
Fluorenemethanol derivatives: lumefantrine.
1,4-Naphthoquinone derivatives: atovaquone.
Antifolates: pyrimethamine and proguanil/cycloguanil.
Synergistic activity of atovaquone and proguanil. Synergistic activity of pyrimethamine and sulfonamides.
## Amoebiasis
General information and the life cycle of *Entamoeba histolytica*. Pharmacological treatment: structures, mechanisms of action, and therapeutic uses of antiamoebic drugs.
Luminal antiamoebic agents: 8-hydroxyquinoline derivatives (iodoquinol), diloxanide furoate, and paromomycin.
Systemic antiamoebic agents: emetine, dehydroemetine, and chloroquine.
Mixed-action antiamoebic agents: metronidazole and tinidazole.
Other intestinal protozoal infections and their pharmacological treatment: giardiasis, balantidiasis, toxoplasmosis, cryptosporidiosis, and isosporiasis.
Pharmacological treatment of giardiasis: metronidazole, furazolidone, quinacrine, and nitazoxanide.
Treatment of genitourinary trichomoniasis: metronidazole and tinidazole.
## Leishmaniasis
General information, life cycle of protozoa belonging to the genus *Leishmania*, vector, and pharmacological treatment.
Antileishmanial drugs: sodium stibogluconate, meglumine antimoniate, amphotericin B, pentamidine isethionate, and miltefosine.
## African Trypanosomiasis
African trypanosomiasis, or sleeping sickness: general information, life cycle of *Trypanosoma brucei*, and vector.
Pharmacological treatment: sodium suramin, pentamidine, melarsoprol, eflornithine, and fexinidazole.
## American Trypanosomiasis
American trypanosomiasis, or Chagas disease: general information, life cycle of *Trypanosoma cruzi*, and vector.
Pharmacological treatment: nifurtimox and benznidazole.
# 7. Antiviral Agents
General information. Historical overview and human pathogenic viruses. Viral structure and replication cycle.
## Drugs Active Against DNA Viruses
General information, mechanism of action, structures, and clinical aspects.
Acyclovir [S], valaciclovir [S], ganciclovir, valganciclovir, penciclovir, famciclovir, cidofovir, foscarnet, idoxuridine, trifluridine, brivudine, docosanol, and VariZIG®.
Drugs used for hepatitis B virus (HBV) infection: entecavir, Adifovir dipivoxil, telbivudine, and interferons.
## Drugs Active Against RNA Viruses
Anti-influenza drugs: general information, viral replication cycle, and pharmacological targets.
M2 ion-channel blockers: mechanism of action and structures. Adamantane amines: amantadine and rimantadine.
Neuraminidase inhibitors: design, mechanism of action, structures, and SAR. Mechanism of sialic acid hydrolysis. Zanamivir, laninamivir octanoate, oseltamivir phosphate, and peramivir.
Inhibitors of viral RNA-dependent RNA polymerase: baloxavir marboxil and favipiravir.
# 8. Antiseptics and Disinfectants
Antiseptics and disinfectants: key definitions. Bacteriostatic, bactericidal, and bacteriolytic agents.
Classification of antiseptics and disinfectants according to efficacy.
Major chemical classification— inorganic substances: basic substances, oxidising agents including halogens and their derivatives and oxygen and its derivatives, reducing agents, and metal salts.
Major chemical classification—organic substances: alcohols and phenols, aldehydes, carboxylic acids, amines, quaternary ammonium salts, biguanides, and polycyclic dyes.
Major mechanisms of action and mechanisms of resistance. Criteria for appropriate selection and responsible use.
**[S] = Chemical synthesis, including the mechanisms of all chemical reactions involved.**
Medicinal Chemistry (G.L. Patrick)
Foye's Principles of Medicinal Chemistry
Medicinal Chemistry (A. Gasco, F. Gualtieri, C. Melchiorre)
Programme
# 1. Introduction to Medicinal ChemistryDefinitions: drug and medicinal product. Brief history of drugs. Scope of medicinal chemistry and the role of the medicinal chemist in the modern drug discovery and development process. Origins of drugs: naturally derived drugs, semisynthetic drugs, synthetic drugs, biotechnology-derived drugs/biopharmaceuticals (overview), and cell therapies (overview).
# 2. Essential Concepts of Organic Chemistry and Biochemistry for Medicinal Chemistry
Organic chemistry and biochemistry as applied to medicinal chemistry: recognition of functional groups, amino acids, nucleobases, and sugars. Fundamental concepts of stereochemistry. Structure of protein and nucleic acid macromolecules, including the structure and functions of DNA and RNA.
# 3. Pharmaceutical and Pharmacokinetic Phases
Definitions. Pharmaceutical phase: routes of drug administration, including enteral, sublingual, rectal, parenteral, and topical routes. Bioavailability.
Pharmacokinetic phase and ADMET properties. Drug absorption: major physicochemical and biological factors. Absorption by paracellular diffusion or filtration, convective diffusion, simple passive diffusion, facilitated passive diffusion, primary or secondary active transport, endocytosis/pinocytosis, and transcytosis.
Intrinsic partition coefficient, P (logP and clogP), and methods for its determination. Apparent partition or distribution coefficient (logD). Oral absorption and Lipinski’s Rule of Five. Drug–drug interactions. Drug–food interactions. Interactions with the microbiota. Pulmonary and percutaneous/dermal absorption.
Drug distribution. Major factors affecting biodistribution. Plasma protein binding. Volume of distribution, loading dose, and elimination rate.
Drug metabolism: first-pass metabolism; Phase I metabolism, including the structure and reactions of cytochrome P450 enzymes, the oxidative cycle, oxidative reactions catalysed by other enzymes, reduction reactions, hydrolysis reactions, and metabolic activation; Phase II metabolism, including conjugation reactions, conjugation cofactors, glucuronidation, sulfation, glutathione conjugation, methylation and acetylation, and amino acid conjugation.
Prodrugs and bioprecursors. Examples of Phase I and Phase II metabolism: norepinephrine, benzo[a]pyrene, and paracetamol. Metabolic stability. *Hard* and *soft drugs*. Metabolism of the antiviral agent indinavir.
Drug excretion. Routes of excretion. Characteristics and major factors affecting renal and biliary excretion. Major pharmacokinetic parameters—plasma half-life, clearance, and volume of distribution—and their interrelationships. Repeated-dose administration.
# 4. Pharmacodynamic Phase
Drug–macromolecule interactions and types of interactions: covalent bonds, ionic interactions, ion–dipole and dipole–dipole interactions, hydrogen bonds, *charge-transfer complexes*, hydrophobic interactions, cation–π interactions, π–π interactions, amide–π interactions, *halogen bonding*, van der Waals forces, and London dispersion forces.
Enzymes as drug targets: types of inhibition, enzyme kinetics, Ki, and IC50.
Receptors: classification; orphan receptors; major characteristics of ligands acting as agonists, antagonists, partial agonists, and inverse agonists; receptor desensitisation and sensitisation; tolerance and dependence; receptor types and subtypes; affinity, efficacy, and potency.
Nucleic acids as drug targets. Lipids as drug targets. Drugs lacking a macromolecular target.
# 3. Drug Discovery and Development
Identification of a prototype compound (*hit* or *lead*) and prototype optimisation (*hit-to-lead* and *lead optimisation*).
Identification of prototype compounds through extensive screening; random screening; high-throughput screening (HTS); virtual screening (VS); isolation, testing, and investigation of the effects of naturally occurring substances derived from microorganisms, plants, and animals; screening of libraries of synthetic intermediates, products, and by-products; modification of existing drugs, including “*me-too*” and “*me-better*” drugs, *chiral switching*, amplification and selective optimisation of side activities (*Selective Optimization of Side Activity*, SOSA), and investigation of the metabolism of known drugs.
Use of endogenous natural ligands or modulators as prototype compounds, including natural receptor ligands, substrates, intermediates and products of enzymatic reactions, and allosteric modulators of receptors and enzymes.
Fortuitous or accidental discovery (*serendipity*). Identification of prototype compounds from molecular fragments (*fragment-based drug discovery*). *Computer-aided drug design* (CADD) using structure-based and ligand-based approaches.
Optimisation of interactions with the biological target. Structure–Activity Relationships (SAR) and Quantitative Structure–Activity Relationships (QSAR). Role of the major functional groups in interactions with pharmacological targets.
The principle of isosterism: historical development and major examples of classical and non-classical (bio)isosteres. Identification of a pharmacophore.
Strategies used in drug design and in the optimisation of pharmacodynamic and pharmacokinetic properties: modification of substituents, including alkyl substituents and substituents on aromatic rings; molecular variations within homologous series, including linear and cyclic homology; isosteres and bioisosteres; vinylogues and benzologues; molecular simplification or disjunctive approaches (*molecular striptease*); analogue-based approaches (*benzo cracking*, ring opening and fusion, and modification of ring systems); and molecular complication or conjunctive approaches, including the addition of fused or condensed rings, structural extension, conformational rigidification, molecular duplication, and multi-target drugs or *multi-target-directed ligands* (MTDLs) obtained through molecular addition, molecular hybridisation, and the development of chimeric drugs.
Structure-based drug design using the structure of the interaction/binding site and molecular modelling.
Design of prodrugs or bioprecursors to achieve different objectives: improving membrane permeability, including enhancement of oral absorption/bioavailability or biodistribution to specific organs; prolonging duration of action; improving chemical and/or enzymatic stability; reducing toxicity and adverse effects; improving patient acceptability and compliance; increasing aqueous solubility; and targeting the drug to its intended site of action.
# 4. Antibacterial Agents
General principles of anti-infective or antimicrobial drugs. Classification of anti-infective drugs. General principles of antibacterial drugs. Bactericidal and bacteriostatic agents. Brief historical overview of antibacterial drugs. Mechanisms of bacterial resistance. Clinically important bacteria: the 2024 WHO Bacterial Priority Pathogens List and ESKAPE pathogens.
The bacterial cell. Gram-positive and Gram-negative bacteria. Classification of antibacterial drugs according to their mechanism of action.
## Inhibitors of Bacterial Cell Metabolism: Antimetabolites
Inhibitors of folate biosynthesis.
Sulfonamides: origin, including Prontosil and its metabolism; mechanism of action; SAR; spectrum of activity; resistance mechanisms; pharmacokinetics; classification; and therapeutic uses. Synthesis of sulfanilamide and sulfacetamide and general synthetic scheme for sulfonamides [S].
Trimethoprim: structure, mechanism of action, activity, spectrum of activity, combination with sulfonamides as co-trimoxazole, and major therapeutic applications.
## Inhibitors of Bacterial Cell-Wall Biosynthesis
Penicillins: origin, structure, biosynthesis, mechanism of action, mechanisms of resistance, overview of β-lactamase classification, benzylpenicillin (Penicillin G), adverse effects of penicillins, structure–activity relationships of penicillins, and major limitations of Penicillin G, including acid sensitivity, susceptibility to penicillinases, limited spectrum of activity, and short half-life.
Acid-resistant penicillins. Phenoxymethylpenicillin (Penicillin V).
Natural penicillins and production of penicillins by fermentation and semisynthesis [S].
Classification of penicillins: narrow-spectrum, β-lactamase-sensitive penicillins, including benzylpenicillin and benzathine benzylpenicillin; naturally occurring orally active penicillins; penicillinase-resistant penicillins, including methicillin, nafcillin, and the isoxazolyl penicillins oxacillin, cloxacillin, flucloxacillin, and dicloxacillin; and broad-spectrum penicillins, including aminopenicillins (ampicillin, amoxicillin, bacampicillin), carboxypenicillins (ticarcillin), and ureidopenicillins (piperacillin).
General characteristics of penicillins. Clinical aspects. Ambler classification of β-lactamases.
β-Lactam β-lactamase inhibitors: clavulanic acid, sulbactam, and tazobactam. Combinations of penicillins with β-lactamase inhibitors and the mutual prodrug sultamicillin.
Cephalosporins: history and general principles. Structural properties of cephalosporin C, comparison with Penicillin G, and SAR of cephalosporins. Biocatalytic and chemical methods for the preparation of 7-ACA [S] for cephalosporin synthesis.
Classification of cephalosporins into five generations. Major chemical, pharmaceutical, pharmacological, and clinical characteristics of first-generation cephalosporins (cephalothin, cefazolin, cephalexin, cefadroxil); second-generation cephalosporins (cefaclor, Cefoxitima, cefuroxime, cefamandole, cefonicid); third-generation cephalosporins (cefotaxime, ceftazidime, cefixime, cefoperazone, cefpodoxime proxetil, ceftriaxone); fourth-generation cephalosporins (cefepime); and fifth-generation cephalosporins (ceftaroline fosamil and ceftobiprole medocaril).
Summary of the general characteristics of cephalosporins.
Carbapenems and monobactams: thienamycin, imipenem, meropenem, ertapenem, nocardicin A, and aztreonam.
Non-β-lactam β-lactamase inhibitors: avibactam, including mechanism of action and use in combination therapy.
Non-β-lactam inhibitors of bacterial cell-wall biosynthesis: general information and mechanisms of action. Fosfomycin. *D*-Cycloserine.
(Lipo)glycopeptide antibiotics: vancomycin, teicoplanins, and second-generation lipoglycopeptides, including dalbavancin, oritavancin, and telavancin.
Polypeptide antibiotics: bacitracins, polymyxins, and tyrothricin, including gramicidins and tyrocidines.
## Inhibitors of Bacterial Protein Biosynthesis Acting at the Translational Level
Oxazolidinones: general information, mechanism of action, and SAR. Linezolid [S] and tedizolid phosphate.
Tetracyclines: general information, mechanism of action, and SAR.
Naturally occurring tetracyclines: acid–base equilibria, chelating properties, spectrum of activity, mechanisms of resistance, chemical instability, and pharmacokinetic characteristics. Tetracycline, chlortetracycline (Aureomycin), demeclocycline, and oxytetracycline.
Semisynthetic tetracyclines and their advantages over naturally occurring compounds: methacycline, meclocycline, doxycycline, minocycline, and tigecycline.
Tetracycline prodrugs: rolitetracycline and lymecycline.
Amphenicols—chloramphenicol and thiamphenicol: general information, stereochemistry, mechanism of action, SAR, activity, spectrum of activity, resistance mechanisms, therapeutic uses, and toxicity.
Macrolides: general information, structures, mechanism of action, activity, spectrum of activity, resistance mechanisms, drug interactions, and chemical instability. Erythromycin, clarithromycin, flurithromycin, azithromycin, roxithromycin, josamycin, miocamycin, and spiramycins.
Lincosamides: general information and mechanism of action. Lincomycin, clindamycin, and clindamycin phosphate.
Aminoglycosides: general information, structural classes, mechanisms of action, SAR, spectrum of activity, resistance mechanisms, pharmacokinetic characteristics, toxicity, and therapeutic applications. Gentamicin, kanamycin, tobramycin, amikacin, netilmicin, neomycin, paromomycin, and streptomycin.
## Drugs Acting on Nucleic Acid Replication and Transcription
Quinolones and fluoroquinolones: general information; development through four generations; mechanism of action; SAR and pharmacophore; activity and spectrum of action; mechanisms of resistance; pharmacokinetic characteristics; adverse effects; and therapeutic applications.
Nalidixic acid, pipemidic acid, enoxacin, norfloxacin, ciprofloxacin [S], lomefloxacin, ofloxacin, levofloxacin, rufloxacin, moxifloxacin, prulifloxacin, and delafloxacin.
Brief overview of rifamycins; see antimycobacterial drugs.
Nitrofurans: nitrofurazone, nifuratel, nitrofurantoin, and nifurtimox.
# 4. Antimycobacterial Agents
Mycobacteria: general information, structure of the mycobacterial cell wall, and structure of mycolic acids. Types of mycobacteria pathogenic to humans.
Tuberculosis: current global tuberculosis situation and brief history of antitubercular drugs. First-line, second-line, and more recently approved antitubercular drugs.
Antitubercular chemotherapy: drug-susceptible strains, multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant tuberculosis (XDR-TB).
First-line antitubercular drugs: general information, structures, stereochemistry, mechanisms of action, resistance mechanisms, SAR, metabolism, and toxicity. Isoniazid [S], pyrazinamide [S], rifampicin (rifampin), and ethambutol.
Rifamycins: general information, structural characteristics, mechanism of action, SAR, spectrum of activity, pharmacokinetic properties, toxicity, and therapeutic uses. Rifamycin B, rifamycin SV, rifampicin (rifampin), rifabutin, rifapentine, and rifaximin.
Second-line antitubercular drugs: general information, structures, mechanisms of action, and SAR. Streptomycin, para-aminosalicylic acid (PAS), amikacin, kanamycin, polypeptide antibiotics, *D*-cycloserine, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), linezolid, clofazimine, and thioamides (ethionamide and prothionamide).
More recently approved antitubercular drugs: general information, chemical structures, mechanisms of action, essential SAR, and major therapeutic indications. Bedaquiline, delamanid, and pretomanid.
Novel antitubercular treatment regimens and recent clinical guidelines.
Leprosy: disease overview. Antileprosy drugs: general information, structures, mechanisms of action, and SAR. Dapsone, rifampicin (rifampin), and clofazimine.
# 5. Antifungal Agents
Fungi, mycoses, and the major fungal infections affecting humans. Classification of antifungal agents. Antifungal drugs and their principal molecular targets.
## Antifungal Antibiotics
Echinocandins: general information, mechanism of action, SAR, and resistance. Caspofungin, anidulafungin, and micafungin.
Polyene antibiotics: general information, mechanism of action, SAR, and therapeutic applications. Amphotericin B and nystatin.
Inhibitors of microtubule function: general information, mechanism of action, and SAR. Griseofulvin.
## Synthetic Antifungal Agents
Ergosterol biosynthesis and the major therapeutic targets of antifungal agents.
Azole antifungal agents, including imidazoles and 1,2,4-triazoles: general information, structural characteristics, stereochemistry, mechanism of action, SAR, mechanisms of resistance, pharmacokinetics, toxicity, drug interactions, and therapeutic applications.
Imidazoles: clotrimazole, bifonazole, isoconazole, econazole, miconazole, tiaconazole, fenticonazole, sertaconazole, and ketoconazole [S].
1,2,4-Triazoles: itraconazole, posaconazole, fluconazole [S], voriconazole, and isavuconazole.
Allylamines: general information, mechanism of action, and SAR. Terbinafine, naftifine, and butenafine.
Morpholines: general information, mechanism of action, and SAR. Amorolfine.
Inhibitors of DNA/RNA synthesis and function: general information, activity, spectrum of activity, bioactivation, mechanism of action, resistance, SAR, and therapeutic applications.
Pyrimidine antifungal agents: flucytosine.
Pyridine antifungal agents: ciclopirox.
# 6. Antiprotozoal Agents
Protozoa and their classification. Pathogenic protozoa, protozoal infections, and the principal mechanisms of infection transmission.
## Malaria
Current global burden of malaria; general information; vector; clinical manifestations; vaccines; the *Plasmodium* life cycle; and pharmacological treatment, including causal prophylaxis, radical cure, clinical cure, and interruption of disease transmission.
Naturally derived antimalarial drugs: Cinchona alkaloids and artemisinins.
Cinchona and Cinchona alkaloids: history, extraction, structures, stereochemistry, mechanism of action, SAR, resistance, pharmacokinetics, toxicity, and therapeutic applications. Quinine, quinidine, cinchonine, and cinchonidine. *Gin & tonic*.
Artemisinin and semisynthetic derivatives: history, structures, mechanisms of action, resistance, SAR, ADMET properties, and therapeutic applications. Dihydroartemisinin (DHA), artemether, arteether, and sodium artesunate.
Synthetic antimalarial drugs: structures, stereochemistry, mechanisms of action, resistance, SAR, ADMET properties, and therapeutic applications.
4-Aminoquinoline derivatives: chloroquine [S] and hydroxychloroquine.
Quinolinemethanol derivatives: mefloquine.
8-Aminoquinoline derivatives: primaquine [S] and tafenoquine.
Fluorenemethanol derivatives: lumefantrine.
1,4-Naphthoquinone derivatives: atovaquone.
Antifolates: pyrimethamine and proguanil/cycloguanil.
Synergistic activity of atovaquone and proguanil. Synergistic activity of pyrimethamine and sulfonamides.
## Amoebiasis
General information and the life cycle of *Entamoeba histolytica*. Pharmacological treatment: structures, mechanisms of action, and therapeutic uses of antiamoebic drugs.
Luminal antiamoebic agents: 8-hydroxyquinoline derivatives (iodoquinol), diloxanide furoate, and paromomycin.
Systemic antiamoebic agents: emetine, dehydroemetine, and chloroquine.
Mixed-action antiamoebic agents: metronidazole and tinidazole.
Other intestinal protozoal infections and their pharmacological treatment: giardiasis, balantidiasis, toxoplasmosis, cryptosporidiosis, and isosporiasis.
Pharmacological treatment of giardiasis: metronidazole, furazolidone, quinacrine, and nitazoxanide.
Treatment of genitourinary trichomoniasis: metronidazole and tinidazole.
## Leishmaniasis
General information, life cycle of protozoa belonging to the genus *Leishmania*, vector, and pharmacological treatment.
Antileishmanial drugs: sodium stibogluconate, meglumine antimoniate, amphotericin B, pentamidine isethionate, and miltefosine.
## African Trypanosomiasis
African trypanosomiasis, or sleeping sickness: general information, life cycle of *Trypanosoma brucei*, and vector.
Pharmacological treatment: sodium suramin, pentamidine, melarsoprol, eflornithine, and fexinidazole.
## American Trypanosomiasis
American trypanosomiasis, or Chagas disease: general information, life cycle of *Trypanosoma cruzi*, and vector.
Pharmacological treatment: nifurtimox and benznidazole.
# 7. Antiviral Agents
General information. Historical overview and human pathogenic viruses. Viral structure and replication cycle.
## Drugs Active Against DNA Viruses
General information, mechanism of action, structures, and clinical aspects.
Acyclovir [S], valaciclovir [S], ganciclovir, valganciclovir, penciclovir, famciclovir, cidofovir, foscarnet, idoxuridine, trifluridine, brivudine, docosanol, and VariZIG®.
Drugs used for hepatitis B virus (HBV) infection: entecavir, Adifovir dipivoxil, telbivudine, and interferons.
## Drugs Active Against RNA Viruses
Anti-influenza drugs: general information, viral replication cycle, and pharmacological targets.
M2 ion-channel blockers: mechanism of action and structures. Adamantane amines: amantadine and rimantadine.
Neuraminidase inhibitors: design, mechanism of action, structures, and SAR. Mechanism of sialic acid hydrolysis. Zanamivir, laninamivir octanoate, oseltamivir phosphate, and peramivir.
Inhibitors of viral RNA-dependent RNA polymerase: baloxavir marboxil and favipiravir.
# 8. Antiseptics and Disinfectants
Antiseptics and disinfectants: key definitions. Bacteriostatic, bactericidal, and bacteriolytic agents.
Classification of antiseptics and disinfectants according to efficacy.
Major chemical classification— inorganic substances: basic substances, oxidising agents including halogens and their derivatives and oxygen and its derivatives, reducing agents, and metal salts.
Major chemical classification—organic substances: alcohols and phenols, aldehydes, carboxylic acids, amines, quaternary ammonium salts, biguanides, and polycyclic dyes.
Major mechanisms of action and mechanisms of resistance. Criteria for appropriate selection and responsible use.
**[S] = Chemical synthesis, including the mechanisms of all chemical reactions involved.**
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.