Pharmaceutical Chemistry I

Code:

MI072220

Acronym:

QFARM1

Keywords
Classification	Keyword
OFICIAL	Physical Sciences

Instance: 2021/2022 - 2S

Active?	Yes
Responsible unit:	Organic and Pharmaceutical Chemistry Laboratory
Course/CS Responsible:	MSc in Pharmaceutical Sciences

Cycles of Study/Courses

Acronym	No. of Students	Study Plan	Curricular Years	Credits UCN	Credits ECTS	Contact hours	Total Time
MICF	203	Official Curriculum	2	-	6	78	162

Teaching language

Portuguese

Objectives

In this UC it is intended that students acquire the general principles in pharmaceutical and medicinal chemistry and contact the sources, methodologies and strategies used to obtain new drugs and thus be able to propose molecular changes, interpret the structure-activity relationship (SAR) , metabolism and mechanisms of action at the molecular level for different groups of drugs.

With this objective it is intended that students:

* use appropriate terminology to explain basic chemical, pharmacological and therapeutic concepts;

* acquire, understand, apply and analyze information on the chemical structure of drugs and the relationship with therapeutic applications, as a tool for the discovery of new drugs;

* select a suitable drug candidate based on knowledge of the chemical, physical properties of a molecule;

* apply the knowledge of structural characteristics to predict mechanisms, adverse effects, metabolism, solubility, acid / base characteristics, potential drug interactions and therapeutic effects of potential drugs.

* have a perception of computational methods

* understand the management of intellectual property

* understand Pharmaceutical Analysis in the discovery, development and production of drugs; in the drug quality and monitoring.

They must acquire an overview of the drug development process from an industrial point of view and on clinical trials and safety.
More particularly, at the level of the therapeutic classes covered, students will be able to:

* acquire an overview of the pharmaceutical and medicinal chemistry of chemotherapic drugs.

* identify the chemical and / or pharmacological classification to which a drug belongs based on the pharmacophore;

* predict therapeutic applications for individual drugs based on knowledge of the chemical and / or pharmacological classification and based on the structure-activity relationship (SAR) and the structural characteristics responsible for the interaction with biological targets;

* select within a chemical and / or pharmacological class a lead compound based on structural characteristics that affect absorption, distribution, metabolism and excretion;

At the level of case studies of bioactive compounds in research, students should be able, in the context of research, to know how to apply the acquired knowledge and their ability to understand, as well as to solve problems, in new and unfamiliar situations, broad and multidisciplinary contexts.




- The therapeutical applications shall be related to "Acto Farmacêutico".

With classes on application of concepts, students will have the opportunity to integrate knowledge, deal with complex or multidisciplinary issues, develop solutions and be able to communicate their conclusions and the knowledge and reasoning underlying them, whether to specialists or non-specialists, in a clear and unambiguous way.


- In the laboratorial classes it is intended that the student acquire knowledge on methodologies used on the analysis of drugs, having in line a programmatic coordination with the theory lectured

Learning outcomes and competences

At the end of the CU, students must have a broad and integrated understanding of the entire chemical and pharmaceutical drugs discovery, planning, and development. The CU also aims to promote and develop critical thinking, teamwork and autonomy. At the end of the CU, students should be able to easily communicate their ideas, collaborate and work in team and to be able to solve problems using the scientific and investigational method.

The theoretical program of the UC can be divided into 3 parts: a first where the general principles in pharmaceutical and medicinal chemistry are presented, a second for the presentation of case studies of therapeutic classes and bioactive compounds under investigation and a third for the application of concepts. In the first part, understanding the interaction with molecular targets and physicochemical properties helps to understand the mechanisms of action at the molecular level for various groups of drugs and ADMET behaviors as well as the industrial development and intellectual protection phase. The study of the main methodologies in natural products and in synthesis allows to understand the discovery of new drugs and the strategies used in the optimization of a leading compound. With the knowledge acquired on molecular, pharmacokinetic and metabolic modulation, students will be able to propose molecular changes, interpret the structure-activity relationship and metabolism for different groups of drugs, thus achieving the main objectives intended in this UC.

In a second part, with the presentation of case studies, students will be able to apply the acquired knowledge and their ability to understand in broad and multidisciplinary contexts.

In a third part, held at different times of the theoretical program, students contact with questions and that allow articulating their understanding of the subjects taught. In this process, it is possible for the teacher to assess the degree of understanding of the subject taught and allows the student to retain the most relevant information, articulate program contents, reinforce knowledge , improve skills related to communication, to express ideas or concepts.

The laboratory program addresses topics related to the theoretical program and allows contact with in silico methodologies and common techniques used in pharmaceutical and medicinal chemistry laboratories.

Working method

Presencial

Pre-requirements (prior knowledge) and co-requirements (common knowledge)

- It is assumed students have the basic knowledge provided by the subjects: Organic Chemistry I, Organic Chemistry II, Pharmaceutical Chemistry I, Biochemistry, Pharmacology and Instrumental Analysis Methods.

Program

THEORETICAL COMPONENT

 

1. Introduction to pharmaceutical and medicinal chemistry in the drug discovery and development process
2. Molecular recognition

2.1. Molecular targets for drug action

2.2. Chemical interactions involved in molecular recognition

 

3. Properties that affect drug activity

3.1. Pharmacokinetic notions and influence of the pharmaceutical phase

 

3.2. Influence of properties sharing coefficient, ionization coefficient, distribution coefficient, and stereochemistry on the activity of drugs

 

3.3. Drug-likness concept

 

4. Metabolism as an interdisciplinary area
5. Discovery and development of new drugs

5.1. Sources

 

5.1.1. Natural products: vegetable, marine, bacteria and fungi, poisons and toxins of animal origin

 

5.1.2. Synthesis: strategies (TOS, DOS, FOS, SOS) and methodologies (combinatorial synthesis, solid phase synthesis)

 

5.1.3. Other sources: endogenous ligands and substrates; existing drugs

 

5.2. Classic strategies in the discovery of hits, leader compounds and new drugs: serendipism, screening, natural molecules as a model, taking advantage of side effects, improving existing drugs, screening of synthetic intermediates, active metabolites of phase I of the metabolism

 

5.3. Computer-aided drug design

 

5.3.1. Notion of pharmacophore. Hansch's analysis. Establishment of the structure-activity relationship, QSAR

 

5.3.2. Docking, structure-based design and ligand-based design study

5.3.3. Current strategies: fragment-based design, PROTACs, ligand efficiency, residence time

 

6. Hit-to-lead chemistry

6.1. Drug discovery based on analogues

 

6.1.1 Strategies for simplification, association and molecular modulating replication

 

6.1.2. Classical criteria for molecular modification: opening and formation of rings, introduction of double bonds, homology, introduction of bulky groups, introduction / variation of substituents in aromatic rings, strategies for isosteric molecular modifications

 

6.2. Metabolic modulation: hard drugs, soft drugs

 

6.3. Pharmacokinetic modulation: prodrugs, antedrugs

 

7. Structures, syntheses, mechanisms of action, structure-activity relationships and metabolism of the following families of drugs:

- GENERAL ANESTHETICS Drugs that act on the central nervous system Classes Characteristics that affect the permeation through the blood-brain barrier. General anesthetics: Therapeutic effects. Historical perspective. Inhalation Anesthetics: Applications and properties that affect effectiveness. Intravenous anesthetics: applications. Balanced anesthesia. Mechanism of action of general anesthetics. Future prospects.

- LOCAL ANESTHETICS: Therapeutic applications (and associations). Historical perspective. Pharmacophore. Chemical Classification. Esters and amides. Mechanism of action at the cellular and molecular level. Factors / properties that affect the potency, onset and duration of action of local anesthetics. Influence of stereochemistry on activity. Toxicity. Future perspectives in the investigation of new anesthetics.

- HYPNOTICS, SEDATIVES AND ANXIOLYTICS: Historical perspective Barbiturics: therapeutic application, classification, structure-activity relationship, metabolism, mechanism of action.
enzodiazepines: discovery and development, structure-activity relationship, classic and 3D pharmacophore, classification according to the characterization of receptors. mechanism of action at the molecular level, influence of metabolism and pharmacokinetics, therapeutic applications. Other anxiolytics: azopyrones and cyclopyrrolones.

- ANTIPSYCHOTICS: Historical development. Role of dopamine as a CNS transmitter, pharmacological intervention in dopaminergic ways. Phenotiazines. Tioxanthenes. Butyrophenones. Diphenylbutylamines. Atypical antipsychotics. Neuroleptic pharmacophore and its evolution, mechanism of action, SAR and adverse effects. Recent advances.

- ANTIDEPRESSANTS: Neuronal systems involved in humour regulation, involved messengers, possibilities of pharmacological intervention. Historical development MAO-A inhibitors. Tricyclic and tetracyclic agents. Selective serotonin reuptake inhibitors. Serotonin and norepinephrine reuptake inhibitors. Selective noradrenaline reuptake inhibitors. Other "atypical" antidepressant agents; analog of melatonin, multifunctional drugs. Ketamine in treatment-resistant depression.

NARCOTIC ANALGESICS: Morphine- chemical structure, physicochemical properties, stereochemistry, therapeutic applications, contraindications, side effects, withdrawal effects associated with morphine and interactions with other drugs. Metabolism of opioid drugs. Molecular modification strategies in the development of morphine analogs as potential drugs. Structure-activity relationship studies. Beckett and Casey's opioid receptor model (hypothesis). Opioid pharmacophore. Molecular modifications in C-3, C-6, C-14 and modifications of the N-methyl group in the morphine molecule. Extension of the morphine molecule. Obtaining analogues with antagonist and partial agonist activity. Molecular simplification: morfinans, benzomorphs, arylpiperidines, anilidopiperidines and diphenylpropylamines: Molecular rigidification: oripavine semisynthesis.
- obtaining compounds with agonist, antagonist and partial agonist activity. Opioid receptors and mechanism of action. Theory of opioid receptor proposed by Snyder et al. Endogenous opiates: enkephalins, endorphins and dynorphins. Studies on the structure-activity relationship of enkephalins. Obtaining analogs of encephalins resistant to peptidase enzymes. Opioid drug delivery systems in the CNS. Opioid analgesics in therapy.

- HISTAMINERGIC AGENTS: Histamine and other autacoids: chemical structure and functions. Histaminic receptors. H1 antagonists: First generation (ethanolamine, alkylamine, ethylenodiamine, piperazine and phenothiazine derivatives). New generation antihistaminic agents. Antihistaminic potency and stereochemistry relationships. Classical and actual pharmacophore for antihistaminic H1 H2 antagonists: structural evolution and pharmacophore; applications as antisecretors in peptic ulcer. H3 antagonists: “state of art” and perspectives for therapeutic application.

- ANALGESICS- ANTIPYRETICS AND non-steroid ANTI-INFLAMMATORY AGENTS (NSAID): Pain, fever, inflammation: mechanism and transmitters involved. Arachidonic acid cascade (leukotrienes, prostaglandins, thromboxanes). Arachidonic acid methabolism via cycloxygenase (COX). COX 1 e COX 2 structure and functions. Classes of anti-inflammatory agents (AINEs): Salicilic acid and derivatives. Fenamates Arylacetic acid. Profens: Chirality-activity and -toxicity relationships. Oxicams: supramolecular chemistry; formation of inclusion complexes. Other NSAID groups: diclofenac, etodolac, ketorolac, nabumetone, acidic sulfonamides Main secondary effects and strategies for avowing them. Preferential/selective COX2 inhibitors - structures, pharmacophore, mechanism of action and side effects. Current trends in the research for new NSAIDs, namely multitarget and NO-NSAIDs. Acetaminophen as an antipyretic and analgesic: mechanism of action and side effects. Other therapeutic applications of some NSAIDs. Other targets: Microsomal prostaglandin E2 synthase-1 (mPGES) -1 and prostaglandin E2 receptor (PGE2) subtype 4 (EP4) - selective antagonism.

- PARKINSON AND ALZHEIMER: Traditional and recent therapeutics approaches.

- STEROIDS AND RELATED COMPOUNDS

steroids as privileged structures; steroid nomenclature and stereochemistry and the relationship between its three-dimensionality and the different biological activities described; General mechanism of action at the molecular level

-CORTICOSTEROIDS - Glucocorticoids and mineralocorticoids: structural requirements for biological activities; main interactions with the corticosteroid receptor. Glucocorticoids: Strategies for molecular modification in glucocorticoid agonists; topical action glucocorticoids; anti-inflammatory activity of glucocorticoids. Mineralocorticoids: aldosterone; agonists and antagonists, main therapeutic applications and molecular changes in mineralocorticoid antagonists. Mineralocorticoid receptor antagonists such as diuretics and agents for the treatment of hypertension and diabetic nephropathy.

 - MALE SEX HORMONES: Androgenic steroids - testosterone as lead compound of androgenic steroids; androgenic and anabolic activity and main applications in therapy; main strategies for molecular modification of agonists; anabolic / androgenic structure-activity relationship. Antiandrogens: mechanism of action at the molecular level.

- FEMALE SEX HORMONES: Estrogenic steroids; estradiol as the lead compound of estrogenic steroids; estrogen receptor. Estrogenic agonists by molecular modification of estradiol. Non-steroidal estrogens: Synthetic and natural. Antiestrogens: as ovulation inducers and as antitumor agents. Progestogens: progesterone as lead compound of progestogens; progestagenic agonists by molecular modification of progesterone and derivatives of the testosterone nucleus. Antiprogestagens: structures and therapeutic applications. Steroid anticonceptives: anovulatory and non-anovulatory.

 

- LABORATORIAL COMPONENT

Execution, analysis and interpretation of the fundamentals of laboratory work:

Chemical model to study the influence of pH on the absorption of aspirin, paracetamol and diphenhydramine.

Racemic Ibuprofen and S-ibuprofen: analysis by formation of diasterioisomeric derivatives.

Synthesis and analysis of acetylsalicylic acid.

Search for Acetylcholinesterase Inhibitors.

Dye dialysis.

Norgestrel and Ethinylestradiol identification in dragees.

Quantification of Norgestrel and Ethinylestradiol in dragees.

Construction of a pharmacophore and virtual screening

Pharmacopoeia Analysis: Biological standards and reference chemical substances. Degrees of purity. Impurities and limit tests.

Determination of hydrophobic sulfonamide constants by reverse phase TLC.

Mandatory literature

British Pharmacopeia, British Pharmacopeia Commision, The Stationary Office, London, 2001
M.M. Pinto, H.M. Cidade; Obtenção de complexos de inclusão; Inclusion complex of Diazepam with Cyclodextrins in Solid Phase, Pratical Studies for Medicinal Chemistry, Exercise 1.8, Ed., CYTED, 2006
C.M. Corrêa; Latenciação do Sulfatiazol" Práticas de Química Farmaceutica y Medicinal, M.A.F.Prado e E.J.Barreiro,Ed., CYTED, 92-94, 2002
Barreiro Eliezer J.; Química medicinal: as bases moleculares da ação dos fármacos. ISBN: 85-7307-782-4
United States Pharmacopeial Convention, Inc.; The United States pharmacopeia. ISBN: 1-889788-10-4
Carmén Avendano; Introduccion a la quimica farmacêutica, McGaw Hill-Interamerica de Espana, 2001
Martindale The Complete Drug Reference, 33Th Ed., Pharmaceutical Press, London, 2002
Silverman Richard B.; The^organic chemistry of drug design and drug action. ISBN: 0-12-643732-7
R.J.S. Hickman, J. Neill; Influence of pH on drug absorption from the gastrointestinal tract, J. Chem. Ed.,74 (7), 855-856, 1997
M.A.F. Prado; Determinação de constantes hidrofóbicas de substituintes de sulfonamidas por meio de cromatografia em camada delgada em fase reversa”, Prácticas de Química Farmacêutica y Medicinal do Sulfatiazol, Ed,. CYTED, 8-11, 2002
Nogrady Thomas; Medicinal chemistry: a biochemical approach. ISBN: 0-19-505369-9
Comissão da Farmacopeia Portuguesa; Farmacopeia portuguesa VIII. ISBN: 972-8425-67-8
Patrick Graham L.; An^introduction to medicinal chemistry. ISBN: 0 19 850533 7
Pinto Madalena M. M. 340; Manual de trabalhos laboratoriais de química orgânica e farmacêutica. ISBN: 978-972-757-750-7

Teaching methods and learning activities

The teaching of this UC implies:

- a masterful component with theoretical expository classes, using PowerPoint presentations, films, case studies of chemical / therapeutic classes and investigative works and using the Socrative® application to elaborate quick questions and get an immediate answer; supporting documents for classes are made available on an e-learning platform;

- classes to clarify doubts and apply concepts with exercises developed by the teacher;

-  in a practical work, the students of Pharmaceutical Chemistry I accompany the students of Organic Chemistry II of the 1st year in a work where they revisit with more maturity the basic knowledge essential for the understanding of Pharmaceutical Chemistry. The resulting works are presented in the context of inverted classes focusing on autonomy, critical thinking and the integration of digital skills in education;

- carrying out experimental work on computers and in the laboratory;

- distributed evaluation of laboratory and theoretical contents.

  In the case of a UC that seeks to demonstrate the path of drug discovery and development, relating the sources, methodologies and strategies to the chemical entity and also to the molecular target, the methodologies described and the presentation of case studies allow to achieve the intended objectives.

With applied teaching methodologies, the aim is to promote a critical spirit and the interrelationship of knowledge between theory and practice, between disciplines, between research and teaching, between the student and the teacher, between students. The Socrative® application allows the content covered to be explored in the form of questions and instills an interactive dynamic. The main objective of the pedagogical strategy “Question / answer classes” is for students to learn how to elaborate questions that allow them to articulate their understanding of the subjects taught. These methodologies allow real-time feedback

- The laboratorial tasks (3 hours/week) are performed individually, according to a chronogram. The logic of execution and its objectives are previously explained in the theoretical and laboratorial demonstration classes.
- The lecturer responsible is available for students consultation on the times announced at the beginning of the semester or at a time previously arranged and agreed. 

keywords

Physical sciences > Chemistry > Organic chemistry
Physical sciences > Chemistry > Computational chemistry
Natural sciences > Biological sciences > Biodiversity
Physical sciences > Chemistry > Combinatorial chemistry
Physical sciences > Chemistry > Applied chemistry > Pharmaceutical chemistry
Health sciences
Health sciences > Pharmacological sciences
Physical sciences > Chemistry > Biochemistry > Metabolism

Evaluation Type

Distributed evaluation without final exam

Assessment Components

designation	Weight (%)
Trabalho laboratorial	30,00
Teste	70,00
Total:	100,00

Amount of time allocated to each course unit

designation	Time (hours)
Frequência das aulas	40,00
Trabalho laboratorial	20,00
Estudo autónomo	40,00
Total:	100,00

Eligibility for exams

1. Attendance to theoretical classes is not compulsory.


2. Students that do not achieve 9,5 in pratical work distributed evaluation must performe a laboratorial  exam in appeal according to the lective calendar.This laboratorial exam is eliminatory.


3. Students who, by law, are exempt from attending classes, must take an laboratorial exam at the time of exams


4. The classification of the laboratory component obtained in previous years is maintained.

Calculation formula of final grade

a) The assessment methods of the CU follow the stated in the "Evaluation Standards" of FFUP and consists of two components of assessment:
 
- Laboratory practice, which will be distributed and will include the execution of laboratory experiments and respective reports;
- Poster communication;
- Theoretical evaluation, done by performing two theoretical tests on subjects covered during the semester in lectures.
 
b) Students must obtain a minimum score on the average of  the  sum of the written tests/appeal exam of 8.6 out of 20.
 
c) To obtain approval, students must obtain a final mark of 10 values (the sum of the three components of assessment).
 
d) Students with assessments obtained in previous years may give up of the continuous assessment (must contact the Responsible UC) and perform new evaluation laboratory and/or the two frequencies indicated in a).
 
- The laboratory factor 30%.
- The two tests or the appeal theoretical exam will end factor 70%.

 

Internship work/project

not applicable

Special assessment (TE, DA, ...)

- Students that by law do not need to attend the practical classes, and do not have frequency in these classes must perform an laboratorial exam  in date according to the lective calendar. The evaluation of students in the special conditions contemplated by Law follows that specified in the current “Evaluation Norms” of FFUP. 

Classification improvement

For classification improvement the student has to perform the laboratorial exam and/or the written exam.

Observations

Mobility Students

In addition to students who can quickly develop Portuguese comprehension skills (namely Spanish and Italian), Mobility Students with fluency in English are accepted. The UC is taught in Portuguese, however, the teachers provide bibliography and support in English. In addition, the Mobility Students assessment processes can be, if requested, in English.

 

Due to confinement, the following changes can be made:

There should be no changes to the theoretical or laboratory program.

Teaching Methods and Learning Activities:

In scenario C, theoretical classes will be synchronous by videoconference using Zoom Colibri for all students. In scenario B they will be simultaneously in person (for a group of students) and by videoconference using Zoom Colibri (for another group of students).

In Scenario B, the laboratory classes will be divided into shifts and the practical classes that were intended for the preparation of peer-review will be remotely for the shift that is not in person having the laboratory classes.

In scenario C, practical classes will be replaced by mini-tests, films from laboratory classes and virtual works performed experimentally by videoconference using Zoom Colibri.

 

Evaluation process and calculation formula for the final classification

The calculation formula will be maintained. The laboratory evaluation will result from the meeting of the continuous evaluation of classroom classes and / or mini-tests.