Lecture 1

INTRODUCTION TO MEDICINAL CHEMISTRY

Phuong-Thuy Thi PHAN, M.S.
 Recommended Reading

1. Beale, J.M., Block, J.H. (2011). Wilson and Gisvold’s Textbook of Organic
Medicinal and Pharmaceutical Chemistry 12th edition, Lippincott Williams &
Wilkins: Baltimore. Chapter 2. Drug Design Strategies, p.p. 3-42.

2. Thomas L.L., David A.W. (2013). Foye’s Principle of Medicinal Chemistry 7th
edition, Lippincott Williams & Wilkins: Baltimore. Part I. Principles Of Drug
Discovery, p.p. 13-61.

3. Huỳnh Thị Ngọc Phương (2022). Hóa dược 1, NXB Đại học Quốc gia TPHCM.
Phần 1. Những vấn đề cơ bản liên quan đến Hóa Dược, p.p. 3-92.

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 Goals
1. Define medicinal chemistry and what medicinal chemists know

2. Define the major biological targets for drugs and how these drugs achieve their
pharmacological effect

3. Define where new drugs come from

4. Describe qualitatively the relationship between structure and biological activity

of drugs

5. Describe qualitatively the factors affecting drug absorption, distribution and

metabolism

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 Content

1. Introduction to medicinal chemistry

2. Pharmacological response
3. Drug discovery & development

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 Introduction to medicinal chemistry

DISCOVERY, DESIGN, IDENTIFICATION THE STUDY OF THEIR METABOLISM, THE CONSTRUCTION OF STRUCTURE
AND PREPARATION OF BIOLOGICALLY THE INTERPRETATION OF THEIR - ACTIVITY RELATIONSHIPS.
ACTIVE COMPOUNDS. MODE OF ACTION.

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 Introduction to medicinal chemistry
 The core subject
 Basic subject of medicinal chemistry
Organic chemistry, biochemistry, analytical chemistry, microbiology, parasitic,
pathophysiology

 Closely related to
• Pharmacology

• Clinical pharmacy

• Drug quality control

• Pharmaceutic

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 Pharmacological response
Full agonist
Partial agonist

Tác dụng kết hợp của hai thuốc cao hơn tác dụng riêng lẻ

Competitive antagonist
Noncompetive antagonist

Reversible inhibitor: competitive/noncompetitive/uncompetitive

Irreversible inhibitor

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 Pharmacological response

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 Pharmacological response
SYNERGISM

• The combined effect of two drugs effect is higher than either

individual effect
• Sulfamethoxazole + trimethoprim

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 Pharmacological response
SUMMATION

• The combined effect of two drugs same response, but with

different mechanism is equal to their summation
• Aspirin + codeine
• Oleandomycin + tetracycline

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 Pharmacological response
MUTUAL

• The combination of two drugs eliciting different response, and

can increase the effect of one individual effect
• Vitamin K + clofibrate
• Novocain + adrenalin

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 Pharmacological response

ANTAGONISM

• One drug can partially or completely inhibitory effects of other

drug
• Morphine + naloxone

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 Pharmacological response
RECEPTOR-DRUG INTERACTIONS
• Covalent bonding

• Ionic (electrostatic) interaction

• H-bonding
• Charge-transfer interaction
• Hydrophobic interaction
• Cation-π interaction
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 Pharmacological response
COVALENT BONDING

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 Pharmacological response
IONIC INTERACTION

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 Pharmacological response
H-BONDING

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 Pharmacological response
CHARGE-TRANSFER INTERACTION

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 Pharmacological response
HYDROPHOBIC INTERACTION

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 Pharmacological response
CATION-π INTERACTION

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 Pharmacological response
HALOGEN BONDING

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 Pharmacological response
VAN DER WAALS FORCES

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 Pharmacological response
EXERCISE

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 Pharmacological response
ASSESSING EFFECTS

• Affinity: tendency of a drug to bind to a receptor

• Efficacy: the maximum biological effect the drug can produce
• Potency: the amount of drug needed to achieve a defined
biological effect

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 Pharmacological response
CONCENTRATION-RESPONSE CURVES

• Emax is the maximum response that can be achieved by this drug under these conditions
• EC50 is the drug conc. At which 50% of the maximum response is observed
• EC50 provides a measure of drug potency

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 Pharmacological response
ASSESSING EFFECTS

• Sensitization: decrease responsiveness that occurs with repeated or

chronic exposure to antagonist
• Desensitization: decreased responsiveness that occurs with repeated
or chronic exposure to agonist and is a general feature of most
signaling membrane receptors
• Tolerance: when someone develops a tolerance, they need to take a
higher dose to experience the same effects
• Dependence: refers to someone feeling like they cannot function
normally without taking a substance
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 Pharmacological response

EXERCISE

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 Pharmacological response
FACTORS AFFECTING EFFICACY

• Drug-receptor interactions
• Pharmacokinetic
• Pharmaceutical biology

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 Drug-receptors interactions
PHARMACOPHORE

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 Drug-receptors interactions
FRAME CARRY ACTIVE GROUP

Artemisinin Ascaridole
Antimalarial Anthelmintic Vasoconstriction Vasodilator

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 Drug-receptors interactions
SIZE, DISTANCE, LOCATION OF ACTIVE GROUP

Cinchocain
Maximum local anesthetic effect

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 Drug-receptors interactions
SIZE, DISTANCE, LOCATION OF ACTIVE GROUP

Decamethonium
Inhibit neuromuscular conduction
Muscle relaxation effect

N-N distance: 10 N or O atoms

Molecular length: 2 - 2.1 nm
Receptor nicotinic - Decamethonium

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 Drug-receptors interactions
SIZE, DISTANCE, LOCATION OF ACTIVE GROUP

Gallamin Pipecuronium Tubocurarin

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 Drug-receptors interactions
SIZE, DISTANCE, LOCATION OF ACTIVE GROUP

3-aminosalicylic acid 4-aminosalicylic acid 5-aminosalicylic acid 6-aminosalicyclic acid

(Mesalazine)
Treatment tuberculosis Anti-inflammatory

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 Drug-receptors interactions
OPTICAL ISOMERS

(R)-(−)-Epinephrine (S)-(+)-Epinephrine

Increase heart rate 17 times weaker effect

Respiratory stimulation

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 Drug-receptors interactions
OPTICAL ISOMERS

Thalidomide

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 Drug-receptors interactions
OPTICAL ISOMERS

H
OH
N O
N O
Cl

Levocetirizine Levofloxacin

Dexibuprofen Esomeprazol

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 Drug-receptors interactions
GEOMETRICAL ISOMERS

trans-diethylstilbestrol cis-diethylstilbestrol
Treatment of prostate cancer 15 times weaker effect
Prevent miscarriage

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 Factors affecting efficacy
PHARMACOKINETIC

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 Pharmacokinetic
ABSORPTION

• Passive diffusion
• Facilitated passive diffusion
• Active transport
• Pinocytosis

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 Pharmacokinetic
BARRIERS TO ABSORPTION

• Gastrointestinal metabolism

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 Pharmacokinetic
BARRIERS TO ABSORPTION

• GI metabolism
• Solubility
• Permeability

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 Pharmacokinetic
LIPINSKI’S RULES

• MW ≤ 500 g/mol
• Hydrogen bond donors (HBD) ≤ 5 (OH + NH)
• Hydrogen bond acceptors (HBA) ≤ 10 (O + N)
• Log P ≤ 5

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 Pharmacokinetic
LOG P

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 Pharmacokinetic
DRUG-LIKE PROPERTIES

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 Pharmacokinetic
BARRIERS TO ABSORPTION

• Stomach metabolism
• Solubility
• Permeability
• First-pass effect

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 Pharmacokinetic
GOLDEN TRIANGLE

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 Pharmacokinetic
EXERCISE

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 Pharmacokinetic
DISTRIBUTION

• In the bloodstream, drugs are transported partly in solution as free

drug and partly reversibly bound to plasma protein.
• Only unbound drug is available for passive diffusion to
extravascular or tissue sites where the pharmacologic effects of
the drug occur.
• Accumulation of drugs in tissues or body compartments can
prolong drug action because the tissues release the accumulated
drug as plasma drug concentration decreases.

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 Pharmacokinetic
BLOOD-BRAIN BARRIER

• The drug penetration rate into cerebrospinal fluid (CF) is

determined mainly by permeability.
• If aromatic ring density and log P increase, the drug is more likely
to have activity on the central nervous system.
• The penetration rate into the brain is nearly nonexistent for the
ionized form of weak acids and bases.

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 Pharmacological response
PHARMACEUTICAL BIOLOGY

• Interaction between drug form and body to release active

ingredient
• Study the effect of dosage and formulation on therapeutic effects
• Liberation, dissolution, absorbtion (LDA)
• Pharmaceutical equivalence
• Bioequivalence

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 Drug discovery & development

SOURES OF COMPOUNDS FOR SCREENING

• Natural products
• Collections of compounds
• High-throughput synthesis of a library of compounds
• Solid-phase synthesis

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 Drug discovery & development
Aklaloid Year of invention Year of Year of Indication
structure synthesis
determination
Morphine 1803-1804 1925 1952 Opioid analgesic
Ch. Derosne & Séguin
Quinine 1820 1907 1945 Antimalarial
Pelletier & Caventou
Caffeine 1820 1883 1895 Central nervous system
Runge Robique, stimulant
Pelletier & Caventou
Cocaine 1862 1898 1923 Local anesthetic
Wahler
Pilocarpine 1875 1903 1933 Agonist muscarinic
Gérard Hardy

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 Drug discovery & development
LEAD OPTIMIZATION

• Homologation

Effect of carbon chain length on drug potency

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 Drug discovery & development
LEAD OPTIMIZATION

• Chain branching often lowers potency and/ or changes activity; interferes with receptor binding

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 Drug discovery & development

LEAD OPTIMIZATION

• Isosterism
• O - S; F - Cl - Br - I
• CH4 - NH4+
• CO2 - N2O
• NH3 - H3O+
• Bioisosterism

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 Drug discovery & development
STRUCTURE MODIFICATION

Bioavailability 10-20% Bioavailability 55%

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 Pharmacokinetic
STRUCTURE MODIFICATION

Chloramphenicol Chloramphenicol palmitate

oral suspension, less bitter

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 Pharmacokinetic
STRUCTURE MODIFICATION

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 Pharmacokinetic
STRUCTURE MODIFICATION

Narrow spectrum
Destroyed by gastric fluid
Resistance S. aureus

Acid resistance
Oral administration

Sensitive to S. aureus penicillin

resistance

Broad spectrum
Oral administration

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 Pharmacokinetic
STRUCTURE MODIFICATION

Atropine
Decrease Ipratropium bromide Homatropine
smooth Decrease smooth Dilated pupil is shorter
muscle muscle spasm, selective than atropine
spasm, effect on the bronchus
dilated pupil

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