Medicinal Chemistry = chemistry of medicines (=
drugs = therapeutic agents)
≠ Medical Chemistry ( = chemistry for physicians)
●some librarians cannot recognize this difference
●Farmaceutická chemie (Czech)
●Pharmazeutische Chemie (German)
●Chimie Therapéutique (French)
●etc.
© Oldřich Farsa 2011
Medicinal Chemistry (MC) as an scientific field and one of the
key disciplines of pharmaceutical study deals with a drug
prepared in most by means of chemical procedures with
preciously defined structure and properties.
●MC is not only organic or inorganic chemistry simply applied to
synthesis of drugs
●MC studies relationships between chemical structure and
biological activity of drugs (structure-activity relationships, SAR)
by means of chemical, physical, biophysical, biochemical,
pharmacological and other methods
●MC is devoted to design and discovery of novel therapeutic
agents and for such purpose it uses also knowledges of
bioinformatics, genetics, genomics, proteomics and other modern
biological disciplines
• OR: Medicinal Chemistry could be
defined as an interdisciplinary science
situated at the interface of organic and
inorganic chemistry and life sciences (such as
biochemistry, pharmacology, molecular
biology, immunology, pharmacokinetics and
toxicology) on one side and chemistry-based
disciplines (such as physical chemistry,
crystallography, spectroscopy and computerbased
information technologies) on the other.
Chemistry basedChemistry based
disciplinesdisciplines
Organic ChemistryOrganic Chemistry
Life SciencesLife Sciences
Medicinal ChemistryMedicinal Chemistry
Terms more or less synonymous with
medicinal chemistry
Pharmacochemistry
Molecular pharmacochemistry
Drug design
Bioorganic or bioinorganic chemistry
History of Medicinal Chemistry
● Studied/practiced for thousands of years
● Sages, medicine (wo)men / witch doctors
Roots, plants, trees, berries, herbs
Often placebos
Leeches and maggots
AntiquityAntiquity
China – about 3100 b. C. - legendary emperor Sheng Nong:China – about 3100 b. C. - legendary emperor Sheng Nong: ShengSheng
Nong Ben Cao Jing (The Pharmacopoeia of Sheng Nong)Nong Ben Cao Jing (The Pharmacopoeia of Sheng Nong) - book of- book of
herbs:herbs:
Ma Huang - contains ephedrine; used as a heart stimulant and for asthma. Now- contains ephedrine; used as a heart stimulant and for asthma. Now
used by body builders and endurance athletes because it quickly converts fat intoused by body builders and endurance athletes because it quickly converts fat into
energy and increases strength of muscle fibers.energy and increases strength of muscle fibers.
San Qi = Ginseng (Panax notoginseng):
Indications: an anti-stress and mediator of well-being
Egypt
●crude oil used for various therapeutical purposes
●antibacterial effect of plant resins used for conservation of mummies
●origin of alchemy
●Ebers papyrus (about 3000 b.C.) provided 877 prescriptions
and recipes for internal medicine, eye and skin problems, and
gynecology
●Kahun papyrus of around 1800 b.C:, detailed treatments
for gynecological problems. Medications were based mainly on herbal
products such as myrrh, frankincense, castor oil, fennel, sienna,
thyme, linseed, aloe and garlic.
India
●3500 - 3000 b.C.: origin of Ayurvedic medicin
●practiced by the Brahmin sages
●treatments were set out in sacred writings called Vedas
●materia medica extensive, in most based on herbs including
cardamom and cinnamom
Greece
● castor oil and liseed as laxatives
● fennel plant for relief of intestinal colic and gas
● asafetida gum resin as an antispasmodic
● Hippocrates (400 b.C.)
● Hippocratic Corpus
● chew bark of willow tree for pain relief (childbirth and eye
infections) – active component = salicin
● Dioscorides
● De Materia Medica: contained descriptions of treatments
based on 80% plant, 10% animal, and 10% mineral products
● Galenos (AD 129 – 179)
● Opera Omnia: 20 volumes
● contraria contrariis curantur (opposites cure opposites)
Rome
● Pliny the Elder (AD 23–79) (Plinius)
● The Natural History: 900 herbs
Middle Ages
Arab peninsula - 9th
century
● Avicenna – works translated into Latin
● development of alchemy: not theory but practice gave chemistry
including MC useful procedures and compounds
invention of distillation ⇒ concentrated ethanol from
fermentation products (⇒ herbal tinctures)
● slow transfer of knowledges into Europe
● Albertus Magnus
Renaissance (15th
- 17th
century)
Western and Central Europe
● further development of alchemy
● knowledge of:
– sulfuric acid
– diethylether („aether sulphuricus“) - Valerius Cordus 1544
– Hg2
S
– AgNO3
(„lapis infernalis“) etc.
● Paracelsus (own nameTheophrastus Bombastus von
Hohenheim; 1493 - 1541) –
– therapy based on empirical experience, not on
hypotheses taken from old books
– an effect depends on a dose
– founder of iatrochemistry – predecessor of MC
– use of herbal tinctures, but also salts of heavy metals
(Ag, Cu, Hg, Bi …)
– Hg2+
(or Hg+
?) salts in oitments or vapours of metallic Hg
against syphilis – the first known truly effective therapy of
this disease (but overdosage ⇒ intoxication); HgCl2
as
diuretics
– his followers called „Paracelsians“ were in opposition to
„orthodox medicine“
●
further development of European apothecary shops – ancient
pharmacies
● 1668, Darmastadt, Germany: a small apothecary shop had
been founded which later originated Merck Company from
● sodium sulfate prepared as laxative (Glauber 1658)
● preparation of basic bismuth nitrate (Lefèvbre 1661)
● powdered iron used in anemia (Sydeham 1681)
● Columbus: „discovery“ of America
● transfer of new medicaments and raw materials of plant
origin:
● Cortex chinae – transported into Spain 1633:
antimalaric, antipyretic; later source of alkaloida
(quinine, quinidine, cinchonin, cinchoninidine)
● curare – arrow poison of Indians of South America –
mixture of extracts of various plants namely from
families
● coca leaves (Erythroxylon coca) – stimulant and „anti-hunger
agent“ of South American Indians; later cocaine isolated
(better: partially synthetized) – lead compoud for local
anesthetics, drug of abuse
Inventions of 18th
century
● boric acid prepared from borax - „sal sedativum“ - Homberg and
Lemery
● discovery of sugar in beet Beta vulgaris (Marggraf 1747)
● isolation of some organic acids and glycerol (Scheele 1769 -
1785)
● discovery of diuretic action of foxglove Digitalis purpurea
(Withering 1785)
● sodium hypochlorite solution as a desinficient (Berthelot 1786)
19th
century
● Isolation of pure alkaloida
– the word alkaloid = „alkali-like“ introduced by Meissner
(German pharmacist) 1820
● morphine – isolated from opium by Sertürner (German
pharmacist) 1804
● quinine, emetine and strychnine – Pelletier and Caventou 1818
– 1820
● Peyron's chloride cis-[PtII
(NH3
)2
Cl2
] prepared (1845); much later
recognized as an potent antineoplastic (cisplatin)
● Synthetic organic medicines introduced:
● diethylether (1846) and chloroforme (1847) general anesthetics
● cocaine as a local anesthetic (Wöhler 1860)
● phenol as a desinficient in surgery (Lister 1865)
● chloral hydrate as the first synthetic hypnotic (Liebreich 1869)
19th
century – continued
● origin, development and influence of chemical and pharmaceutical
industry
● namely Germany, later UK, USA and other countries
● originaly pharmacies (Merck) or chemical dyes factories
● more organic synthetic drugs introduced:
●
antipyrine (Knorr 1883) and acetanilid (1886 - Antifebrin®
) as
antipyretics
● 1897 Bayer, Leverkusen, Germany: industrial synthesis of
acetylsalicylic acid as an antipyretic drug by Felix Hoffmann –
(Aspirin®
introduced since 1899)
● phenolphtalein as a laxative (Vamosy 1898)
History of acetylsalicylic acid (ASA)
O
O
OHOH
OH
OH
OH
OHO
OH
CH3
CH3
O
O
O
OHO
O CH3
O
OHO
OH CH3
Cl
O OHO
O
CH3
O
OHO
OH
OHO
O
CH3
O
CH3
CH3
O
O
O
salicin
(2-hydroxymethylphenyl)-β -D-glucopyranoside
600 b.C. Hippocrates: chewig of willow bark
(Cortex salicis - Salix sp.)
1827 Leroux: isolation from willow bark
hydrolysis
oxidation
salicylic acid
2-hydroxybenzooic acid
1838 Piria: the first synthesis
Kolbe: efficient industrial synthesis
since 1878 used as antipyretic
and antirheumatic
acetylsalicylic acid
2-acetoxybenzooic acid
1897 Felix Hoffmann - synthesis for
industry
1899 - Aspirin(R) - Bayer
Gerhardt, Justus Liebigs Ann. Chem. 87, 164 (1853)
Gilm, Justus Liebigs Ann. Chem. 112, 181 (1859)
Kraut, Justus Liebigs Ann. Chem. 150, 10 (1869)
Hoffmann
20th
century
● more synthetic drugs:
● barbital as a hypnotic (Fischer, Mehring 1903)
● procaine as local anethetic (Einhorn 1904)
● arsphenamine (Ehrlich 1910) for treatment of syphilis
– first antibacterial chemotherapeutic
OH NH2
As As
OH
NH2
OH NH2
As
OH NH2
As As
OH
NH2
OH OH
n
Structure proposed by Ehrlich Structure as it is recognized today
asphenamine (Salvarsan ® )
●penicillin: 1929 Alexander
Fleming discovered
antibacterial action of
cultivation media of the
mould Penicillium notatum;
1943 Howard Florey and
Ernst Chain isolated
therapeutically usefull
mixture of crystalline
penicillines, the pure
benzylpenicillin was
prepared by addition of
phenylacetic acid into
cultivation media
N
S
O
N
H
CH3
CH3
OH
O
R
O
H
H
H
CH3
C
H2
C
H2
C
H
C
H
C
H2
C
H2
OH
CH3
C
H2
C
H2
C
H2
C
H2
C
H2
CH3
C
H2
C
H2
C
H2
C
H2
R
20th
century
20th
century
Sulfonamides
N
N
S
NH2
OO
NH2
NH2
NH2
S
NH2
O O
NH2
NH2
NH2
4-(2,4-diaminophenylazo)benzenesulfonamide
red.
+
4-aminobenzensufonamide
sulfanilamide
1,2,4-triaminobenzene
Prontosil rubrum
1932: synthesis by Mietsch
and Klarer; successfully
tested by Domagk against
streptococci
1935: Jacques and
Therése Tréfoulé: holder
of activity is
sulfanilamide (Prontosil
album)
Examples of other important drug inventions of 20th
century
●1921 Banting and Best: insuline as the first peptidic hormone
●1928 Szent-Györgyi: isolation of vitamine C
●1935 Domagk: quarternary ammonium salts as disinfectants
●1935 Prelog, Štěpán: prepared „nitrogenous ypperite“ which later became the lead
compound for alkylating antineoplastics
●1939 Müller: DDT as an insecticide
●1944 Waksmann et al.: streptomycine as the first antituberculotic antibiotic
●1946 Saret, Reichstein: partial sythesis of cortisone
●1946 Lehman: p-aminosalicylic acid as an antituberculotic
●1951 Woodward, Robinson: total synthesis of steroidal hormones
●1952 Laborit, Huguenard, Delay, Deniker: chlorpromazine as the first antipsychotic
●1953 Du Vigneaud: synthesis of peptide hormone oxytocine
●1956 Frank, Fuchs: carbutamide as the first oral antidiabetic
●1961 Kappeler et al.: synthesis of tetracosactide as a synthetic analogue of
corticotropine
●
1963 Black et al.: propranolol as the first β-adrenolytic
●1965 Rosenberg et al.: (re)discovery of cisplatin as the first platinum antineoplastic
●1972 Woodward: total synthesis of vitamine B12
●about 1980 Genetech corp.: production of interferone by a recombinat technology
● ...and many others
Drug nomenclature
A drug usually has (at least)3 names:
1. (Systematic) Chemical
2. International Non-proprietary
names and/or other Non-proprietary
3. Commercial or Trade (with ® )
Chemical: 2-[4-(2-methylpropyl)phenyl]propanoic acid
Non-proprietary ： Ibuprofen
Commercial ： Brufen, APO-Ibuprofen, Ibalgin …
Pharmacopoeial: Ibuprofenum PhEur
CH3
OH
CH3
H3C
O
Systematic chemical names
● according to rules of
● IUPAC (International Union of Pure and Applied Chemistry)
and/or IUBMB (International Union of Biochemistry and
Molecular Biology) if the drug is sugar, enzyme, peptide,
steroid …
– Joint Commission on Biochemical Nomenclature (of
IUPAC and IUBMB)
2-[4-(2-methylpropyl)phenyl]propanoic acid or 2-(4-isobutylphenyl)propanoic
acid
● Chemical Abstracts: basic chain or ring followed by
substituents in alphabetic order
propanoic acid, 2-(4-iso-butylphenyl)
● WHO systematic nomenclature: similar to older versions of
IUPAC names; the longest chain with the most priorietary
group need not be basic
α-methyl-4-(2-methylpropyl)acetic acid
Non-proprietary names
Convenient to remember, needed when apply for registration, cannot be
trade marked or patented. One compound has only one name.
–International non-proprietary names (INN) – introduced by
Nomenclature commision of WHO
•names have their Latin form and are transformed into all national
languages with necessary change of both spelling and
pronunciation
ibuprofenum (Latin), ibuprofene (English, French), ibuprofen (Czech),
ibuprofeno (Spanish) ...
–other non-proprietary names – nations or states feeling themselves to
be „drug powers“ have their own nomenclature systems
•USAN: United States Approved Names
•BAN: British Approved Names
•JAN: Japanese Approved Names
Examples of different INN, BAN and USAN names
NH
OH
OH
OH
CH3
NH
OH
OH
OH
CH3
CH3
Systematic (IUPAC): (R)-4-[1-
Hydroxy-2-(methylamino)ethyl]-
1,2-benzenediol
INN = USAN = JAN: epinephrine
BAN: adrenaline
Systematic (IUPAC): (R)-4-[1-
Hydroxy-2-(isopropylamino)ethyl]-
1,2-benzenediol
INN: isoprenaline
JAN = USAN: isoproterenol
Basic principle of INN: common suffixes or prefixes for a particular
therapeutical or chemical group
●
-cillin: β-lactame antibiotics of peniciline group
●
cef-: β-lactame antibiotics of cefalosporine group
●-caine: local anesthetics
●-vir: antivirotics
●-oxacin: anibacterial quinolones
●-nidazol: nitroimidazole antiprotozoal agents
●-tidin: H2
-recepeptor antagonists
●-profen: anti-infalamatory drugs – propionic acid derivatives
●… etc.
Trade or Commercial names
● names of a particular preparation of a particular manufacturer
● usualy with ® : they are trademarks
● protected from (mis)use by another company by patent or copyright
law
● a trademark protects only trade name and/or its graphic form, not a
structure of active ingredient or its manufacturing procedure or a
composition of a drug form; these are protected by patents as an
intelectual property
Generic names
● names given to a drug by its authors
● in older drugs often adopted by WHO as INN names
● actually only alphanumeric codes are given
Pharmacopoeial names
● used for drug substances, not for preparations
● often in Latin and identical with Latin form of INN
● followed by a shortening of a particular Pharmacopoeia (PhEur, USP,
PhB, PhInt ...)