Farmaceutická chemie I. 2. rok studia
Farmaceutická chemie: definice, vymezení, historie oboru. Názvosloví léčiv.
Doc. PharmDr. Oldřich Farsa, Ph.D.
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.
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.
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
● Hippocrates (400 b.C.)
● chew bark of willow tree for pain (childbirth and eye
infections) – active component = salicin
Rome
● Pliny (Plinius)
● Celsus
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 („in opposite to Celsus“; own nameTheophrastus
Bombastus von Hohenheim) – his kno
– 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
●
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
● 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 O
O Na
+
CO2
OH O
O Na
+
OH O
OH
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)
The first published sytheses of ASA
Kolbe's synthesis of salicylic acid
high pressure
acid
20th
century
● more synthetic drugs:
● barbital as a hypnotic (Fischer, Mehring 1903)
● procaine as local anethetics (Einhorn 1904)
● arsphenamine (Ehrlich)
Last 150 years: Mechanism of reaction/responseLast 150 years: Mechanism of reaction/response
1909: first chemotherapy (Ehrlich)1909: first chemotherapy (Ehrlich)
Salvarsan (compound “606”) for syphilisSalvarsan (compound “606”) for syphilis
Aside: naming drugs (drug name vs. trade name)Aside: naming drugs (drug name vs. trade name)
Later replaced with penicillin (1940s)Later replaced with penicillin (1940s)
2005: Structure determination2005: Structure determination