Early drug discovery and the rise of pharmaceutical chemistry

Abstract

Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history.

Full text

337
Historical
Drug Testing
and Analysis
Received: 15 April 2011 Revised: 28 April 2011 Accepted: 28 April 2011 Published online in Wiley Online Library
(www.drugtestinganalysis.com) DOI 10.1002/dta.301
Early drug discovery and the rise
of pharmaceutical chemistry
Alan Wayne Jones∗
Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history
of drug discovery, the various personalities involved, and the events leading to the development and introduction of new
therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines
and fungi. Until the mid-nineteenth century nature’s pharmaceuticals were all that were available to relieve man’s pain and
suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still
available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye
industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics
and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol,
both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries
to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and
irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better
known as Aspirin, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs
entered the pharmacopoeia and the rest, as they say, is history. Copyright c
2011 John Wiley & Sons, Ltd.
Keywords: alkaloids; analgesics; barbiturates; drugs; discovery; plants; natural products; pharmacology
Introduction
The word ‘drug’ is probably of Arabic origin and first appeared in
Old German as dr¨
og, referring to a type of powder.[1] Indeed, the
first pharmaceuticals were obtained from the vegetable kingdom
as the dried parts of plants, herbs, and shrubs. According to
Wikipedia, the etymology of the word ‘drug’ is the Old French
word drogue or the Dutch word droog, both of which refer to dry
barrels containing herbs.
Nature has provided a rich source of pharmacologically active
chemical substances produced by plants, fungi, insects, and
reptiles.[2,3] Biosynthesis of these natural toxins functioned as
a chemical self-defence mechanism and protected the species
from being eaten by predators. Accordingly, these xenobiotics
have been around since the dawn of history. The first human
beings, in their continuous quest for food and survival, must
have experienced the effects of these substances, for better or for
worse.[4] Crude extracts from wild plants and shrubs constituted
the first herbal medicines that were used for the relief of pain
and suffering, to heal wounds, and to treat all types of maladies.
Foremost among these natural products was the juice obtained
from the opium poppy plant (papaver somniferum)datingfrom
∼3000 BC that contained the all powerful painkiller, morphine.[5– 7]
Perhaps the earliest written record of medical therapeutics is
contained in the famous Ebers papyrus, a 20-metre-long, 110-page
medical scroll, named after the German Egyptologist Georg Ebers,
who acquired it in 1872 (Figure 1). The Ebers papyrus described
hundreds of treatments for the many aliments inflicting ancient
Egyptians ∼1500 BC. These were prepared by mixing together
various herbs, shrubs, leaves, minerals, and animal excreta.[1]
These recipes and concoctions represented the earliest record
of medicines in the ancient world and must have had a strong
influence on later generations when knowledge of herbal products
became more organized, as evidence by Greek, Roman, and Indian
cultures, as well as traditional Chinese medicine.[4,8]
Nature’s pharmaceuticals
Examples of pharmacologically active substances derived from
plants include morphine from opium poppy, nicotine from the
tobacco plant, cannabinoids from cannabis leaves, caffeine from
tea and coffee, cardiac glycosides (digoxin and digitoxin) from
woolly foxglove, quinine from the cinchona tree, and salicylates
from the bark of the white willow tree.[8]
The first hunters learnt the trick of spiking their darts and arrows
with plant toxins (poisons), such as curare to kill or stupefy wild
animals.[9] The word ‘toxicology’ derives from the Greek word
toxikos, which literally referred to a bow for shooting arrows.[10]
Other psychoactive substances known since ancient times and
which were popular in certain cultures included cocaine from coca
leaves, psilocybin from mushrooms, mescaline from the peyote
cactus, to name just a few.[11 – 13]
The isolation and characterization of the active principles in
medicinal plants represented a major challenge for analytical
chemists and apothecaries of the time. Morphine was the first
plant alkaloid isolated in a pure state by a 23-year-old apothecary
named Friedrich Willhelm Sert ¨
urner (1783–1841). While working
as an apprentice to a pharmacy in Einback, Germany, in 1805,
∗Correspondence to: Professor Alan Wayne Jones, Department of Forensic
Genetics and Forensic Toxicology, National Board of Forensic Medicine,
Artillerigatan 12, SE-58758 Link ¨
oping, Sweden. E-mail: wayne.jones@RMV.SE
Department of Forensic Genetics and Forensic Toxicology, National Board of
Forensic Medicine, Artillerigatan 12, SE-58758 Link ¨
oping, Sweden
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Drug Testing
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Figure 1. Page from the Ebers papyrus an Egyptian medical scroll dating
from ∼1500 BC, which gives instructions how to prepare hundreds of
purported herbal medicines and cures.
Sert ¨
urner isolated meconic acid from raw opium. The following
year he obtained a substance with the properties of a weak
base.[11] When this base was administered to a dog, the animal
fell into a deep sleep and Sert¨
urner felt that he had discovered
der eigentliche bet¨
aubende Grundstoff of raw opium (the specific
narcotic element of opium).[11] The new substance was christened
‘morphine’ after Morpheus the Greek god of dreams.[10] Sert ¨
urner
tested the pharmacological effects on himself and some young
friends and took unusually large doses (1.5 grains ∼100 mg in
three divided doses).[11] Not long afterwards other alkaloids were
isolated from opium, including codeine and papaverine.
When available in a pure form, the pharmacological activity
and toxicity of these alkaloids increased considerably and many
were deadly poisons.[14] These toxins were incriminated in crimes
of murder by poisoning and development of suitable methods
for extraction and identification of the poison in biological
specimens marked the beginning of forensic pharmacology and
toxicology.[9,15]
Animal chemistry and pharmacology
Apothecaries probably represent the first pharmaceutical chemists
charged with mixing and dispensing all kinds of herbal remedies in
the hope of finding a cure for their customer’s medical complaints.
Foremost among the early apothecaries was the Swede Carl
Wilhelm Scheele (1742– 1786), who is known and admired by all
historians of chemistry as a veritable pioneer.[16] Another pioneer
chemist was J ¨
ons Jacob Berzelius (1779–1848), who was born
in the vicinity of Link ¨
oping in Sweden, and made enormous
contributions to the chemical sciences, even writing the first book
on animal (physiological) chemistry.[17,18]
By the mid-1800s, German scientists began to dominate the
field of analytical and organic chemistry, with such luminaries as
Friedrich W ¨
ohler (1800–1882), famed for the synthesis of urea
‘without the help of a kidney’ simply by heating ammonium
cyanate.[19] A contemporary, close friend and sometimes scientific
rival of W ¨
ohler was the celebrated Justus von Liebig (1803–1873),
whose chemical discoveries are legendary. Liebig is considered
by many as the founding father of organic and clinical chemistry
(Figure 2).[20]
The subject of pharmacology (Materia Medica) was established
as a scientific discipline in the latter half of the nineteenth
century by people such as Rudolf Buchheim (1820– 1879), Oswald
Schmiedeberg (1838–1921), Paul Ehrlich (1854–1915), and Henry
Dale (1875– 1968).[11] Another venerable pioneer in pharmacology
and toxicology was Louis Lewin (1850– 1929), who was one of the
founding fathers of psychopharmacology as evidenced by his
many published papers and the textbook Phantastica.[21] He also
wrote the first book devoted to adverse drug reactions.[22]
Alkaloids
The word ‘alkaloid’ (Figure 3) was coined in 1819 by a German
chemist Carl F. Wilhelm Meissner (1792– 1853) and this class of
organic compounds played a prominent role in the development
of forensic toxicology as a scientific discipline.[23] These bitter-
tasting (alkaline) substances produced by nature contain one or
more nitrogen atoms in the molecule and are deadly poisonous in
a pure state.[24] One notorious alkaloid, strychnine, derived from
the plant strychnos nux-vomica has been implicated in murder
by poisoning in many criminal prosecutions.[14] The complex
chemical structure of alkaloids meant they were difficult to extract
from body organs and tissue, a daunting task for the first analytical
chemists. Without being able to extract and identify a poison from
the body, it was not possible to prove its use in the crime of
murder.
A major preoccupation of analytical chemists and early toxi-
cologists was to develop methods that allowed the identification
of plant alkaloids in blood and human viscera as evidence of
poisoning. Foremost among these pioneers was Mathieu JB Orfila
(1787–1853), born on the Spanish island of Minorca but who lived
and worked in Paris as Professor of Medical Jurisprudence and
later Dean of the Medical Faculty.[25] Orfila is considered as the
father of forensic toxicology as a scientific discipline and he also
wrote the first textbook on drugs and poisons in 1814 (Figure 4).[26]
Many of the first forensic chemists and toxicologists began their
careers by visiting and studying under Orfila. These individuals
included Jean-Servais Stas (1813 –1881) in Belgium, [27] Robert
Christison (1797–1882) in Scotland, [28] and Alfred Swaine Taylor
(1806–1880) from London.[29]
Examples of common alkaloids and their botanical plant origin
include morphine (papaver somniferum), LSD (ergot fungus), eme-
tine (cephaelis ipecacuanha) strychnine (strychnos nux-vomica),
physostigmine (calabar beans), scopolamine (scopolia carniolica),
atropine (atropa belladona), ricinine (castor oil beans), and coniine
(spotted hemlock).
The first synthetic drugs
The doyen among German organic chemists during much of
the nineteenth century was Justus von Liebig (1803–1872), the
renowned Professor of Chemistry in Munich.[30] One of his many
discoveries was the volatile liquid chloroform (CHCl3), which
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Jöns Jakob Berzelius
(1779-1848) Friedrich Wöhler
(1800-1882)
Justus von Liebig
(1803-1873)
Rudolf Buchheim
(1820-1879)
Louis Lewin
(1850-1929) Paul Erlich
(1854-1915)
Oswald Schmiedeberg
(1838-1921)
Henry Dale
(1875-1968)
Figure 2. Some early scientific luminaries in the field of chemistry, pharmacology, and toxicology.
Figure 3. Title of Meissner’s article in which he coined the word ‘alkaloid’ and his reasoning for the choice of this word.
later became important as a general anesthetic drug. The use
of chloroform as a volatile anesthetic in surgery is credited to a
Scottish physician James Young Simpson (1811– 1870). Simpson
demonstrated the benefits of chloroform to deaden the pain
associated with child birth and one of his first patients in 1872 was
none other than Queen Victoria of England.[11]
In 1832, Liebig also prepared chloral hydrate and showed that
in alkaline solution it was converted into chloroform and formic
acid. This prompted the German physician and pharmacologist
Oscar Liebreich (1839–1908) to investigate whether the same
reaction might occur directly in the blood, which would mean that
chloral hydrate might also be useful anesthetic in the same way as
chloroform.[11] The results of these investigations were reported
in a classic monograph (Figure 5).
Administration of chloral hydrate to animals put them into a
deep sleep, but without loss of pain sensation, which meant its
pharmacological effects differed from that of chloroform. Further
studies showed that chloral hydrate was a relatively safe sleeping
aid (hypnotic) and entered the pharmacopeia as early as 1869
and still exists today (Noctec) in some countries. Indeed, chloral
hydrate was incriminated in the accidental death of the Playboy
model Anna-Nicole Smith (1967– 2007), who overdosed on a
mixture of pharmaceuticals. Other early drugs used as sedative-
hypnotic include bromide salts, paraldehyde, and urethanes,
although these were made more or less redundant when the
barbiturate class of drugs appeared in the first decade of the
twentieth century.
Barbiturates
Barbiturates represent a remarkable class of therapeutic agents
and function as sleeping aids, anaesthetics, and anticonvulsants.
They entered the pharmacopoeia in the first decade of the
twentieth century.[31] The parent compound of barbiturates,
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Figure 4. Portrait of Mathieu JB Orfila alongside the first page of his famous 1814 treatise on the general toxicology of poisons.
Figure 5. Portrait of Oscar Liebreich alongside the first page of his 1869 monograph on chloral hydrate and its use as a hypnotic.
barbituric acid, was synthesized in 1864 by Adolf von Baeyer
(1835–1917) as part of research for his thesis (habilitation).[32]
He reacted uric acid, an animal waste product, with malonic acid
(from apples) to produce a new compound with empirical formula
of C4H4N2O3, although its chemical structure was unknown at
the time. The development of structural formulae, including
aromatic and aliphatic rings, had to await the work of August
Kekul´
e (1829–1896) from Germany [33] and Archibald Scott
Couper (1831–1892) from Scotland.[34] In 1857–1858, more or
less simultaneously, these structural chemists published novel
ideas about the tetravalent nature of the carbon atom and its
ability to self-link into chains and ring structures
The synthesis of barbituric acid was only a very small fraction of
the many contributions to organic chemistry made by Adolf Von
Baeyer and he justifiably received a Nobel Prize in 1905, mainly for
work he had done on synthetic indigo dyes.[35] Whether the name
barbituric acid was coined in honour of a lady named Barbara
that von Baeyer was allegedly dating at the time or if it comes
from St Barbara the patron saint of artillery officers, we will never
know.[36,37]
Later work showed that barbituric acid contained a 6-membered
pyrimidine ring (Figure 6), although it was pharmacologically
inactive, owing to the low pKa of 4.12, which meant that it
was poorly absorbed from the gut. After the chemical structure of
barbituric acid was elucidated, the physician and pharmacologist
Josef von Mering (1849–1908) had the idea of replacing two
adjacent hydrogen atoms in the pyrimidine ring with ethyl groups.
He knew from earlier research that two alkyl groups bonded to
the same carbon atom imparted pharmacological activity so he
synthesized diethyl barbituric acid. With a higher pKa (7.9), this
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Adolf von Baeyer
(1835-1917)
Josef von Mering
(1849-1908)
Emil Fischer
(1852-1919)
N
H
N
H
O
O
O
H
H
O
O
OH
OH
O
NH2
NH2
++
2H2O
Synthesis of barbituric acid
Figure 6. Scientists credited with the development of barbiturates and the synthesis of barbituric acid by Adolf von Baeyer in a condensation reaction
between urea and malonic acid.
diethyl derivative of barbituric acid was more easily absorbed from
the gut, it had a greater solubility in lipids, which meant that it
more easily crossed the blood-brain barrier.[38]
As von Mering was a pharmacologist and not a chemist,
he contacted Emil Fischer (1852–1919), the acknowledged
authority in organic chemistry in Germany at the time, and
asked him to verify the structure and check the purity of
the new compound.[39] Together with his students, Fischer
succeeded in making a more potent derivative of barbituric acid,
which he patented in 1903 under the trade name Veronal,
allegedly named after the peaceful Italian city of Verona.[40]
Fischer and von Mering also conducted clinical trials with
barbital as a sleeping aid and published their findings in
1903.[11,40] The success of barbital as a hypnotic led to the
synthesis of scores of other derivatives of barbituric acid with
the two hydrogen atoms on the 5,5-position of the pyrimidine
ring being replaced with alkyl, aryl, allyl or aromatic groups.
Many of these compounds were further developed into useful
pharmaceutical products, notable phenobarbital (Luminal)
which appeared in 1909 and is still in use today as an
anticonvulsant.[36 – 38]
After prescribing the barbiturate group of drugs on a large-
scale, problems arose, with reports of acute toxicity when
used as sleeping aids; there was a narrow margin between a
therapeutic dose and a lethal dose.[41] Moreover, barbiturates
carry a high abuse potential and some people develop tolerance
and dependence on their medication. Toxicity is enhanced if taken
together with other depressant drugs, such as alcohol.[41] Among
other famous names, the pop star Jimi Hendrix (1943– 1970)
died from asphyxia after inhalation of vomit when sedated after
a night of heavy drinking and the prescription sleeping aid
Vesparax, a mixture of two barbiturates, namely brallobarbital
and secobarbital, as well as a small amount of hydroxyzine.
The barbiturate family of drugs, without any shadow of a doubt,
represented a major advance in pharmacotherapy and some,
such as thiopental an intravenous anaesthetic agent (e.g. sodium
pentothal), are still in use today. Thiopental is one of a three-drug
cocktail used in connection with capital punishment by lethal
injection in several US states.[42] The development of methods for
extraction, identification, and quantitative analysis of barbiturates
in blood and liver tissue belong to classic procedures in the field
of analytical and forensic toxicology.[43]
The first analgesics and antipyretics
The first synthetic drugs and, indeed, the entire pharmaceutical
industry can be traced to the manufacture of textiles and synthetic
dyes, as exemplified by mauveine (mauve), which was discovered
by a young British chemist William Henry Perkin (1838–1907).[44]
One of the first German chemical firms to show an interest
in pharmaceuticals was the Friedrich Bayer Company, founded
in 1863, and originally located in Barmen, Germany (today in
Leverkusen). The black sticky mass (tar) remaining after distillation
of coal under a vacuum provided a rich source of aromatic
chemicals, including benzene, naphthalene, phenol and aniline.[45]
An example of one of the many aromatic compounds derived
from coal-tar was naphthalene, which was used as an intestinal
antiseptic for, among other things, the irradiation of worms. When
a patient with this condition who also happened to be suffering
from a fever received naphthalene, the fever was cured but not the
worms.[45] On closer inspection it turned out that the pharmacist
hadmade a mistake andinstead of naphthalene,another derivative
of coal-tar, acetanilide (Figure 7) had been prescribed. This led the
Bayer Company to develop and market acetanilide as the first
synthetic antipyretic drug, which became known commercially as
Antifebrin(fever-reducing).
The success of Antifebrin prompted the Bayer Company to
search for other chemicals in the waste products from the dye-
works for possible use as pharmaceuticals. One such substance
was p-nitrophenol, which was easily converted into the ethyl ester
derivative of acetanilide (Figure 7) to give another commercial
product phenacetin. In 1887, the Bayer Company began
to manufacture phenacetinwhich eventually became more
successful as an analgesic-antipyretic agent than acetanilide.[45]
Another derivative of acetanilide prepared around the same time
was N-acetyl-p-aminophenol (paracetamol), but as a commercial
product this was overlooked in favour of phenacetin.
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NH O
HO
CH3
Paracetamol (1887)
NH O
O
CH3
H3C
Phenacetin (1887)
NH O
CH3
Acetanilide (1886)
O
O
O
OH
CH3
Aspirin (1899)
Figure 7. Chemical structures of early analgesic and anti-pyretic drugs.
Figure 8. The white willow tree (Salix alba), the bark of which is rich in salicylates (left), US patent 1900 granted to Bayer’s Felix Hoffmann for the synthesis
of acetylsalicylic acid (middle) and an old bottle of aspirin (right).
Phenacetin was not without its problems because some
patients, after long-term use of the drug, developed a medical
condition known as methemoglobinemia. The ability of red blood
cells to distribute oxygen is lost and as a result the patient’s
skin turns a blue-purple color (cyanosis). This problem was
investigatedby two Americans, namely Julies Axelrod(1912 – 2004)
and Bernard B Brodie (1907– 1989) who identified aniline, a
minor metabolite of phenacetin, as the cause of the problem.[45]
Another metabolite they identified was N-acetyl-p-aminophenol,
better known today as acetaminophen (USA) or paracetamol
(Europe), which retained the antipyretic and analgesic properties
of the parent drug but was lacking the methemoglobinemia
side-effect.[45]
In the 1950s, a small US drug firm, McNeil laboratories, began
to develop N-acetyl-p-aminophenol as a new pharmaceutical
product, named Tylenol Elixir.[45] This liquid formulation was
especially suitable for children and the elderly and was approved
for this purpose by the Food and Drug Administration (FDA)
in 1955. Shortly afterwards, Tylenol was also manufactured in
tablet form (500 mg), becoming a blockbuster drug available
over-the-counter and found in bathroom cabinets of virtually
every home.
Aspirin - a wonder drug
This historical account of early drug discovery of mild analgesics
and antipyretics would not be complete without mentioning
acetylsalicylic acid, better known around the world as Aspirin.
Aspirin was marketed as a highly successful pharmaceutical
product by the Bayer Company in 1897, although plant extracts
rich in salicylates enjoy a much longer history and were used for
the treatment of fevers and other ailments since ancient times.[46]
Many plants, shrubs, and trees of the Spiraea genus contain
salicin, a naturally occurring glycoside of salicyl alcohol, which
after hydrolysis and oxidation gives salicylic acid.
The first well-documented clinical trial of salicylates in medicine
is credited to an English clergyman, the Reverend Edward Stone
(1702– 1768).[47] Reverend Stone, who lived in Chipping Norton,
Oxfordshire, had an inquisitive mind and was interested in the
health and well-being of the rural community where he lived. He
was well aware of the rumours that circulated for years about the
curative properties of extracts of bark from the white willow, a tree
that flourishes in wet or damp environments and grows close to
river banks and streams in many countries (Figure 8). Willow-bark
extracts had been used with great benefit in the treatment of a
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Figure 9. Title and opening paragraph of the letter sent in 1765 by the
Reverend Edward Stone to the Royal Society of London to inform them of
the usefulness of extracts of willow bark as a cure for various fevers.
host of medical complaints, including aches and pains, fevers and
chills.
Around 1763, Reverend Stone decided to undertake a scientific
experiment to test the efficacy and curative properties of white
willow bark (Salix alba) as a herbal medicine. In a clinical trial, he
gave extracts of willow bark to a total of 50 patients sufferingfrom
agues (fevers), albeit without a control or placebo treatment, to
verify any beneficial effects for this condition. The results were
communicated to the Royal Society of London and published in
its Philosophical Transactions (Figure 9), and this represented the
first peer-reviewed documentation of the medicinal properties of
willow bark. The article was entitled An account of the success of
the bark of the willow in the cure of agues. [47]
During the first decades of the nineteenth century, French,
Italian, and German chemists attempted to isolate the active
principle contained in willow bark (salicin or salicylic acid), but the
crude substances they obtained were not much better than the
raw material, because of a lack of chemical purity.[48] In 1853, a
French chemist Charles Frederic Gerhardt (1816–1856) heated an
extract of willow bark with acetyl chloride and in this reaction he
succeeded in producing, for the first time, acetylsalicylic acid.[49]
However, the chemical structure of this derivative was unknown
and acetylsalicylic acid was ignored as a potential therapeutic
agent. A major breakthrough in research on salicylates occurred in
1860 when Hermann Kolbe (1818– 1884), a Professor of Chemistry
first in Marburg and later in Leipzig, discovered an efficient way to
synthesize salicylic acid also establishing its correct structure.[50] By
1874, Kolbe, in association with his student Fredrich von Heyden,
began to produce salicylic acid on an industrial scale and this
synthetic product was much cheaper than that derived from
willow bark.[49]
The Bayer Company, already the manufacturer of phenacetin,
was naturally much interested in this rival compound salicylic
acid and its sodium salt. Two of the movers and shakers
in the development of Bayer’s Aspirinwere Heinrich Dreser
(1860–1924), who was head of pharmacology, and a young
chemist Felix Hoffmann (1868– 1946).[49,50] Legend has it that
Hoffmann was inspired to make an improved form of salicylic
acid because his father was a long-time sufferer of rheumatism
and often complained about the bitter taste of his medicine
and the irritation it caused to the mucosa surfaces of his
stomach.[50] Hoffmann succeeded in preparing acetylsalicylic acid
in a chemically pure form and on behalf of the Bayer Company
even filed a patent for the discovery, which was granted in 1899 in
Germany and the following year in the USA (Figure 8).
The world-famous name Aspirin gets the ‘a’ from acetyl, the
‘spir’ from the Latin genus spiraea, the botanical name of the
meadowsweet plant rich in salicin, and the ‘in’ was added as
a common ending for drug names at the time.[49,51] Besides its
usefulness for the treatment of rheumatic pain, headaches, and
fever, aspirin has found many other medical uses, most notably as
an anti-clotting agent and a prophylactic treatment for thrombosis
and stroke.[52] Hundreds or even thousands of scientific articles
appear each year dealing with one or other aspect of Aspirin and
its usefulness in medicine and therapeutics.
Concluding remarks
This account of early drug discovery has highlighted the human
side of pharmacology including the various chemists, physicians
and other scientists involved. To paraphrase the famous French
chemist and microbiologist Louis Pasteur (1822–1895) It is by
reading what discoverers have done that we lift and maintain the
sacred flame of discovery.
References
[1] R. Porter, The Greatest Benefit to Mankind.W.W.Norton&Company:
New York, 1997.
[2] P. J. Houghton, J. Chem. Ed. 2001,78, 175.
[3] W. C. Agosta, J. Chem. Ed. 1997,74, 857.
[4] W. Sneader, Drug Discovery, A History. John Wiley & Sons Ltd.:
Chichester, 2005.
[5] R. J. Miller, P. B. Tran, TIPS 2000,21, 299.
[6] R. J. Huxtable, S. K. W. Schwarz, Molec. Interv. 2001,1, 189.
[7] F.W.A.Sert¨
urner, Annal der Physik 1817,55, 56.
[8] M. Weatherall, In Search of a Cure: A History of Pharmaceutical
Discovery. Oxford University Press: Oxford, 1990.
[9] J. Mann, Murder, Magic and Medicine. Oxford, Oxford University
Press: 1992.
[10] H. Askitopoulou, I. A. Ramoutsaki, E. Konsolaki,Anesth. Analg. 2000,
91, 486.
[11] B. Holmstedt, G. Liljestrand, Readings in Pharmacology.Pergamon
Press: London, 1963.
[12] B. Holmstedt, A. Fredga, J. Ethnopharmacol 1981,3, 113.
[13] J. C. Bruhn, B. Holmstedt, Econ. Bot. 1974,28, 353.
[14] J. Buckingham, Bitter Nemesis– The Intimate History of Strychnine.
CRC Press: Boca Raton, 2008.
[15] N. G. Coley, Clin. Chem. 2004,50, 961.
[16] H. Fors, Mutual Favours: The Social and Scientific Practice
of Eighteenth-Century Swedish Chemistry. Dissertation, Uppsala
University, 2003.
[17] J. E. Jorpes, Jac Berzelius: His Life and Work. Almqvist & Wiksell:
Stockholm, 1966.
[18] N. G. Coley, Ambix 1996,43, 164.
[19] G. B. Kauffman, S. H. Chooljian, Chem. Educator 2001,6, 121.
[20] L. Rosenfeld, Clin. Chem. 2003,49, 1696.
[21] L. Lewin, Phantastica. Park Street Press: Rochester, 1998.
[22] L. Lewin, The Untoward Effects of Drugs – A Pharmacological and
Clinical Handbook. Brown Press: Alcester, 2010.
[23] C. F. W. Meissner, J. Chemie. Physik 1819,25, 377.
[24] W. Vycudilik, G. Gmeiner, Drug Test. Anal. 2009,1, 177.
[25] J. R. Bertomeu-S´
anchez, A. Nieto-Galan, Chemistry, Medicine and
Crime – Mateu JB Orfila (1787 –1853) and his Times. Sagamore Beach
MA, Science, 2006.
[26] J. R. Bertomeu-S´
anchez, Med. Hist. 2009,53, 351.
[27] R. Wennig, Drug Test. Anal. 2009,1, 153.
[28] J. S. Cameron. J. R. Coll. Physicians Edinb. 2007,37, 155.
[29] N. G. Coley, Med. Hist. 1991,35, 409.
[30] W. H. Brock, Justus von Liebig: The Chemical Gatekeeper. Cambridge
University Press: Cambridge, MA, 1997.
Drug Test. Analysis 2011,3, 337 –344 Copyright c
2011 John Wiley & Sons, Ltd. www.drugtestinganalysis.com

344
Drug Testing
and Analysis A. W. Jones
[31] K. C. Niclaou, T. Montagnon, Molecules that Changed the World.
Wiley-VCH: Weinheim, 2008.
[32] A. Baeyer, Ann. Chem. Pharm. 1864,130, 129.
[33] H. Goodman, Bull. N.Y . Acad. Med. 1942,18, 150.
[34] M. Sutton, Chem. World 2008,May, 44.
[35] R. Huisgen, Angew.Chem.Int.Ed.1986,25, 297.
[36] J. W. Dundee, P. D. A. McIlroy, Anaesthesia 1982,37, 726.
[37] D. A. Cozanitis, J. Roy. Soc. Med. 2004,97, 594.
[38] F. Lopez-Munoz, R. Ucha-Udabe, C. Alamo, Neuropsychiatr. Dis.
Treat. 2005,1, 329.
[39] H. Kunz, Angew.Chem.Int.Ed.2002,41, 4439.
[40] E. Fisher, J. von Mering, Ther. D. Gegenw. 1903,44, 97.
[41] R. D. Gillespie, Lancet 1934,February, 337.
[42] J. I. Groner, B. M. J. 2002,325, 1026.
[43] R. Bonnichsen, A. C. Maehly, A. Frank, J. Forensic Sci. 1961,6, 411.
[44] S. Garfield, Mauve – How One Man Invented a Color that Changed the
World. WW Norton & Co.: New York, 2000.
[45] M. E. Bowden, A. B. Crow, T. Sullivan, Pharmaceutical Achievers.
Chemical Heritage Press: Philadelphia, 2003.
[46] W. Sneader, B. M. J. 2000,321, 1591.
[47] E. Stone, Phil. Trans. 1763,53, 195.
[48] H. Haas, Am. J. Med. 1983,75,1.
[49] D. Jeffreys, Aspirin: The Remarkable Story of a Wonder Drug.
Bloomsbury: London, 2004.
[50] H. Kolbe, Ann. Chem. Pharm. 1860,113, 125.
[51] T. J. Rinsema, Med. Hist. 1999,43, 502.
[52] J. Vane, Thorax 2000,5,S3.
www.drugtestinganalysis.com Copyright c
2011 John Wiley & Sons, Ltd. Drug Test. Analysis 2011,3, 337 –344