There is a long history of plants being used to treat various diseases. They figure in the records of early civilisations in Babylon, Egypt, India and China. The therapeutic properties of plants were described by the Ancient Greeks and by the Romans and are recorded in the writings of Hippocrates, Dioscorides, Pliny and Galenus. Some metals and metal salts were also used at this time. In the Middle Ages various 'Materia Medica and pharmacopeas brought together traditional uses of plants. The herbals of John Gerard (1596), John Parkinson (1640) and Nicolas Culpeper (1649) provide an insight into this widespread use of herbs. Exploration in the seventeenth and eighteenth centuries led to the addition of a number of useful tropical plants to those of European origin.
The nineteenth century saw the beginnings of modern organic chemistry and consequently of medicinal chemistry. Their development is intertwined. The isolation of a number of alkaloids including morphine (1805), quinine (1823) and atropine (1834) from crude medicinal plant extracts was part of the analytical effort to standardize drug preparations and overcome fraud.
General anaesthetics were introduced in surgery from 1842 onwards (diethyl ether (1842), nitrous oxide (1845) and chloroform (1847)). Antiseptics such as iodine (1839) and phenol (1860) also made an important contribution to the success of surgery. The hypnotic activity of chloral (trichloroethanal) (1869) was also reported.
Many of the developments after the 1860s arose from the synthesis of compounds specifically for their medicinal action. Although the use of willow bark as a pain-killer was known to the herbalists, the analgesic activity of its constituent salicin 1.1 and of salicylic acid 1.2 were developed in the 1860s and 1870s. p-Hydroxyacetanilide 1.4 (paracetamol) and phenacetin 1.5 (1886) were also recognized as pain-killers. Acetylation of salicylic acid to reduce its deleterious effect on the stomach led to the introduction of aspirin 1.3 in 1899. However its mode of action was not established until 1971.
The local anaesthetic action of cocaine was reported in 1884 although its structure was not known at the time.
Various modifications of the dialkylamino esters of aromatic acids modelled on part of the structure of cocaine 1.6 led to benzocaine (1892) and procaine 1.7 (1905). The barbiturates, veronal (1903) and phenobarbital 1.8 (1911) were introduced as sleeping tablets.
Once ideas of chemical structure were formulated in the mid-nineteenth century, the first theories of the relationships between chemical structure and biological activity began to emerge. Thus Crum-Brown and Fraser (1869) noted that a 'relationship exists between the physiological action of a substance and its chemical composition' leading to the idea that cells can respond to the signals from specific molecules. On the basis of observations that certain dyes selectively stained micro-organisms, Ehrlich in the 1890s put forward the idea that there were specific receptors for biologically active compounds - 'lock and key' relationships. This led to the examination in 1904 of dyestuffs such as trypan red for the treatment of trypanosomiasis and the development (1907) of salvarsan 1.9 for the treatment of syphilis by what turned out to be a false structural analogy (see Chapter 6). In the First World War acriflavine and proflavine 1.10 dyestuffs were used for the treatment of sepsis in wounds. The work of Meyer and Overton (1899-1901) to relate a physical property (the oil: water distribution co-efficient) to biological activity (anaesthesia) were the first rudimentary QSAR. Another quantitative measurement that was made was the chemotherapeutic index, which was the ratio of the minimum curative dose to the maximum tolerated dose (CD50/LD50).
The action of acetylcholine on nerve tissue had been recognized in the late nineteenth century. Barger and Dale (1910) examined the response of various tissues to acetylcholine agonists and showed that there were different receptor sub-types; some responding to muscarine and others to nicotine.
The 1920s and 1930s saw the recognition of vitamin deficiency diseases and the elucidation of the structure of various vitamins. It was also a period in which there was exposure of many Europeans to tropical diseases. The iodinated quinolines such as entero-vioform 1.11 were introduced to combat amoebic dysentary and complex dyestuff derivatives such as suramin and germanin were developed in the 1920s to treat sleeping sickness. Synthetic anti-malarials such as pamaquine (1926), mepacrine (1932) and later chloroquine 1.12 (1943) and paludrine 1.13 (1946) were introduced as quinine replacements.
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In 1935 Domagk observed the anti-bacterial action of the sulfonamide dyestuff, prontosil red 1.14, from which the important family of sulfonamide 1.15 anti-bacterial agents were developed. The activity of these compounds as inhibitors of folic acid biosynthesis was rationalized by Woods (1940) as anti-metabolites of p-aminobenzoic acid. With the onset of the Second World War, there was a need for new antibiotics. In 1929 Fleming had observed that a strain of Penicillium notatum inhibited the growth of a Staphylococcus. In 1940-1941 Chain, Florey and Heaton isolated benzylpenicillin 1.16. After considerable chemical work, the b-lactam structure for the penicillins was established. The relatively easy bio-assays for anti-bacterial and anti-fungal activity led to the isolation of a number of antibiotics including streptomycin (1944), chloramphenicol (1949) and the tetracyclines such as aureomycin 1.17 (1949).
Several different aspects of medicinal chemistry developed in parallel through the second half of the twentieth century. Although they did not develop independantly, it is easier to follow their progression by considering them separately.
The structures of the steroid hormones were established in the 1930s and 1940s. The discovery in 1949 of the beneficial effect of cortisone 1.18 in alleviating the inflammation associated with rheumatism provided the stimulus for synthetic activity in this area. A number of anti-inflammatory semi-synthetic corticosteroids such as prednisolone, betamethasone 1.19 and triamcinolone became available in the late 1950s and 1960s.
Animal experiments to develop steroidal oral contraceptives were carried out before the Second World War but the first preparations (e.g. Enovid®) containing a synthetic estrogen, for example ethynylestradiol 1.20 and progestogen were not available until 1959. Subsequent preparations have been developed to reduce the estrogen level. Mifepristone 1.21, which is an anti-progestogen and forms the basis of the 'morning-after pill', was introduced in 1985. Whereas many of the medicines that had been developed prior to this time were administered for only short periods of time, this was not true of the steroids and concerns developed over the effects of long-term therapy.
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Problems associated with separating the anti-inflammatory activity from the mineralcorticoid activity of the cortical steroids led to interest in the development of non-steroidal anti-inflammatory agents (NSAIDs). The long-term use of aspirin as a pain-killer for arthritic conditions brought side-effects such as stomach ulcers. Indomethacin and ibuprofen (nurofen®) 1.22 were introduced in 1965 and 1971 respectively as alternatives.
During the 1960s the prostaglandin hormones were implicated in inflammation and in the protection of the stomach against ulcers. In 1971 aspirin was shown to inhibit the biosynthesis of the prostaglandins from arachidonic acid by the enzyme system, cyclo-oxygenase. The subsequent realization that there were several forms of cyclo-oxygenase provided the framework for developing selective non-steroidal anti-inflammatory agents that only targeted some of the multiple activities of the prostaglandins. One result was the introduction in 1999 of celecoxib (Celebrex®) 1.23 and rofecoxib (Vioxx®) as selective cyclo-
oxygenase (COX-2) inhibitors. Recently cardiovascular side effects of these compounds have begun to emerge and Vioxx® has been withdrawn.
A number of developments took place in the 1960s, which changed medicinal chemistry. It was found that a drug, thalidomide 1.24, which had been introduced as a sedative, when used by pregnant women, led to the birth of deformed children. The consequences of this teratogenic effect brought about a major tightening of the regulations regarding drug registration and the safety of medicines. Unfortunately there was some tardiness in the recognition of this side-effect. Second in 1964 Hansch published correlations between substituent effects (Hammett parameters) and the biological activity of some aromatic compounds. These QSAR began to provide a framework for the systematic development of drugs and for decisions to be made in the planning of a research programme.
The logical development during the 1960s of histamine antagonists for the treatment of peptic ulcers led to cimetidine 1.25 (1976) and then ranitidine (1981). The reasoning behind this work had a major impact on the development of medicinal chemistry.
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