Mankind has ever been in need for food and for medicines; food to keep the physiological systems functioning and medicines to restore the situation when something went wrong with that system. For both food and medicines nature offered much and beyond any doubt men have found by trial and error - and likely many fatal accidents as well –the materials they needed; only much, much later in history, only in the current era, food became also important for avoiding diseases, whereas preventive medicines were later introduced as well.
For food the products applied came from plants and animal sources both, whereas for medicines especially plants were important, but animals also served as a source. For medicinal use also mineral products found an application. As knowledge of physiology, pathology, and chemistry was absent, there was not any rationale for using certain products for a particular affection.
Medicines could be found by accident only. When during history professions emerged, certain people specialized in providing medicines, medicine – men. As they just could not have any special knowledge, but an experience only, they were of course eager to protect their expertise for being used by others.
As a patient had no other way to find a cure than asking a medicine- man, those people became respected and influential.
Alchimistry has played a special role in the history of medicines. The alchimist had developed a special way to protect their position as healers of diseases. They used cryptograms as names for their medicines as well as anagrams (xidar was radix).
As examples of their secret language, “young –lady at the river “meant mercury and a name like tigerlegs was used for arum-lily. Clearly when strange products – for medical use – as lion feces are found in books of alchimist one can be sure that something completely different is meant.
The alchimist used material from plants, animals and mineral sources, obviously without any specific knowledge of disease and medicines both; they became a kind of witchdoctors making use of their strong position.
At a certain moment – in Europe during the middle ages – plants became selected for use in treating a given disease on basis specific features of the plant, such as shape or color. To mention a few examples: the walnut was due to its appearance useful for diseases of the brain and red cabbage for its color for blood related diseases. A very special example is the roots of the mandrake; it was said that this plant grew under the gallows from the semen of a hung criminal.
The roots of the mandrake have – more or less - the shape of a human being and that was subsequently used as the reason to use them as a virtually omnipotent medicine. It is remarkable that a would-be omnipotent medicines of our days, ginseng derived products, are often promoted by presenting the roots (the source of the preparations) in the shape of a small humanlike figure, just as the mandrake.
It should not surprise that many “medicines” were not effective at all. Some of the products from plants, however, had really useful properties. Well known examples are preparations from the foxglove (digitalis, decompensated heart), the Peruvian cinchona tree (quinine, malaria), the ephedra scrub (ephedrine, asthma), and the Salix tree (salicylderivatives, fever, pain).
Medicines from mineral origin seemed to be very effective; the effects they produced were easily observed and strong. These effects were, however, more of a toxic nature than being beneficial for the patient.
Due to the negative outcome of especially mineral derived medicines (metal salts and -oxides) Hahnemann proposed his remarkable homeopathic principle; as a personal point of view I might say that the only positive property of his homeopathic preparations was - and is - the absence of any side effects, at the cost of the absence of a therapeutic result as well, however.
During the ages not much changed in the situation: witchdoctors, no effective medicines, many fatal diseases. The matter changed much for the better when around 1850 for the first time organic compounds could be synthesized, the first artificial dye synthesis by Perkin.
When at roughly the same time pharmacology became an experimental approach with which effect of compounds in animals could be tested, ways to new medicines could be explored. Soon thereafter scientists as Crum Brown and Fraser realized that it was the chemical structure and nature of compounds which determine their effects on biological systems and therefore their potential usefulness as medicines.
After the historical paper by Crum Brown and Fraser ”On the Connection between Chemical Constitution and Physiological Action”, some scientists became euphoric. Soon they predicted, we can design(!) medicines for any disease. And the pharmacopeia can be written from the laboratory table directly.
But again things developed in a rather different way. In the 1930ies the famous pharmacologist Clark stated that we had studied the relationships between chemical structure of compounds and their biological effects to such a level that we obtained a fair understanding of the level of our ignorance.
Indeed, new medicines could be reached only via the empirical route, a matter of trial and error, of good luck and bad luck. Moreover, this trial and error method was applicable for both the wanted and the unwanted properties of the new compounds.
The cynics of Clark despite, many very useful new medicines resulted, effective and relatively safe as well. These new synthetic medicines have contributed much to health of men, to quality of life, have in several cases had even great influence on patterns in society.
Gradually making new medicines became a special art and a new chemical subdiscipline emerged, medicinal chemistry. The new field developed first in the United States, especially in research groups of the pharmaceutical industry; Europe followed and also academia, but both much later in time.
The term medicinal chemistry became accepted when the American Chemical Society changed the name of its Division of Pharmaceutical Chemistry (founded in 1909) via Division of Chemistry and Medicinal Products (1920), in 1948 into Division of Medicinal Chemistry. In the beginning the search for new medicines was considered to belong to the field of pharmaceutical chemistry, together with pharmaceutical analysis, including the analysis of the formulation of medicines.
For the new discipline- medicinal chemistry - organic chemistry, and more precisely organic synthesis remained the far most important contributor to this interdisciplinary new field of chemistry.
However, the study of the relationships between chemical structure (or better their properties) and biological activity, as well as the interpretation of mechanisms of action of bioactive compounds became more and more part of medicinal chemistry.
A proper definition, however, was not provided and the field was included in schools of chemistry in some cases, but mostly it was part of departments of pharmacy.
The new division of the American Chemical Society became a major succes. In 1966 the division started to publish its Annual Reports in Medicinal Chemistry, a series highlighting each year the most important developments in the field. The extremely useful books have never stopped to be published since. Another success of the division became the Journal of Medicinal Chemistry, which grew to become the leading journal for the discipline.
Europe was slow in picking up the developments. The strong position of organic chemistry at universities may have been the cause of the situation that scientist working on the synthesis of potentially new interesting compounds for use in medicines were considered to be poor organic chemists. But history goes its own ways, also for developments in science.
In 1962 the Società Italiana di Scienze Farmaceutiche organized in Milan what might be considered as the first medicinal chemistry symposium in Europe. The meeting was sponsored by the International Union of Pure and Applied Chemistry, IUPAC. In 1970 the IUPAC established a Section on Medicinal Chemistry, as a committee of its Division for Organic Chemistry. In 1968 a 2nd International Symposium “Pharmaceutical Chemistry” had been organized jointly by IUPAC’s Divisions of Organic and the one of Applied Chemistry in Mqnster, Germany. It was quite remarkable and not without meaning that the opening lecture of this meeting was on the subject “The open field of pharmacology”; it was a sign that medicinal chemistry became more and more dependent on the pharmacology,
To be continued; next time: "The founding of the European Federation for Medicinal Chemistry"
By Henk Timmerman
