There are a number of candidates for humanity’s greatest advances. The control of fire 400,000 years ago may be at the top of the list, because fire provided warmth, cooked food, and the ability to smelt metals from ores.
Agriculture dating back to about 9500 BCE is certainly in the running, because without adequate food, population growth and permanent settlements would not have been possible. Without the invention of writing (3200 BCE), acquired knowledge could not have been properly disseminated. Sanitation was unquestionably a huge advance. Sewer systems, provision of clean water, removal of garbage, and regulation of slaughterhouses in the 1800s kept pathogens away from people, and vaccination saved millions from dying of measles, reduced polio by over 99 percent, and eradicated smallpox.
The steam engine undoubtedly reshaped life, and then electricity totally transformed it with electric motors, the telegraph, the telephone, television, and computers. In the 21st century, the internet and artificial intelligence opened the gates to a whole new world.
However, when considering great advances, the development of effective medicines, first through trial and error and later through chemistry, has to rank high on the list. The introduction of painkillers, antibiotics, insulin therapy, blood pressure medications, statins to control cholesterol, antivirals, immunosuppressants, chemotherapeutic drugs, and psychiatric medications has alleviated misery.
Famed Canadian physician William Osler once famously remarked, “The desire to take medicine is perhaps the greatest feature that distinguishes man from animals.”
A witty line to be sure, but not literally correct given that some chimps are known to seek out plants with biologically active substances. Still, there is evidence that as early as 3400 BCE, the Sumerians of Mesopotamia were cultivating the opium poppy and were using it as medicine. The poppy produces morphine, which would eventually become the first pure drug to be isolated, but that would not occur until 1804, when German pharmacist Friedrich Serturner managed to isolate it from opium, the resin secreted by the poppy.
Other botanicals such as willow bark, henbane or cannabis for pain, mandrake root as a sedative, ephedra for breathing problems, and garlic for all sorts of ailments trace back to antiquity.
Raising the question of the identity of the first drug that was not isolated from a plant but synthesized in the lab starts a journey down an interesting path.
An argument can be made for the sedative chloral hydrate, synthesized by German chemist Justus von Liebig in 1832. He was not attempting to make a medicine but was just experimenting with the novel field of organic chemistry. Four years earlier, Friedrich Wöhler had serendipitously made urea in the lab from ammonium cyanate, an inorganic substance. Urea is found in urine and had been considered to be an “organic” substance that could only be produced by a living system equipped with the “vital force” needed to make it.
Wohler’s discovery jettisoned the concept that organic compounds could only be made by living systems and opened the gates for manipulating such compounds in the lab. Liebig took up that challenge and began to experiment with alcohol, heretofore labeled an organic compound because it was made by living yeast cells. When he reacted it with chlorine, he produced a novel compound he called “chloral” because it had been made from alcohol and chlorine. Aside from recording the synthesis and noting that when combined with water it produced crystalline chloral hydrate, Liebig did nothing further with the compound. Only 37 years later did Berlin pharmacologist Oscar Liebreich discover that chloral hydrate was capable of inducing sleep.
That discovery has an interesting backstory because it was based on faulty reasoning. Chloroform, first synthesized by Liebig in 1831, had in 1847 been found by Scottish obstetrician James Simpson to have sleep-inducing properties by testing its vapors on his friends and himself. Liebreich knew that blood is slightly alkaline and that in an alkaline solution chloral hydrate breaks down to yield chloroform. He hypothesized that chloral hydrate could therefore induce sleep, which it did, but not because it turns into chloroform. It is metabolized to trichloroethanol, which is the active hypnotic.
Liebreich got it right, but for the wrong reason.
In 1869, chloral hydrate was introduced as a medicine to treat insomnia and anxiety, becoming the first example of a synthetic drug introduced into medicine. The asterisk here is that chloral hydrate was not originally synthesized as a medicine. The first synthetic compound that was specifically developed as a pharmaceutical was “antipyrine,” introduced in 1883 to treat fever and pain.
By this time, much had been learned about transforming organic compounds, and Ludwig Knorr was experimenting with reactions with the intention of making quinine, an important antimalarial drug. He produced a number of compounds that were tested pharmacologically, one of which, antipyrine, turned out to have fever- and pain-reducing properties. Although it had turned up during medicinally motivated research, it was not designed to reduce pain or fever. That was just a chance finding.
The first drug that was deliberately designed to treat a specific disease was Salvarsan, synthesized by German physician-scientist Paul Ehrlich in 1909 to treat syphilis [1]. There is an asterisk here, too.
In 1856, William Henry Perkin made the accidental, landmark discovery of synthesizing the dye mauve from chemicals in coal tar while trying to make quinine. This opened the way to producing other dyes from coal tar, one of which was methylene blue, synthesized by Heinrich Caro in 1876. Ehrlich found that this dye had the ability to stain certain microbes specifically, making them more visible under the microscope.
Not only did methylene blue stain the parasite that causes malaria; it killed it. Methylene blue became a synthetic antimalarial drug, although its antimalarial effect had been discovered accidentally. Still, methylene blue can make the claim of being the first synthetic drug [2]. More importantly, the success with methylene blue gave Ehrlich the idea of incorporating a toxic element, such as arsenic, into a dye to design a “magic bullet” that would target specific microbes. After many attempts, he came up with Salvarsan, a drug that killed the syphilis-causing bacteria, making this the first drug to be deliberately synthesized to target a disease.
As for chloral hydrate, its luster as a sleep-inducer faded when it was learned that the difference between a sedative dose and a dangerous dose was small. Furthermore, stories began to spread about a Chicago bartender, Mickey Finn, slipping it into drinks as a “knockout” drug so he could rob his customers.
Chloral hydrate’s importance as a hypnotic declined further with the introduction of barbiturates in 1903, but it remains a strong candidate as the first synthetic drug introduced, although methylene blue and antipyrine are hard on its heels.
NOTE:
[1] Salvarsan (compound 606) was synthesized in 1907; its effectiveness against syphilis was demonstrated by Sahachiro Hata in Paul Ehrlich’s laboratory in 1909.
[2] The identity of the “first synthetic drug” depends on how the term is defined. Chloral hydrate, antipyrine, and methylene blue have all been given that distinction under different criteria.
# Reprinted with permission. Dr. Schwarcz’s original article can be found on the OSS website
Joe Schwarcz
Dr. Joe Schwarcz is Director of McGill University's “Office for Science and Society” which has the mission of separating sense from nonsense. He is well known for his informative and entertaining public lectures on topics ranging from the chemistry of food to the connection between the body and the mind.
