Being 'First' in Drug Discovery: Tracing the Origins of Synthetic Medicines
核心洞察
Chloral hydrate, synthesized by Justus von Liebig in 1832, became the first synthetic drug introduced into medicine in 1869 to treat insomnia and anxiety.
The first synthetic compound specifically developed as a pharmaceutical was antipyrine, introduced in 1883 to treat fever and pain.
Salvarsan (搜索), synthesized by Paul Ehrlich in 1909, was the first drug deliberately designed to target a specific disease, syphilis (搜索).
The development of effective medicines ranks among humanity's greatest advances, alongside the control of fire, agriculture, and sanitation. As famed Canadian physician William Osler remarked, "The desire to take medicine is perhaps the greatest feature that distinguishes man from animals." Yet the question of which drug deserves the title of "first" synthetic medicine reveals a surprisingly nebulous history, one shaped as much by accident and faulty reasoning as by deliberate design.
The story begins with a foundational breakthrough in chemistry. In 1828, Friedrich Wohler serendipitously synthesized urea in the laboratory from ammonium cyanate, an inorganic substance. Urea, found in urine, had been considered 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.
The First Synthetic Drug: Chloral Hydrate
German chemist Justus von Liebig took up that challenge, experimenting with alcohol—heretofore labeled an organic compound because it was made by living yeast cells. When he reacted alcohol with chlorine, he produced a novel compound he called "chloral." 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, in 1869, did Berlin pharmacologist Oscar Liebreich discover that chloral hydrate was capable of inducing sleep, leading to its introduction as a medicine to treat insomnia and anxiety. This made chloral hydrate the first example of a synthetic drug introduced into medicine.
That discovery carries a notable asterisk, however, 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. 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 actually metabolized to trichloroethanol, the active hypnotic. As the source notes, "Liebrich got it right, but for the wrong reason."
Antipyrine: The First Purpose-Developed Pharmaceutical
The first synthetic compound 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 emerged during medicinally motivated research, it was not designed to reduce pain or fever; that was a chance finding.
Salvarsan: The First Rationally Designed Drug
The first drug deliberately designed to treat a specific disease was Salvarsan (搜索), synthesized by German physician-scientist Paul Ehrlich in 1909 to treat syphilis (搜索). This achievement also carries an asterisk, rooted in an earlier accidental discovery. In 1856, William Henry Perkin made the 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 methylene blue could stain certain microbes specifically, making them more visible under the microscope. Not only did methylene blue stain the parasite that causes malaria (搜索), it killed it—becoming a synthetic antimalarial drug, though its antimalarial effect had been discovered accidentally. 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 produced Salvarsan (搜索), a drug that killed the syphilis (搜索)-causing bacteria, making it the first drug to be deliberately synthesized to target a disease.
The Fading Legacy of Chloral Hydrate
Chloral hydrate's lustre as a sleep-inducer faded when it was learned that the difference between a sedative dose and a dangerous dose was small. Furthermore, stories spread about a Chicago bartender, Mickey Finn, slipping it into drinks as a "knockout" drug so he could rob his customers. Its 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.
The broader arc of this history underscores a central theme: the introduction of pain killers, antibiotics, insulin therapy, blood pressure medications, statins to control cholesterol, antivirals, immunosuppressants, chemotherapeutic drugs, and psychiatric medications has alleviated misery. And while the title of "first" in drug discovery may be a nebulous honour, the journey from serendipitous synthesis to rational, disease-targeted design marks one of medicine's most consequential trajectories.