From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy
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- Krafts, K., Hempelmann, E. & Skórska-Stania, A. Parasitol Res (2012) 111: 1. doi:10.1007/s00436-012-2886-x
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Malarial treatment is widely and readily available today. However, there was a time in the not-so-distant past when malaria was a deadly disease with no known cause or cure. In this article, we trace the origins of an antimalarial therapy from the discovery of the nature of the malarial parasite through the development of chloroquine. We dedicate this article to Johann “Hans” Andersag, the scientist who developed chloroquine, on the 110th anniversary of his birth, 16 February 1902.
Elucidation of the cause of malaria
In 1887, the Polish pathologist Czesław Chęciński applied a combination of methylene blue and eosin to blood smears and discovered the daisy-like and sickle-shaped parasites we now know as Plasmodium malariae and Plasmodium falciparum. Until this time, there were many hypotheses regarding the causative agent of this disease, from poisonous air (a theory mentioned as early as 1476 by Leonardo Bruni (Bruni 1476)) to bacteria (Klebs and Tommasi-Crudeli 1879). Three years after Chęciński’s stain was published, the German physician Ernst Malachowski discovered a method of polychroming methylene blue that, when used in combination with eosin, revealed not only a range of colors within leukocytes, but also the elusive purple-red nucleus of the malarial parasite (Krafts et al. 2011). The discovery of the malarial nucleus provided definitive proof that the malarial organism was a eukaryote. A search for an effective antiparasitic malarial treatment could now begin in earnest.
Paul Ehrlich (1854–1915)
Hans Andersag (1902–1955)
In July, 1934, Andersag modified atabrine by replacing its acridine ring with a quinoline ring. The resulting compound, which would later be termed chloroquine (Fig. 3c), was found to have high antimalarial activity, and unlike methylene blue or atabrine, did not discolor skin and eyes.
Condensation of m-chloroaniline with oxaloacetic acid diethylester
Saponification and thermal decarboxylation
Reaction with phosphorus oxychloride (POCl3)
Substitution by a diamino group
Andersag made a salt of the base using 2,4,-dihydroxybenzoic acid. This salt received the name resochin, being the RESOrcinate of a 4-aminoCHINolin.
Resochin was tested in 1935 by Bayer against blood-induced vivax malaria in four paretics at a psychiatric clinic in Düsseldorf but was found to be “too toxic for practical use in humans” (Coatney 1963). Subsequently, Bayer shelved the drug for more than 10 years, a decision that would come to be known as “the resochin error.”
Meanwhile, Andersag continued to modify the drug to minimize the toxic effect, producing the compound 3-methylresochin (Dünschede 1971). This compound was named “sontochin” and was tested at the Institute for Tropical Diseases in Hamburg. By the end of 1939, over 1,100 patients with malaria had been treated with sontochin.
Both drugs, resochin and sontochin, were patented in November 1939 (Reichspatentamt, Patentschrift Nr 683692) and later issued to The Winthrop Chemical Company through their IG Farben cartel arrangement with Bayer (US Patent 2 233 970). Clinical trials with sontochin were also conducted jointly by French and German scientists in Tunisia in 1941–1943, with very impressive results. In May, 1943, drug supplies and accompanying data were handed over by the French authorities to the Allied Forces. During the following years, resochin was rediscovered; it was given the name “chloroquine” by EK Marshall in November 1945 (Coatney 1963).
Chloroquine was a first-line antimalarial therapy for many years. As is the case for most antimicrobial drugs, resistant strains of the target organism eventually developed. However, since the mechanism of the drug (inhibition of hemozoin biocrystallization) involves a host-derived drug target (which cannot be modified by the malarial parasite), it took over 20 years for resistant forms of malaria to develop (Hempelmann 2007). For those 20 years, Andersag’s drug saved countless lives and it continues to be an effective antimalarial treatment nearly 80 years later.