The development of drugs for treatment of sleeping sickness: a historical review
© Steverding; licensee BioMed Central Ltd. 2010
Received: 18 January 2010
Accepted: 10 March 2010
Published: 10 March 2010
Only four drugs are available for the chemotherapy of human African trypanosomiasis or sleeping sickness; Suramin, pentamidine, melarsoprol and eflornithine. The history of the development of these drugs is well known and documented. suramin, pentamidine and melarsoprol were developed in the first half of the last century by the then recently established methods of medicinal chemistry. Eflornithine, originally developed in the 1970s as an anti-cancer drug, became a treatment of sleeping sickness largely by accident. This review summarises the developmental processes which led to these chemotherapies from the discovery of the first bioactive lead compounds to the identification of the final drugs.
Human African trypanosomiasis or sleeping sickness is a disease caused by two subspecies of Trypanosoma brucei, T. b. rhodesiense and T. b. gambiense. The parasites live and multiply extracellularly in blood and tissue fluids of their human host and are transmitted by the bite of infected tsetse flies (Glossina spp.). The occurrence of sleeping sickness is restricted to the distribution of tsetse flies which are exclusively found in sub-Saharan Africa between 14°N and 20°S . More than 250 discrete active sleeping sickness foci in 36 African countries are recognised most of which are in rural areas .
Trypanosoma b. rhodesiense is found in East and southern Africa whereas T. b. gambiense occurs in West and Central Africa. The course of sleeping sickness is different depending on the subspecies. Infections with T. b. rhodesiense lead to an acute form of the disease while infections with T. b. gambiense give rise to a chronic infection. The symptoms of the first stage of the disease, defined by the restriction of trypanosomes to the blood and lymph system, include fever, headache, joint pain and itching [3, 4]. The clinical signs of the second stage of the disease, characterised by the invasion of trypanosomes into the central nervous system, are neurological and endocrinal disorders [3, 4]. If left untreated, sleeping sickness patients infected with T. b. rhodesiense will die within months whereas those infected with T. b. gambiense usually survive for several years.
In the late 19th Century, Africa experienced several sleeping sickness epidemics the most devastating of which was an epidemic with 300,000 to 500,000 deaths between 1896 and 1906 which mainly affected the Congo Basin and the Busoga focus in Uganda and Kenya . The disastrous effect of this epidemic persuaded the various colonial administrations to call for their medical scientists to develop a cure for sleeping sickness. At that time, the field of chemotherapy was developing and had begun to make use of the novel methods of medicinal chemistry, i.e. the identification, synthesis and development of new chemical entities suitable for therapeutic use. In fact, it was for the development of early anti-sleeping sickness drugs that medicinal chemistry was first used [6, 7].
From 1906, the German Bayer pharmaceutical company supplied the French bacteriologist Maurice Nicolle and the French zoologist Felix Mesnil from the Pasteur Institute with benzopurpurine dyes to be tested for trypanocidal activities . One blue benzopurpurine derivative, Trypan Blue (Fig. 1), was found to be very effective in eliminating all trypanosomes from the blood of infected animals [13, 14] but as the drug stained the skin of the animals bluish it was unacceptable for use in patients [9, 10]. For this reason Wilhelm Roehl a former assistant of Ehrlich who had joined the Bayer research group at Elberfeld in 1905, sought a colourless compounds with trypanocidal activities. The chemists Oskar Dressel and Richard Kothe of Roehl's team synthesised derivatives of Afridol Violet (Fig. 1), a naphthalene urea compound that was less colour-intensive but also less trypanocidal in screens carried out by Nicolle and Mesnil. Several derivatives, however, displayed better activity against trypanosomes than the parent compound. In 1917, after the synthesis and screening of more than 1000 naphthalene ureas, the breakthrough came in the form of Bayer 205 (Fig. 1), later named Germanin, a colourless compound that cured trypanosomiasis in both experimental animals and in humans . The Bayer Company understood the political importance of Bayer 205 for the commercial exploitation of African colonies and offered the formula of the drug to the British Government in exchange for the return of Germany's lost African territories . When the British declined the offer, the Bayer Company refused to disclose the chemical structure of the drug. Eventually, in 1924, the French pharmacist Ernest Fourneau published the structure of Bayer 205 . Four years later, the Bayer Company confirmed that Fourneau's structure was identical with that of Germanin. The drug was later renamed suramin and is still in use in the therapy of early-stage T. b. rhodesiense sleeping sickness.
Ehrlich obtained another arsenobenzene, arsenophenol, by inserting a hydroxyl group in para position of the benzene ring of Atoxyl followed by reduction. This compound was highly effective against trypanosomes but prone to oxidation and difficult to purify. Based on his experience with chemotherapeutic dyes, Ehrlich knew that the addition of a substituent in ortho position to the hydroxyl group would enhance the chemotherapeutic activity. The introduction of an amino group led to the compound 606 or arsphenamine, which was synthesised by Bertheim in 1907 but which turned out to be ineffective against trypanosomes [6, 9]. Interestingly, however, in 1909 Ehrlich and his colleague Sahachiro Hata, a Japanese bacteriologist, discovered that arsphenamine had excellent curative properties against syphilis. It became the first truly effective drug for treatment of the disease and was marketed by Farbwerke Hoechst under the proprietary name Salvarsan, 'the arsenic that saves' .
In 1919, the American chemist Walter Jacobs and the American immunologist Michael Heidelberger reported the synthesis of tryparsamide (Fig. 2), a derivative of Atoxyl . As this compound was able to enter the central nervous system it was the first drug for treating the second stage of sleeping sickness alone or in combination with suramin. Although tryparsamide also caused damage to the optical nerve, it remained the drug of choice for chemotherapy of sleeping sickness until the early 1960s  and was also used in the treatment of animal trypanosomiasis .
In 1977, Das and Boykin reported on the trypanocidal activity of a series of novel aromatic diamidines, with DB75 (2,5-bis(4-aminophenyl)-furan; Fig. 4) as the most trypanocidal compound active against T. b. rhodesiense in mice and rhesus monkeys [39, 40]. As DB75 is poorly absorbed across the gastrointestinal tract due to its positively charged amidine group, a prodrug, DB289 (2,5-bis(4-amidinophenyl)-furan-bis-O-methylamidoxime; Fig. 4), was synthesised . DB289 was the first oral drug for treatment of first-stage sleeping sickness to enter clinical trials . However, an extended phase I study to complete the safety assessment for registration of DB289 for sleeping sickness revealed severe liver toxicity and delayed renal insufficiency . As a consequence, the program to develop DB289 as an oral drug for treatment of sleeping sickness was discontinued .
In 1980, the American biologist Cyrus Bacchi heard about DFMO and tested the drug in a murine trypanosomiasis model and showed that DFMO cured mice infected with a virulent strain of T. b. brucei without any apparent toxic side effects . Based on this remarkable result, several clinical trials were carried out demonstrating that DFMO can cure second-stage T. b. gambiense sleeping sickness patients who were refractory to melarsoprol treatment [52–55]. The reason why DFMO is only active against T. b. gambiense is that the ornithine decarboxylase of this trypanosome species is very stable (t1/2 = 18-19 h) . In contrast, the DFMO tolerance of T. b. rhodesiense is due to a faster turnover rate of the enzyme (t1/2 = 4.3 h) . In 1990, DFMO was approved for the treatment of human trypanosomiasis caused by T. b. gambiense  and is currently the only treatment available for melarsoprol-refractory sleeping sickness.
In recent years, eflornithine has been tested in combination with nifurtimox in the treatment of second-stage T. b. gambiense sleeping sickness [58–60]. A recently completed multicentre, randomised, phase III trial revealed that the efficacy of nifurtimox-eflornithine combination therapy is no worse than that of eflornithine monotherapy . However, this combination therapy represents a major advance in terms of making the treatment safer, cheaper and easier to administer .
The development of the anti-sleeping sickness drugs is an early example of the employment of medicinal chemistry, the stepwise application of structure-activity relationships in order to increase the trypanocidal activity of a lead compound and to simultaneously reduce toxic side effects by modifying its chemical structure. Rational drug design, the inventive process of finding new drugs based on the knowledge of a biological target, has so far produced only one drug for treatment of sleeping sickness, eflornithine, although this drug was initially developed as an anti-cancer agent. Thus, it seems that the traditional methods of medical chemistry may be more effective in the development of new chemotherapies for this important disease.
I thank Professor Frank Cox and Dr Kevin Tyler for critical reading of the manuscript.
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