New drugs against trypanosomatid parasites : rediscovery of fexinidazole

Kaiser, Marcel. New drugs against trypanosomatid parasites : rediscovery of fexinidazole. 2014, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_11111

Downloads: Statistics Overview


Neglected tropical diseases (NTDs) are a group of communicable diseases mostly affecting people in developing countries. These diseases are responsible for a major part of the global morbidity, mortality and poverty. There is no doubt that the well-being of people in the developing world can only be improved if the NTDs are controlled. An important tool for disease control is the drug treatment. The few available drugs are unsatisfactory because of the limited efficacy, adverse effects and the high price. Chagas disease, leishmaniasis and human African trypanosomiasis belong to this group of NTDs. They are caused by infections with protozoa of the family Trypanosomatidae. For these three diseases new drugs are urgently needed.
By definition there is no commercial market for drugs against NTDs. Drug research and development (R&D) for NTDs is mainly driven by the public sector, the so-called product development partnerships (PDPs). Drug R&D is a very long (10-15 years), risky and therefore expensive process. Three different series of compounds (agrochemicals, marketed drugs and nitro-heterocyclic compounds) were tested for their antiparasitic effects, with the aim to identify new lead compounds or even clinical candidates against leishmaniasis, sleeping sickness, and Chagas disease.
Agrochemicals are used worldwide on a large scale in food production. They undergo a rigorous toxicological testing prior to launch. Over 600 compounds were screened for their antiparasitic activity. Agrochemicals are not optimized for use in mammals, yet a significant number of molecules were found with good and selective in vitro activity. Some of them showed also efficacy in the corresponding rodent model. These results indicate that agrochemicals can provide very interesting starting structures for drug research against parasitic diseases.
Drugs or drug-like compounds are an ideal starting point for antiparasitic drug discovery, because very often pharmacokinetic and toxicological data are available. A number of drugs, including antibiotics, antivirals, antifungals, and anti-psychotics were assayed for antiparasitic activity. Some of the drugs tested showed selective antiparasitic activity. These compounds can be regarded as new lead structures and should be further investigated.
Nitroheterocycles belong to a well- known class of compounds with the stigma of being mutagenic or genotoxic. Over 700 compounds, mainly nitroimidazoles, have been systematically tested for their antiparasitic activity, and their pharmacokinetics and mutagenicity was investigated. A number of effective, non-mutagenic and non- genotoxic compounds was identified. So fexinidazole was rediscovered, a drug that had been in clinical development already in the 70’s as a broad-spectrum antimicrobial drug. Fexinidazole is rapidly metabolized to fexinidazole-sulfoxide and -sulfone. The parent compound and the two principle metabolites showed in vitro trypanocidal activity against all (sensitive and resistant) tested T. brucei strains (IC50 of 0.2 - 0.9 ug / ml). Fexinidazole cured the first stage mouse model with a 4-day oral treatment of 100 mg/kg/day and the 2nd stage mouse model with a 5-day oral treatment of 200 mg/kg/day. The two metabolites are mainly responsible for the good efficacy in animal models. Both reach very high concentrations in blood and brain tissue. Fexinidazole has successfully completed preclinical development and Phase I clinical trials and is currently in a clinical phase II / III study.
With the approach of phenotypic screening of compounds that have been developed for other purposes, new leads for drug R&D against Chagas’ disease, leishmaniasis and human African trypanosomiasis were identified.
Fexinidazole is the first drug candidate in clinical Phase II / III trials since decades. It would be the first oral drug for the treatment of stage 1 and 2 of human African sleeping sickness. If fexinidazole overcomes all obstacles, this would be a major breakthrough in the fight against African sleeping sickness. With a well tolerated, orally active drug like Fexinidazole the elimination of sleeping sickness seems finally tangible.
Advisors:Brun, Reto
Committee Members:Croft, Simon
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Kaiser, Marcel and Brun, Reto
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:11111
Thesis status:Complete
Number of Pages:283 p.
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:52
Deposited On:12 Feb 2015 13:15

Repository Staff Only: item control page